掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1038/s41698-024-00515-y

PubMed

DOI： 10.21873/invivo.13796

PubMed

掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.esmoop.2024.103726

PubMed

DOI： 10.7759/cureus.71661

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1007/s00428-024-03840-6

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1016/j.labinv.2024.102093

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1002/cncy.22888

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1097/PAS.0000000000002243

PubMed

DOI： 10.1007/s13691-024-00682-6

PubMed

DOI： 10.1016/j.prp.2024.155348

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.

DOI： 10.1007/s00256-024-04647-x

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1016/j.humpath.2024.02.007

PubMed

DOI： 10.11477/mf.1403203479

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

BACKGROUND: There is limited published information regarding the expression of mechanistic target of rapamycin (mTOR) in vessels that encapsulate tumor cluster (VETC)-positive hepatocellular carcinoma (HCC). The mTOR inhibitor, everolimus, has been approved as an immunosuppressant for use in HCC patients after living donor liver transplantation (LDLT). METHODS: Using a database of 214 patients who underwent LDLT for HCC, we examined the mTOR protein and angiopoietin-2 (Ang-2) in VETC-positive HCC by immunohistochemical staining. The presence of VETC and mTOR expression were evaluated in both primary and recurrent HCC lesions. RESULTS: Forty-three of the 214 patients (20.1%) were VETC-positive, and 29 of these 43 patients (67.4%) expressed mTOR. Relative Ang-2 expression was significantly higher in the mTOR-positive than in the mTOR-negative group (p = 0.037). Thirty-four of the 214 patients experienced HCC recurrence after LDLT; 20 of these were operable. The primary lesions of six of these 20 patients were VETC-positive; five of these six patients also had VETC-positive recurrent lesions (p < 0.001). The expression of mTOR was significantly higher in the VETC-positive lesions (p = 0.0018). CONCLUSIONS: We showed that mTOR expression was higher in the VETC-positive primary and recurrent lesions than in the VETC-negative ones.

DOI： 10.1002/ags3.12735

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1007/s00256-024-04604-8

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1007/s00428-024-03796-7

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

DOI： 10.1007/s10120-024-01474-w

PubMed

DOI： 10.1177/10668969241226695

PubMed

DOI： 10.1684/ejd.2023.4583

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear. METHODS: The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro. RESULTS: For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines. CONCLUSION: TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

DOI： 10.1245/s10434-023-14053-7

PubMed

DOI： 10.24479/ps.0000000547

国際・国内誌：国際誌  

Synovial sarcoma (SS) is a malignant soft tissue tumor that usually arises in the para-articular regions of the extremities. Only nine cases of SS in the mandible have been reported to date. The present study described a case of SS arising from the left mandible. A 54-year-old woman was referred to Kyushu University Hospital (Fukuoka, Japan) with a complaint of numbness in the left mental nerve area. Computed tomography revealed replacement of the left mandibular bone marrow with soft tissue and destruction of the mandibular canal. Magnetic resonance imaging revealed an isointense mass on T1-weighted images and hyperintensity on T2-weighted images. The tumor showed homogeneous enhancement. A biopsy was performed, and monophasic SS was diagnosed based on immunohistochemical staining features and genetic analysis. Hemimandible dissection and supraomophyoid neck resection were performed with fibular osteocutaneous flap reconstruction, followed by adjuvant chemotherapy. There was no evidence of recurrence or distant metastases. The present study also reviewed the clinical, imaging, histological, and immunohistochemical features of the SS in the mandible.

DOI： 10.3892/ol.2023.13904

PubMed

症例は70議,男性。多発性骨髄腫に対してDkD療法(ダラツムマブ,カルフィルゾミブ,デキサメタゾン)を施行中であった。202X年2月より尿定性検査で尿潜血を認めるようになったため当科に紹介となった。膀胱鏡で左尿管口外側に15mm大の結節型腫瘍を認め,尿細胞診はClass Vだった。CTでは膀胱左後壁に15mm大の造影効果を伴う結節と,腰椎L4の高さで左尿管に腫瘍を疑われた。202X年3月に経尿道的膀胱腫瘍切除術(TURBT)と左尿管鏡下生検を施行した。病理診断は形質細胞が認められ,Plasma cell myelomaの診断であった。現在,多発性骨髄腫の再発に対して化学療法を継続している。多発性骨髄腫の膀胱転移・尿管転移は極めて稀であり,若干の文献的考察を加えて報告する。(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Liposarcoma is a malignant soft tissue tumour with adipocytic differentiation. Dedifferentiated liposarcoma (DDLS) and myxoid liposarcoma (MLS) are classified as high-grade liposarcomas. Lipid droplet-associated protein (also known as perilipin 1 (PLIN1)) is the predominant perilipin and has utility as a specific marker of adipogenic differentiation. Adipose differentiation-related protein (also known as adipophilin (ADRP)) is ubiquitously expressed in a range of tissues. High ADRP expression is reportedly a poor prognostic factor in several cancer types. However, no previous studies have examined the association between PLIN1 or ADRP expression and prognosis in sarcoma. This study therefore aimed to evaluate the association between PLIN1 or ADRP expression and prognosis in liposarcoma. METHODS: In total, 97 primary resection specimens (53 MLS and 44 DDLS) were examined in this study. PLIN1 and ADRP expression was evaluated by immunohistochemistry. Survival analyses were performed for MLS and DDLS. RESULTS: Of the 53 MLS specimens, 15 (28.3%) exhibited high PLIN1 expression. PLIN1 expression was not observed in DDLS specimens. High PLIN1 expression was significantly associated with increased disease-free survival (DFS) among patients with MLS (p=0.045). Distinct ADRP expression was observed in 13 of 53 (24.5%) MLS specimens and 5 of 44 (11.4%) DDLS specimens. High ADRP expression was associated with shorter overall survival (OS) in MLS (p=0.042) and DFS and shorter OS in DDLS (p=0.024 and p<0.001, respectively). CONCLUSIONS: PLIN1 and ADRP expression is associated with poor prognosis in high-grade liposarcoma.

DOI： 10.1136/jcp-2023-208814

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

BACKGROUND: The hemoglobin-albumin-lymphocyte-platelet (HALP) score is a combination index that assesses nutritional status and systemic inflammatory response and is reported to predict prognosis in several cancer types. However, researches about the usefulness of the HALP score in intrahepatic cholangiocarcinoma (ICC) are limited. METHODS: This was a single-center, retrospective study of 95 patients who underwent surgical resection for ICC between 1998 and 2018. We divided patients into two groups by calculating the cutoff value of the HALP score and examined clinicopathological characteristics, prognosis, and sarcopenia. Tumor-infiltrating lymphocytes (TILs), CD8 + TILs, and FOXP3 + TILs were evaluated by immunohistochemical staining of resected tumors. RESULTS: Of 95 patients, 22 were HALP-low. The HALP-low group had significantly lower hemoglobin (p = 0.0007), lower albumin (p = 0.0013), higher platelet counts (p < 0.0001), fewer lymphocytes (p < 0.0001), higher CA19-9 levels (p = 0.0431), and more lymph node metastasis (p = 0.0013). Multivariate analysis revealed that the independent prognostic factors for disease-free survival were maximum tumor size (≥ 5.0 cm) (p = 0.0033), microvascular invasion (p = 0.0108), and HALP score (≤ 25.2) (p = 0.0349), and that factors for overall survival were lymph node metastasis (p = 0.0020) and HALP score (≤ 25.2) (p = 0.0014). The HALP-low group contained significantly more patients with sarcopenia (p = 0.0015). Immunohistochemistry showed that counts of CD8 + TILs were significantly lower in the HALP-low group (p = 0.0075). CONCLUSIONS: We demonstrated that low HALP score is an independent prognostic factor for ICC patients undergoing curative hepatic resection and is associated with sarcopenia and the immune microenvironment.

DOI： 10.1007/s10147-023-02358-2

PubMed

融合遺伝子の検出により裏付けられた粘液型脂肪肉腫(MLS)症例の核形態、細胞密度、遺伝的背景を調査し、MLSの予後予測においてより信頼性の高い評価法を検討した。MLS患者64例(年齢中央値48歳)について、核異型を評価するために確立された2つの等級付けシステム(腎細胞癌における世界保健機構/国際泌尿器科病理学会[WHO/ISUP]等級付けおよびフールマン等級付け)を修正し適用した。さらに、形態と細胞密度の詳細なソフトウェアによる評価を行い、DNA変異解析、包括的mRNA発現解析、免疫組織化学検査も行った。その結果、修正フールマン等級付けシステムによる高い核グレード群では、無病生存率が有意に不良であった。修正フールマン高悪性度群では細胞密度が有意に高かったが、それ自体は生存率解析における予後不良因子にはならなかった。修正フールマン高悪性度群では、細胞周期関連遺伝子(FOXM1、PLK1、CDK1など)が有意に発現していた。以上より、MLSの予後予測では、核形態に焦点を当てた評価がより信頼できることが示唆された。

根治的肝切除が施行された肝内胆管細胞癌患者92例を対象とした後ろ向き研究を実施し、FGFR2発現の臨床的意義および予後を評価した。評価項目は臨床病理学的特徴、転帰などとした。患者をFGFR2陽性群18例(男性16例、年齢中央値65歳)、陰性群74例(男性46例、年齢中央値66歳)に分けて検討した。その結果、FGFR2陽性群では男性が多く、血清アルブミン低値であり、癌胎児性抗原が高値であった(p<0.0001、p=0.0355、p=0.0099)。多変量解析の結果、FGFR2陽性群は無病生存率が不良であることが明らかになった(p=0.0002)。最大腫瘍径(≧5cm)、腫瘍局在(傍肝門型)、FGFR2陽性が無病生存の独立した予測因子であった(p=0.0011、p=0.0180、p=0.0029)。両群間で腫瘍浸潤リンパ球に有意差は認められなかった。以上から、FGFR2高発現は肝切除施行原発性胆管癌患者の再発の独立した予測因子であることが示された。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

CASE: In a 54-year-old man, imaging findings suggested a malignant bone tumor having 2 distinct components of the left ilium. Histopathologically, the resected tumor was diagnosed as dedifferentiated chondrosarcoma (CS) arising in secondary peripheral CS. CONCLUSION: Dedifferentiated CS consists of a high-grade noncartilaginous sarcoma adjacent to a preexisting low-grade CS, among which the peripheral type is extremely rare. Because the bimorphic imaging findings reflected the dedifferentiated area and the CS area, they were considered useful for diagnosis. In addition, the dedifferentiated area was localized to the tumor's edge, suggesting that the dedifferentiation originated from the cartilage cap.

PubMed

当初肺転移を伴う切除不能進行肝細胞癌であった77歳男性に対する治癒的肝切除例を報告した。この稀なコンバージョン肝切除術は、アテゾリズマブとベバシズマブの併用療法(atezo/bev)によるものであった。atezo/bev中に有害事象として免疫関連肝炎と腫瘍内出血が認められたが、7サイクルの治療後、腫瘍マーカーは正常化し、腫瘍は著明に縮小し、転移は消失した。その後、コンバージョン肝切除術が行われ、病理検査で腫瘍の完全壊死が確認された。術後8ヵ月の経過観察で癌の再発は認められず、薬物投与なしで経過している。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

A combined therapy of atezolizumab and bevacizumab (atezo/bev) is used as the first-line treatment for unresectable hepatocellular carcinoma (HCC). In this study, we report the case of curative hepatic resection in a 77-year-old man who initially had unresectable advanced-stage HCC with lung metastases. This rare hepatectomy conversion was owing to the administration of atezo/bev. Notwithstanding the side effects of immune-related adverse event hepatitis and intratumoral hemorrhage developed during atezo/bev treatment; after seven treatment cycles, the patient's tumor markers normalized, the tumor shrank markedly, and the metastasis disappeared. Subsequently, conversion therapy with hepatic resection was performed, and pathology confirmed complete tumor necrosis. No cancer recurrence was observed at the 8-month postoperative follow-up, and the patient remained drug free.

DOI： 10.1007/s12328-022-01744-z

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

One of the most aggressive forms of kidney cancer is renal cell carcinoma (RCC) with sarcomatoid changes and rhabdoid features (S/R). Adenosine produced via CD73 binds to adenosine 2 A receptor (A2AR) and suppress antitumor immunity. Here, we attempted to analyze the expression of CD73/A2AR in S/R RCC and examined its relationships with other immune microenvironments and prognostic effect. Sixty cases of S/R RCC were selected. CD73/A2AR expression levels were graded in the tumor cells or infiltrating immune cells on a score of 0-3 and divided into low (0 or 1) or high (2 or 3) groups. PD-L1 results were defined by the tumor proportion score (TPS). We counted the numbers of CD8+, FOXP3+, CD68+, and CD163+ immune cells. The rates of CD73/A2AR expression in epithelial component (23.3% and 15.0%) were lower than those in high-grade component (70.0% and 45.0%). CD73/A2AR were significantly correlated to high numbers of regulatory Tcells and macrophages of M2 subtype (CD73: P = 0.0059 and 0.0002; A2AR: P = 0.0002 and 0.018, respectively). Multivariate analysis showed that CD73/A2AR expressions were independent markers of unfavorable prognosis in S/R RCCs (P = 0.0204 and 0.0116, respectively). In RCC, the S/R component had higher expressions of CD73/A2AR than the epithelial component, and CD73/A2AR were independent prognostic factors. Compared with other RCCs, S/R RCCs are more effective at blocking adenosine signaling and CD73/A2AR inhibitors are expected to enhance the therapeutic efficacy and improve the prognosis of immune checkpoint inhibitor therapies.

DOI： 10.1016/j.prp.2023.154423

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIM: We aimed to evaluate the association between the intraoperative indocyanine green (ICG) fluorescence imaging (FI) pattern, preoperative magnetic resonance imaging (MRI) findings using gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), preoperative diffusion-weighted imaging (DWI) of MRI, and histological differentiation of hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the data for 80 tumors of 64 patients. Intraoperative ICG FI patterns were classified into cancerous or rim-positive type. We evaluated the signal intensity ratio of the tumor and the surrounding liver tissue in the portal phase (SIRPP) and intensity in the hepatobiliary phase (HBP) of Gd-EOB-DTPA-enhanced MRI, the apparent diffusion coefficient (ADC) in the DWI of MRI, and clinicopathologic factors. RESULTS: In the rim-positive group, the rate of poorly differentiated HCC and hypointensity type in HBP were significantly higher, and SIRPP and ADC were significantly lower than the rim-negative group. In the cancerous group, the rate of well or moderately differentiated HCC and hyperintensity type in HBP, SIRPP, and ADC were significantly higher than the noncancerous group. Multivariate analysis identified low SIRPP, low ADC, and hypointensity type in HBP as the significant predictive factors for rim-positive HCC and high SIRPP, high ADC, and hyperintensity type in HBP as the significant predictive factors for cancerous HCC. The positive rate of programmed cell death 1-ligand 1 and vessels that encapsulate tumor clusters status of the rim-positive HCC and HCC with low SIRPP were significantly higher than the control group. CONCLUSIONS: The intraoperative ICG FI pattern of HCC closely correlated with histological differentiation, preoperative SIRPP and intensity type in the Gd-EOB-DTPA MRI, and preoperative ADC in the DWI of MRI.

DOI： 10.1111/hepr.13902

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Gastrointestinal symptoms are one of the most common presentations of Coronavirus disease-19 (COVID-19), even in children. Higher rates of complicated appendicitis have been demonstrated in the era of the COVID-19 outbreak, and it has been recently suggested that acute appendicitis may occur as a complication of COVID-19. However, the relationship between appendicitis and COVID-19 remains unclear. CASE PRESENTATION: A 7-year-old male presented to the pediatric emergency department with 2 days' history of lower abdominal discomfort and tenderness. On examination, his abdomen was distended with diffuse mild tenderness at the lower abdomen, which was aggravated by movement. He was also tested and was found to be positive for SARS-CoV-2. Computed tomography showed perforated appendicitis with a fecalith. The patient was admitted and laparoscopic appendectomy was successfully performed. Postoperatively, a minor intra-abdominal abscess was present, which successfully treated with antibiotics. Histopathology showed a markedly inflamed appendix with mucosal ulceration and transmural neutrophilic inflammation, which was consistent with phlegmonous appendicitis. Reverse transcription quantitative polymerase chain reaction using a surgically extracted appendix specimen revealed the presence of SARS-CoV-2 virus, which indicated a pathophysiological relationship between appendicitis and COVID-19. CONCLUSION: The present case will provide further understanding of pediatric patients with concomitant COVID-19 and acute appendicitis.

DOI： 10.1186/s40792-023-01618-7

PubMed

症例は7歳男児。父親に新型コロナウイルス感染症(SARS-CoV-2)の既往があった。2日前からの下腹部痛のため救急医療部へ搬送された。搬送時の体温は39.1度で、血圧は102/61mmHg、心拍数は101bpmであった。受診時に腹部膨満を認め、下腹部にびまん性の圧痛を認めた。臨床検査で白血球数は9900/μL、C反応性蛋白は12.3mg/dLであった。造影CTで腫大した虫垂を認めた。虫垂根部に異常はなく、虫垂内部に糞石と穿孔を認めた。穿孔性虫垂炎と診断し、腹腔鏡下虫垂切除術を施行した。サージカルマスク、N95マスク、フェイスシールド等の個人防護具を装着し、緊急手術を施行した。手術時間は93分であった。術後の培養検査で大腸菌、Streptococcus constellatus、Bacteroides fragilisが検出された。抗菌剤をタゾバクタム/ピペラシリンからメロペネムとメトロニダゾールに変更した。切除標本を用いたリアルタイムPCR法でSARS-CoV-2に陽性を認めた。術後経過は良好で、呼吸器症状もなく、17日後に退院となった。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: The aim of this study was to clarify the appropriate management after birth for congenital biliary dilatation (CBD, choledochal cyst) patients with a prenatal diagnosis. METHOD: Thirteen patients with a prenatal diagnosis of CBD who underwent liver biopsy during excision surgery were divided into two groups and retrospectively analyzed: group A, with liver fibrosis above F1 and group B, without liver fibrosis. RESULTS: Excision surgery was performed earlier in group A (F1-F2), at a median of 106 days old (p = 0.04). There were significant differences between the two groups in the presence symptoms and sludge, the cyst size, and the level of serum bilirubin and gamma glutamyl transpeptidase (GGT) before excision surgery (p < 0.05). Especially, in group A, prolonged serum GGT elevation and larger cysts were consistently observed from birth. The cut-off values of predictions for the presence of liver fibrosis in serum GGT and cyst size were 319 U/l and 45 mm. No significant differences were observed in the postoperative liver function or complications during the follow-up period. CONCLUSION: In patients with prenatally diagnosed CBD, the postnatal serial changes of serum GGT values and cyst size, in addition to symptoms, could help to prevent progressive liver fibrosis. LEVEL OF EVIDENCE: Ⅲ. TYPE OF STUDY: Treatment Study.

DOI： 10.1016/j.jpedsurg.2023.01.050

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1245/s10434-023-13182-3

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

It is possible that PRCCs may still contain a variety of unknown histologic subtypes. Some PRCCs express high expression of TFE3 protein without TFE3 gene rearrangement, but no reports have investigated the significance of this. Here we attempted to examine clinicopathological and molecular significance of the TFE3-immunopositive PRCC. We reviewed the histology and immunohistochemistry in 58 PRCCs. TFE3 immunoexpression was recognized in 7 cases. Because TFE3 immunostaining shows false-positive, to ensure the integrity of TFE3 immunostaining, the immunostaining was performed under strict control of internal controls and western blotting was performed on 2 positive cases and 5 negative cases, and differences in protein expression between two groups were confirmed. Significant immunohistochemical expressions of autophagy/lysosome proteins were observed in TFE3-positive group. No TFE3 gene arrangement was detected in all positive cases by fluorescence in situ hybridization. Whole-exome sequencing was performed on 6 TFE3-positive and 2 TFE3-negative cases. Gain of chromosome 7 was found in five of 6 TFE3-positive cases (83%). TFE3-positive group was correlated significantly with higher pTstage, cNstage, WHO/ISUP nuclear grade, and decreased OS. TFE3-immunopositive PRCC group had a poorer prognosis than TFE3-negative PRCC group and showed correlation with expressions of autophagy/lysosome proteins, suggesting that enhancement of autophagy/lysosome function drives an environment of energy metabolism that is favorable for cancer. It is necessary to recognize that there is TFE3-immunopositive group without TFE3 gene rearrangement within PRCC. Because of its aggressive biological behaviour, TFE3 can act as a biomarker in PRCC; moreover, autophagy-inhibiting drugs may have therapeutic effects on TFE3-immunopositive PRCC.

DOI： 10.1016/j.prp.2023.154313

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1016/j.gie.2023.01.032

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Myxoid liposarcoma (MLS) accounts for 20%-30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization / International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software-based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high nuclear grade group according to the modified Fuhrman grading system exhibited a significantly poor disease-free survival (hazard ratio: 4.43; 95% confidence interval: 0.9-22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high-grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density), but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high-grade group significantly expressed the cell cycle-related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

DOI： 10.1111/cas.15729

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Signal regulatory protein alpha (SIRPα), expressed in the macrophage membrane, inhibits phagocytosis of tumor cells via CD47/SIRPα interaction, which acts as an immune checkpoint factor in cancers. This study aimed to clarify the clinical significance of SIRPα expression in hepatocellular carcinoma (HCC). METHODS: This study analyzed SIRPα expression using RNA sequencing data of 372 HCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of our 189 HCC patient cohort. The correlation between SIRPα expression and clinicopathologic factors, patient survival, and intratumor infiltration of immune cells was investigated. RESULTS: Overall survival (OS) was significantly poorer with high SIRPα expression than with low expression in both TCGA and our cohort. High SIRPα expression correlated with lower recurrence-free survival (RFS) in our cohort. High SIRPα expression was associated with higher rates of microvascular invasion and lower serum albumin levels and correlated with greater intratumor infiltration of CD68-positive macrophages and myeloid-derived suppressor cells (MDSCs). Multivariate analysis showed that SIRPα expression and high infiltration of CD8-positive T cells and MDSCs were predictive factors for both RFS and OS. Patients with high SIRPα expression and infiltration of CD8-positive T cells and MDSCs had significantly lower RFS and OS rates. In spatial transcriptomics sequencing, SIRPα expression was significantly correlated with CD163 expression. CONCLUSIONS: High SIRPα expression in HCC indicates poor prognosis, possibly by inhibiting macrophage phagocytosis of tumor cells, promoting MDSC infiltration and inducing antitumor immunity. Treatment alternatives using SIRPα blockage should be considered in HCC as inhibiting macrophage antitumor immunity and MDSCs.

DOI： 10.1245/s10434-022-13058-y

PubMed

症例は68歳男性で、肝S1の肝細胞癌について造影CTで最大径6.0cmの腫瘤を認めた。拡大肝左葉切除術と尾状葉切除術を施行した。病理診断では中・低分化型肝細胞癌で、脈管侵襲や肝内転移は認めなかった。手術標本ではプログラム細胞死リガンド-1の高発現とCD8陽性T細胞の存在を認め、腫瘍浸潤性マクロファージが多数観察された。切除4ヵ月後、造影CTで13個の再発結節を認めた。切除不能な肝細胞癌の再発と診断し、系統的な化学療法を行うことにした。一次治療としてレンバチニブを約2年間投与し、肝内腫瘍の縮小を認めた。しかし、経過観察の造影CTで新たな病変、肝胃腸間膜リンパ節腫脹、腹膜播種を認めた。高頻度マイクロサテライト不安定性(MSI-high)が検出されたため、ペムブロリズマブ(200mg、3週ごと)の投与を開始した。約8ヵ月間で11サイクルのペムブロリズマブ療法を施行した結果、肝胃腸間膜リンパ節腫脹と腹膜播種径は縮小したが、その後に再び増加した。三次治療としてソラフェニブを投与したところ、病変は一旦縮小したが、皮疹(グレード3)を認めたため、治療を中止した。さらに、四次治療としてカボザンチニブを8ヵ月間投与した。その結果、腫瘍とリンパ節腫脹が縮小した。MSI-highの肝細胞癌に対してマルチキナーゼ阻害剤が有効であった。

国際・国内誌：国際誌  

Hepatocellular carcinoma (HCC) is a common cause of cancer-related deaths worldwide, and the mortality rate of patients with unresectable HCC is very high. Microsatellite instability (MSI) is an essential biomarker for response to immune checkpoint inhibitors (ICI) in various tumors. However, the frequency of MSI in HCC is low (1.11%). There is only one case report of MSI-high HCC, and it is not well understood how high MSI affects the tumor microenvironment of HCC. Hence, we describe an interesting patient with unresectable MSI-high HCC, including the evaluation of immune status in the tumor microenvironment. A 68-year-old man presented to our department with HCC in liver segment 1. Contrast-enhanced CT revealed a liver tumor of 6.0 cm in maximum size. The patient underwent extended left and caudate lobectomy of the liver for HCC. Four months after surgical resection, contrast-enhanced computed tomography (CECT) detected 13 recurrent nodules. The patient was diagnosed with unresectable hepatocellular carcinoma recurrence, and we decided to administer systematic chemotherapy. Lenvatinib was administered over approximately 2 years as a first-line treatment, which resulted in intrahepatic tumor shrinkage. However, follow-up CECT showed new lesions, hepatogastric mesentery lymph node swelling, and peritoneal dissemination. After MSI-high status was identified, the patient began to receive pembrolizumab (200 mg, every 3 weeks). Eleven cycles of pembrolizumab therapy were administered over approximately 8 months, during which the diameter of the hepatogastric mesentery lymph node swelling and peritoneal dissemination showed shrinkage but later re-increased. As the third- and fourth-line therapy has been administered, the tumors and lymph nodes have shrunk. We report a rare case in which multikinase inhibitors were effectively used to treat MSI-high HCC.

DOI： 10.1007/s13691-022-00585-4

PubMed

DOI： 10.1016/j.jiac.2023.12.002

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: The fibroblast growth factor receptor 2 (FGFR2) fusion gene is frequently found as a genetic abnormality in the FGFR pathway in patients with intrahepatic cholangiocarcinoma (ICC). The FGFR fusion protein, produced from the FGFR fusion gene, is thought to cause tumor cell growth. To date, there have been few reports on the relationship between pathologic FGFR2 expression and prognosis in patients who have undergone hepatectomy for ICC, and on the relationship between FGFR2 and tumor-infiltrating lymphocytes (TILs). METHODS AND RESULTS: We enrolled 92 patients who underwent hepatectomy for ICC and performed immunohistochemical staining for FGFR2 and cluster of differentiation 8, and hematoxylin and eosin staining for evaluating TILSs. The relationships between the FGFR2 and clinicopathological characteristics and outcomes were analyzed, and patients were classified into positive (n = 18) and negative (n = 74) FGFR2 groups. The FGFR2-positive group contained more men (p < 0.0001) and had lower serum albumin (p = 0.0355) and higher carcinoembryonic antigen (p = 0.0099). Furthermore, multivariable analyses revealed that the FGFR2-positive group had worse disease-free survival (DFS) (p = 0.0002). Multivariate analysis showed that the independent prognostic factors for DFS were maximum tumor size (≥5 cm) (p = 0.0011), tumor localization (perihilar type) (p = 0.0180), and FGFR2 positivity (p = 0.0029). There was no significant difference in TILs count between the two groups. CONCLUSION: We showed that FGFR2 high expression was an independent prognostic factor for recurrence of resected ICC.

DOI： 10.1111/hepr.13875

PubMed

国際・国内誌：国際誌  

DOI： 10.1002/pbc.30155

PubMed

DOI： 10.1016/j.gim.2022.08.007

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature.

DOI： 10.1016/j.prp.2022.154239

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Collecting duct carcinoma (CDC) and fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) have similar histological morphologies and both show a poor prognosis. Programmed death ligand 1 (PD-L1) inhibitor has been approved for the treatment of RCC. However, tumour-infiltrating neutrophils stimulated by interleukin-8 (IL-8) interfere with PD-L1 inhibitors. Here, we retrospectively analysed PD-L1 and IL-8 expression, and examined its relationship with infiltrating immune cells. METHODS: Nine cases of CDC and seven cases of FH-deficient RCC were selected. We defined PD-L1 and IL-8 expression by the Tumour Proportion Score and Combined Positive Score (CPS). We counted the numbers of CD8+, CXCR2+, CD11b+, CD66b+ and CD33+ immune cells located in the tumour components. RESULTS: A number of CXCR2+ (p=0.0058), CD11b+ (p=0.0070) and CD66b+ (p=0.0067) immune cells infiltrating into CDC were significantly higher than those infiltrating into FH-deficient RCC. In CDC, PD-L1 expression was correlated with a high density of CD8+ lymphocytes (p=0.0389), but was not in FH-deficient RCC (p=0.6985). IL-8 CPS was significantly higher in CDC than in FH-deficient RCC (p=0.0069). In addition, among the CDC cases, IL-8 CPS showed significant positive correlations with CXCR2+, CD11b+ and CD66b+ immune cell densities (p=0.0250, p=0.0104 and p=0.0374, respectively), whereas FH-deficient RCC showed no significant correlations between IL-8 CPS and immune cell densities. CONCLUSIONS: Our results suggest the difference of each tumour microenvironment between CDC and FH-deficient RCC, and IL-8 is a potential therapeutic target for treating CDC, but not FH-deficient RCC.

DOI： 10.1136/jcp-2022-208589

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Chondrosarcoma is the second most common primary malignant bone tumor, which produces cartilaginous matrix without neoplastic osteoid or bone formation. The histological grade in the WHO Classification of Soft Tissue and Bone (2020 edition) is the most important factor in predicting the clinical outcome of conventional chondrosarcoma, but the lack of clarity in its detailed definition is occasionally problematic. Here, we reviewed conventional chondrosarcoma cases and validated the significance of histological findings. Moreover, we proposed a new scoring system of conventional chondrosarcoma. MATERIAL AND METHODS: Clinicopathological features of 60 cases of conventional chondrosarcoma and 21 cases of dedifferentiated chondrosarcoma were reviewed. RESULTS: Moderate to severe nuclear atypia was correlated with distant metastasis. Moderate and severe nuclear atypia, high cellularity, and >1 % myxoid change were correlated with adverse overall survival. On the other hand, cases with mild nuclear atypia showed no tumor-related death and no metastases. Based on the above results, we proposed a new scoring system based on nuclear atypia (mild: 0, moderate: +1, severe: +2), cellularity (no and mildly increased cellularity: 0, moderately and diffusely increased cellularity: +1), necrosis [(-): 0, (+): + 1], and chondromyxoid area [(-): 0, (+): + 1]. Each grade was defined as follows: cases with only mild nuclear atypia as grade 1, cases with total score 1-3 excluding mild nuclear atypia as grade 2, and cases with total score 4 or 5 as grade 3. There were 18 cases (30 %) of grade 1 including 5 cases (28 %) of local recurrence, but no metastasis or tumor-related death; 26 cases (43 %) of grade 2 including 2 cases (8 %) of local recurrence, 3 cases (12 %) of metastasis, and 1 case (4 %) of tumor-related death; and 16 cases (27 %) of grade 3 including 4 cases (25 %) of local recurrence, 6 cases (38 %) of metastasis, and 5 cases (31 %) of tumor-related death. There was no statistically significant association between the histological findings and dedifferentiation. CONCLUSION: From this study, we propose a new histological scoring system for the grading of conventional chondrosarcoma, based on nuclear atypia, cellularity, necrosis, and myxoid change. Using this system, conventional chondrosarcoma may be clearly classified into three grades: grade 1, non-metastasizing; grade 2, metastasizing but rarely life-threatening; and grade 3, frequently metastasizing and life-threatening.

DOI： 10.1016/j.prp.2022.154125

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Solid-type poorly differentiated adenocarcinoma (solid-type-PDA) of the stomach is a unique histological subtype of "tubular adenocarcinoma", but little is known about its clinicopathological features, molecular pathological characteristics and immunoregulatory tumor microenvironment. Herein, we examined the immunohistochemical expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) in 57 cases of solid-type-PDA and classified them as either MMR-deficient or -proficient (dMMR, N = 23; pMMR, N = 34), and additionally identified 18 dMMR-well-differentiated adenocarcinoma (WDA) and 34 pMMR-WDA as control groups. We analyzed and compared solid-type-PDA with WDA by evaluating the immunoexpressions of key immune pathway proteins (programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1)) and tumor-infiltrating lymphocytes (TILs) (CD8, Foxp3 and PD-1). The results reveled IDO1 was significantly more frequent in dMMR-solid-type-PDA than in dMMR-WDA (P = 0.0046). Moreover, dMMR-solid-type-PDA tended to have higher mean CD8+ and Foxp3+ TILs compared with dMMR-WDA [P = 0.0006 (CD8+) and P = 0.1061 (Foxp3+)], and IDO1-positive tended to be associated with a large number of CD8+, Foxp3+ or PD-1+ TILs in almost all tumor subtypes. PD-L1 was significantly observed in 44 % (15/34) of pMMR-solid-type-PDA compared with 18 % (6/34) of pMMR-WDA (P = 0.0344). Although they are molecularly and morphologically classified as the same chromosomal instability subtype, overall survival (OS) and disease-free-survival (DFS) in pMMR-solid-type-PDA were significantly worse than those in pMMR-WDA [P = 0.0216 (OS) and P = 0.0160 (DFS)]. Our study demonstrates that immunoexpressions of several immunoregulatory proteins and TILs are more prevalent in dMMR-solid-type-PDA, potentially a useful discovery for designing tumor treatments with immune checkpoint inhibitors or combination therapies with a PD-1/PD-L1-inhibitor and IDO1-inhibitor.

DOI： 10.1016/j.prp.2022.154124

PubMed

掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00580-022-03390-w

その他URL： https://link.springer.com/article/10.1007/s00580-022-03390-w/fulltext.html

腫瘍関連マクロファージ(TAM)は種々の癌で腫瘍促進機能を持つので、肝芽腫におけるTAMの役割について検討した。免疫組織化学分析では、CD204陽性TAMの密度は肝芽腫の胚成分において肝芽腫の他の組織学的サブタイプよりも有意に高かった。Huh6細胞とヒト単球由来マクロファージ(HMDM)のin vitroでの共培養では、マクロファージコロニー刺激因子受容体(M-CSFR)がHuh6細胞において強く発現していた。HepG2細胞(M-CSFRを発現する他の肝芽腫株)の増殖はM-CSFR阻害剤で阻害された。M-CSFRは胚成分や再発病変で強く発現していた。CD204陽性マクロファージの数はM-CSFR陰性領域よりもM-CSFR陽性領域で多かった。M-CSFR発現は肝芽腫細胞においてマクロファージとの細胞・細胞接触によって誘導され、M-CSFR阻害剤はM-CSFR陽性肝芽腫特に再発症例で効果があると考えられた。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Immaturity of ganglia (IG), an allied disorder of Hirschsprung disease (AD-HSCR), develops as neonatal ileus, but the dysmotility spontaneously resolves after several months. The diagnosis of IG using HE staining is often difficult. We herein report a new pathological finding of IG called the 'palisading-like pattern', which may be helpful for improving the diagnostic accuracy. METHODS: Cases of IG that were managed over the past 28 years were retrospectively reviewed. We investigated the clinical course and pathological findings for Hematoxylin-Eosin (HE) staining. The conventional diagnostic criteria for IG were (1) a normal or slightly increased number of ganglion cells and (2) ganglion cells with small nuclei. RESULTS: Among the 155 cases, 28 were diagnosed with IG, and 10 were retrospectively confirmed by HE staining. A palisading-like pattern was confirmed at the time of the initial ileostomy (median age, 2.5 days), and the palisading-like pattern had completely disappeared by the time of stoma closure (median age, 215 days) in all 10 cases. A palisading-like pattern is not present in other diseases. CONCLUSIONS: Even if immunostaining data are not available for a further analysis, the detection of a palisading-like pattern on HE staining makes an accurate diagnosis possible. LEVEL OF EVIDENCE: LEVEL IV.

DOI： 10.1016/j.jpedsurg.2022.02.035

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.

DOI： 10.1111/his.14703

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is associated with poor prognosis. Recently, signal regulatory protein alpha (SIRPα), which is the immune checkpoint of macrophages, and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), which is the immune checkpoint of T cells and natural killer cells, have been considered as potential targets for cancer immunotherapy. This study aimed to assess the value of SIRPα and TIGIT as prognostic factors of UPS. MATERIALS AND METHODS: The cBio Cancer Genomics Portal was used to analyze mRNA expression data of 50 UPS cases in the Cancer Genome Atlas. We retrieved 49 UPS cases and performed immunohistochemistry (IHC) to detect programmed death ligand 1 (PD-L1), SIRPα, CD68, CD163, TIGIT, CD155, and CD8. RESULTS: SIRPα was positively associated with CD163 (Pearson's r = 0.51, p = 0.0002) as per open access data and IHC of the cohort (p = 0.002), which revealed that SIRPα-positive macrophage infiltration was higher in UPS cells with ≥ 1% PD-L1 expression than that in UPS cells with < 1% PD-L1 expression (p = 0.047). TIGIT was positively correlated with PD-L1 (r = 0.54, p < 0.0001) and CD8A (r = 0.98, p < 0.0001). In 35 of 49 cases, IHC revealed high levels of TIGIT expression on tumor cells. Furthermore, TIGIT expression on tumor cells was negatively correlated with CD155-positive (p = 0.0144) and CD8-positive (p = 0.0487) cell infiltration. Survival analysis showed that the high degree of SIRPα-positive macrophage infiltration was associated with poor overall survival and metastasis (p < 0.0001, p = 0.0006, respectively). CONCLUSION: SIRPα-positive macrophages infiltrated UPS cells, which predicted poor prognosis. High TIGIT expression on tumor cells was associated with decreased levels of tumor-infiltrating macrophages in UPS.

DOI： 10.1007/s00432-022-04078-y

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs. METHODS: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed. RESULTS: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%). CONCLUSIONS: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation.

DOI： 10.1136/jclinpath-2020-207311

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Collecting duct carcinoma (CDC) is a rare subset of high-grade renal cell carcinoma (RCC). To diagnose CDC, it is necessary to rule out other renal tumors including renal medullary carcinoma and fumarate hydratase (FH)-deficient RCC. However, there is overlap in the morphology of these three tumors, which all have poor outcomes. There is also still a need to sufficiently examine the therapeutic strategies for each of these tumors. In this study, we retrospectively reclassified invasive/infiltrating high-grade RCC and investigated its pathological features. We reviewed 18 cases previously diagnosed as "CDC," "FH-deficient RCC," and "unclassified RCC," which were reclassified as SMARCB1/INI1-deficient RCC, FH-deficient RCC, and CDC by SMARCB1/INI1, FH, and 2SC immunohistochemistry (IHC) and FH gene mutational status. As the result, 18 cases were reclassified into 2 cases of SMARCB1/INI1-deficient RCC, 7 cases of FH-deficient RCC, and 9 cases of CDC. The morphological features of each group overlapped, and no specific immunohistochemical expression except for SMARCB1/INI1, FH, and 2SC was detected. These results suggest that invasive/infiltrating high-grade RCC should be diagnosed by the combination of immunohistochemistry and molecular biological technique.

DOI： 10.1016/j.humpath.2022.03.002

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

Tumor-associated macrophages (TAMs) have protumor functions in various cancers. However, their significance in hepatoblastoma, the most common liver tumor in children, remains unclear. The aim of this study was to explore the potential roles of TAMs in hepatoblastoma. Immunohistochemical analysis revealed that the density of CD204-positive TAMs was significantly higher in the embryonal component than in other histological subtypes of hepatoblastoma. An in vitro co-culture study with Huh6 cells and human monocyte-derived macrophages (HMDMs) showed that macrophage-colony-stimulating factor receptor (M-CSFR) was strongly up-regulated in the Huh6 cells that were directly co-cultured with HMDMs. The expressions of M-CSFR ligands (interleukin-34 and M-CSF) were also increased by co-culture with HMDMs. The proliferation of HepG2 cells (another hepatoblastoma cell line expressing M-CSFR) was inhibited by an M-CSFR inhibitor. M-CSFR was found to be highly expressed in the embryonal component and in recurrent lesions. The number of CD204-positive macrophages was also higher in the M-CSFR-positive areas than in the M-CSFR-negative areas. Thus, M-CSFR expression appeared to be induced by cell-cell contact with macrophages in hepatoblastoma cells, and M-CSFR inhibitor is potentially effective against M-CSFR-positive hepatoblastoma, especially recurrent cases.

DOI： 10.1007/s00795-022-00323-y

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

DOI： 10.1038/s41598-022-12528-3

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Solid-type poorly differentiated adenocarcinoma (PDA) of the stomach is frequently associated with microsatellite instability (MSI) and aberrations of the SWI/SNF chromatin remodeling complex. Previous studies showed that aberrant ARID1A and SMARCA4 expression induces mesenchymal transition. We analyzed 51 primary-site cases and 209 metastatic lymph nodes among solid-type PDA for the expression of SWI/SNF complex subunits (ARID1A, SMARCA4, SMARCB1, SMARCC2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, β-catenin, Snail). We also analyzed 40 cases of non-solid-type PDA as a stage-matched control group. Aberrant expression of ARID1A (39%) and SMARCA4 (49%) was more common in solid-type PDA than in non-solid-type PDA (ARID1A, P = 0.0049; SMARCA4, P < 0.0001). The group of solid-type PDA with aberrant ARID1A showed significantly longer overall and progression-free survival than the corresponding ARID1A-retained group (P = 0.0405 and P = 0.0296, respectively). Aberrant expression of EMT factors inducing mesenchymal transition in the groups with solid-type PDA at the primary site or metastatic lymph nodes with aberrant ARID1A was less common than in the corresponding groups with retained ARID1A (E-cadherin, primary site P = 0.0341, lymph node P < 0.0001; β-catenin, primary site P = 0.0293, lymph node P = 0.0010; Snail, primary site P = 0.0169, lymph node P = 0.0828). Furthermore, N3 of the TNM classification was more frequently observed in the group with solid-type PDA with retained ARID1A than in the corresponding ARID1A-aberrant group (P = 0.0288). Mesenchymal transition was not induced in the ARID1A-aberrant group, in which patients had favorable prognosis, and preserved epithelial characteristics in EMT may play an important role in low tumor aggressiveness of solid-type PDA.

DOI： 10.1007/s00428-021-03261-9

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

DOI： 10.1038/s41379-021-00972-x

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Periosteal chondrosarcoma is an extremely rare malignant cartilage-forming tumour that originates from the periosteum and occurs on the surface of bone. Often, it is difficult to distinguish periosteal chondrosarcoma from other tumours, and reports in the literature are scarce. This study aims to investigate the characteristics of periosteal chondrosarcoma, focusing particularly on medullary invasion. Among 33 periosteal cartilaginous tumours, seven patients with pathologically proven periosteal chondrosarcoma were identified retrospectively. The average tumour size was 5.4 cm in the long axis; two tumours were smaller than 3.0 cm. Six tumours were resected with a wide margin, and the remaining tumour had a marginal margin. Histology revealed that six tumours (85.7%) had invaded the medullary cavity; three of these did not show invasion into the medullary cavity on MRI evaluation. Neither local recurrence nor metastasis was observed among these patients. The frequency of invasion of the medullary cavity was higher than that reported previously. The recommended treatment for periosteal chondrosarcoma is resection with an adequate margin. Therefore, surgeons should consider the possibility of medullary invasion when attempting to achieve a histologically negative margin, even if the tumour does not show invasion into the medullary cavity on MRI.

DOI： 10.3390/jcm11072062

PubMed

症例は2歳男児。1歳頃から増大する右腰部腫瘤が切除された。組織学的に、腫瘍は皮膚の真皮から皮下脂肪組織に、短紡錘形の細胞が多数の多核巨細胞を伴いながら増殖し、深部では脂肪織に分け入るように浸潤していた。免疫染色ではCD34、S100陽性、pan-Trkが核と細胞質に陽性であり、その特徴的な組織像および免疫形質からNTRK-rearranged spindle cell neoplasmを疑った。fluorescence in situ hybridization(FISH)にてNTRK1の5末端の欠失を同定し、pan-Trkの陽性所見と合わせてNTRK-rearranged spindle cell neoplasmと診断した。本腫瘍はTRK阻害薬の普及により診断の必要性が高まると考えられ、組織像、免疫染色結果、分子病理学的解析を総合して診断することが重要である。(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Intimal sarcoma is one of the most common and well-known primary malignant neoplasms of the aorta and heart. The authors reviewed cases of intimal sarcoma from histological, immunohistochemical and genetic perspectives. Twenty cases of intimal sarcoma were retrieved. Immunohistochemistry and FISH of MDM2 and PDGFRA genes were performed. All 20 tumours were composed of spindle-shaped, stellate, oval or polygonal tumour cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism and frequent mitotic figures. Other histological findings were as follows: abnormal mitosis in 10 cases (50%), necrosis in 15 cases (75%), myxoid stroma in 12 cases (60%), cartilaginous formation in 1 case (5%), haemorrhage in 12 cases (60%) and fibrinous deposition in 14 cases (70%). The tumours were positive for MDM2 in 16 cases (80%), ERG in 4 cases (20%), alpha-smooth muscle actin in 6 cases (30%), desmin in 5 cases (25%) and AE1/AE3 in 4 cases (20%). Immunohistochemical positivity was focal in each case. Loss of H3K27me3 expression was noted in 2 cases (10%). MDM2 and PDGFRA gene amplifications were detected in 11 cases (55%) and 1 case (5%), respectively. Fisher's exact test revealed a significant correlation between MDM2 gene amplification and myxoid stroma (p = 0.0194). No parameters showed any association with the anatomical location of the tumours. It was suggested that myxoid histology of intimal sarcoma may be associated with MDM2 gene amplification and that intimal sarcoma may be divided into myxoid and non-myxoid types.

DOI： 10.1007/s00428-022-03293-9

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

We examined phosphorylated nuclear factor erythroid 2-related factor 2 (P-NRF2) expression in surgically resected primary hepatocellular carcinoma (HCC) and investigated the association of P-NRF2 expression with clinicopathological features and patient outcome. We also evaluated the relationship among NRF2, cancer metabolism, and programmed death ligand 1 (PD-L1) expression. In this retrospective study, immunohistochemical staining of P-NRF2 was performed on the samples of 335 patients who underwent hepatic resection for HCC. Tomography/computed tomography using fluorine-18 fluorodeoxyglucose was performed, and HCC cell lines after NRF2 knockdown were analyzed by array. We also analyzed the expression of PD-L1 after hypoxia inducible factor 1α (HIF1A) knockdown in NRF2-overexpressing HCC cell lines. Samples from 121 patients (36.1%) were positive for P-NRF2. Positive P-NRF2 expression was significantly associated with high alpha-fetoprotein (AFP) expression, a high rate of poor differentiation, and microscopic intrahepatic metastasis. In addition, positive P-NRF2 expression was an independent predictor for recurrence-free survival and overall survival. NRF2 regulated glucose transporter 1, hexokinase 2, pyruvate kinase isoenzymes L/R, and phosphoglycerate kinase 1 expression and was related to the maximum standardized uptake value. PD-L1 protein expression levels were increased through hypoxia-inducible factor 1α after NRF2 overexpression in HCC cells. Conclusions: Our large cohort study revealed that P-NRF2 expression in cancer cells was associated with clinical outcome in HCC. Additionally, we found that NRF2 was located upstream of cancer metabolism and tumor immunity.

DOI： 10.1002/hep4.1838

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin-embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage-specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte-derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed. Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co-culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co-culture with macrophages also induced interleukin (IL)-34 overexpression by Huh6 cells via Brd4 signaling. IL-34 overexpression promoted tumor cell proliferation and chemoresistance. High IL-34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL-34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL-34 is a potential therapeutic target for hepatoblastoma.

DOI： 10.1002/cam4.4537

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

The clinicopathological features of myeloid-derived suppressor cell (MDSC) and CD8+ T-cell infiltration in hepatocellular carcinoma (HCC) are poorly understood. The present study examined MDSC and CD8+ T-cell infiltration in surgically resected primary HCC specimens and investigated the association of MDSC and CD8+ T-cell infiltration with clinicopathological features and patient outcomes. Using a database of 466 patients who underwent hepatic resection for HCC, immunohistochemical staining of CD33 (an MDSC marker) and CD8 was performed. High infiltration of MDSCs within the tumor was observed in patients with a poorer Barcelona Clinic Liver Cancer stage, larger tumor size, more poorly differentiated HCC, and greater presence of portal venous thrombosis, microscopic vascular thrombosis and macroscopic intrahepatic metastasis. MDSC infiltration and CD8+ T-cell infiltration were independent predictors of recurrence-free survival and overall survival, respectively. Stratification based on the MDSC and CD8+ T-cell status of the tumors was also associated with recurrence-free survival (10 year-recurrence-free survival; MDSChighCD8+ T-cellLow, 3.68%; others, 25.7%) and overall survival (10 year-overall survival; MDSChighCD8+ T-cellLow, 12.0%; others, 56.7%). In conclusion, the present large cohort study revealed that high MDSC infiltration was associated with a poor clinical outcome in patients with HCC. Furthermore, the combination of the MDSC and tumor-infiltrating CD8+ T-cell status enabled further classification of patients based on their outcomes.

DOI： 10.3892/ol.2022.13213

PubMed

症例は27歳女性で、発熱の為、入院した。肝臓にサテライト病変を複数伴う巨大な結節が認められ、血管造影検査で綿花状動脈が認められた。テクネチウムガラクトシル血清アルブミンシンチグラフィーおよび診断的腹腔鏡検査で、結節自体は機能性であるが、周囲が非機能性線維化領域であることが示された。生検標本より、結節は限局性結節性過形成(FNH)様と診断された。その後、複数回の静脈瘤破裂が認められ、肝不全に陥った為、肝移植を受けた。切除された肝臓には結節に中心性瘢痕が認められ、FNHの確定診断に至った。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Dedifferentiated liposarcoma (DDLS) has varying histopathological features, but their significance for the biological behaviour of this disease has not been fully clarified. The aim of this study was to elucidate the prognostic factors for DDLS by clinicopathologically reviewing a large case series. METHODS AND RESULTS: We clinicopathologically reviewed 123 cases of primary de-novo DDLS without preoperative treatment, including 81 in the internal trunk (internal DDLS) and 42 in peripheral sites (peripheral DDLS). Univariate and multivariate analyses of their features were also performed for all cases, the internal DDLS group, and the peripheral DDLS group. The results showed that, in all three groups, distant metastasis was significantly associated with shorter overall survival (OS) (univariate analysis, P < 0.0001, P = 0.0011, and P = 0.0101, respectively), whereas local recurrence showed no significant effect on prognosis. Histopathologically, a high mitotic count and the presence of round tumour cells were significantly associated with shorter OS in multivariate analysis of the internal DDLS group [respectively: P = 0.0022, hazard ratio (HR) 4.39, 95% confidence interval (CI) 1.71-11.28; and P = 0.0014, HR 7.19, 95% CI 2.14-24.16]. In the peripheral DDLS group, necrosis and high-grade histological components were significantly associated with shorter OS (univariate analysis, P = 0.0068 and P = 0.0174, respectively). CONCLUSIONS: The presence of round tumour cells may be one of the histological factors associated with a worse prognosis of DDLS patients, as previous studies indicated. This study also suggests that distant metastasis may be predictive of prognosis for both internal and peripheral DDLS, rather than local recurrence.

DOI： 10.1111/his.14588

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

Focal nodular hyperplasia (FNH) is a benign nodular lesion, but because of its feature of portal tract vessel abnormality, it may induce portal hypertension. A 27-year-old woman was admitted with a fever. A large nodule with satellite lesions was found in the liver and cotton wool-like feature of arteries were detected on angiography. Technetium galactosyl serum albumin scintigraphy and diagnostic laparoscopy showed that the tumor site was functional, while the surrounding area was a non-functional fibrotic area. A biopsy specimen indicated that the nodular lesion was an FNH-like lesion. She experienced several instances of variceal rupture and suffered liver failure, receiving liver transplantation. The excised liver showed a centrally scarred area in the nodule, indicating that the diagnosis was FNH. We herein report this case as a rare case of FNH that progressed to liver failure.

DOI： 10.1007/s12328-021-01529-w

PubMed

掲載種別：研究論文（学術雑誌）  

Abstract

With the advent of new molecular diagnostic techniques, retrieving DNA from the formalin-fixed paraffin-embedded (FFPE) tissues has become an essential yet challenging step for efficient downstream processes. Owing to low quality and quantity of DNA retrieved from the FFPE sections, the process is often impractical and needs significant improvements. Here, we established an efficient method for the purification of DNA from FFPE specimens by optimizing incubation temperature, incubation time, and the concentration of a formalin scavenger tris(hydroxymethyl)aminomethane (Tris) for reverse-crosslinking. The optimized method, named “Highly concentrated Tris-mediated DNA extraction” (HiTE), yielded three times the DNA yield per tissue slice compared with a representative DNA extraction kit. Moreover, the use of HiTE-extracted DNA increased the yield of the sequencing library three times and accordingly yielded a log higher and more reproducible sequencing library compared with that obtained using the commonly used commercial kit. The sequencing library prepared from HiTE-extracted FFPE-DNA had longer inserts and produced reads that evenly covered the reference genome. Successful application of HiTE-extracted FFPE-DNA for whole-genome and targeted gene panel sequencing indicates its practical usability.

DOI： 10.1093/biomethods/bpac014

その他URL： https://academic.oup.com/biomethods/article-pdf/7/1/bpac014/45249530/bpac014.pdf

メルケル細胞癌(MCC)の治療に役立つ新規分子標的を発見することを目指し、メルケル細胞ポリオーマウイルス(MCPyV)感染とMEK-ERK経路およびJAK-STAT経路との関連性を調べた。MCPyV陽性MCC患者30名(女性19名、平均75.6±8.2歳)(陽性群)と、MCPyV陰性MCC患者20名(女性13名、平均81.2±9.2歳)(陰性群)から得た組織検体で免疫組織化学解析を行った。両群を比較した結果、pJAK2発現とpERK1/2発現のレベルは陰性群が有意に高かった。予後不良を有意に示す臨床病理学的因子として、男性であることと高齢に加え、MCPyV感染状態(ハザード比0.3、P=0.013)が同定された。MCC細胞株で実験を行ったところ、MCPyV陰性のMCCでは、JAK阻害剤(ルキソリチニブ)による細胞増殖阻害作用が陽性株よりも強く現れた。MCPyV陰性株ではpERK1/2とpMEKの発現が陽性株よりも増加していた。こうした結果から、MCPyV陰性MCCでは、陽性のMCCに比べJAK2経路とMEK-ERK経路の活性化がより多くみられること、そしてルキソリチニブはそのMEK-ERK経路活性化を阻害することが示唆された。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Merkel cell polyomavirus (MCPyV) is monoclonally integrated into the genomes of approximately 80% of Merkel cell carcinomas (MCCs). While the presence of MCPyV affects the clinicopathological features of MCC, the molecular mechanisms of MCC pathogenesis after MCPyV infection are unclear. This study investigates the association between MCPyV infection and activation of the MEK-ERK and JAK-STAT signaling pathways in MCC to identify new molecular targets for MCC treatment. The clinicopathological characteristics of 30 MCPyV-positive and 20 MCPyV-negative MCC cases were analyzed. The phosphorylation status of MEK, ERK, JAK, and STAT was determined by immunohistochemical analysis. The activation status of the MEK-ERK and JAK-STAT pathways and the effects of a JAK inhibitor (ruxolitinib) was analyzed in MCC cell lines. Immunohistochemically, the expression of pJAK2 (P = .038) and pERK1/2 (P = .019) was significantly higher in MCPyV-negative than in MCPyV-positive MCCs. Male gender (hazard ratio [HR] 2.882, P = .039), older age (HR 1.137, P < .001), negative MCPyV status (HR 0.324, P = .013), and advanced cancer stage (HR 2.672, P = .041) were identified as unfavorable prognostic factors; however, the phosphorylation states of JAK2, STAT3, MEK1/2, and ERK1/2 were unrelated to the prognosis. The inhibition of cell proliferation by ruxolitinib was greater in MCPyV-negative MCC cell lines than in an MCPyV-positive MCC cell line. The expression of pERK1/2 and pMEK was higher in MCPyV-negative than in MCPyV-positive cell lines. These results suggest that activation of the JAK2 and MEK-ERK pathways was more prevalent in MCPyV-negative than in MCPyV-positive MCC and the JAK inhibitor ruxolitinib inhibited MEK-ERK pathway activation. Consequently, the JAK-STAT and MEK-ERK signaling pathways may be potential targets for MCPyV-negative MCC treatment.

DOI： 10.1111/cas.15187

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Core-needle biopsy (CNB) is used less frequently for the diagnosis of tumors in pediatric patients. In this report, the utility and safety of CNB for pediatric patients are described. METHODS: The medical records of patients who underwent CNB at the Department of Pediatric Surgery, Kyushu University Hospital from April 2020 to November 2021 were retrospectively reviewed. A 14 G or 16 G BARDMISSION Disposable Needle Instrument was used. For the diagnosis of neuroblastoma, a 14 G needle was selected; for the diagnosis of other tumors a 16 G needle was selected. RESULTS: During the above period 17 CNBs were performed in 17 patients, and the median patient age was 8 years (range, 15 days-19 years). The pathological diagnoses of the tumors were as follows: neuroblastoma, n = 6; lymphoma, n = 3; hepatoblastoma, n = 2; and others, n = 6. The quantity and quality of all tumor samples obtained by CNB was sufficient to make a diagnosis. The postoperative course after CNB was uneventful in most cases, with the exception of one case of hepatoblastoma (pseudoaneurysm). CONCLUSIONS: Core-needle biopsy is useful for pediatric patients. Sufficient tumor specimens were able to be obtained in all cases, irrespective of the type of tumor, and an accurate diagnosis could be made.

DOI： 10.1111/ped.15228

PubMed

2020年4月～2021年11月に小児外科でコアニードル生検が実施された患者の診療記録を後向きに評価し、小児におけるコアニードル生検の有用性および安全性について検討した。神経芽腫の診断には14G針が選択され、その他の腫瘍の診断には16G針が選択された。患者17例(中央値8歳)に計17回の生検が実施された。腫瘍の病理診断、神経芽細胞腫6例、リンパ腫3例、肝芽腫2例、その他6例であった。その結果、コアニードル腫瘍生検より得られたすべての腫瘍サンプルの量および質は、診断を下すのに十分であることが示された。コアニードル生検後の術後経過は、肝芽腫1例(偽動脈瘤)を除き、大部分の症例で良好であった。以上から、コアニードル生検は小児患者に有用であることが示された。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

INTRODUCTION: Radiation-associated sarcoma (RAS) is one of the most life-threatening complications associated with the treatment of malignant neoplasms. Because all RAS patients have a history of radiotherapy, there have been no effective treatment options when RAS is not completely resected. METHODS: We retrospectively reviewed 20 RAS patients, including 4 unresectable cases treated by carbon ion radiotherapy (CIRT). RESULTS: The primary diseases targeted by radiotherapy included malignant lymphoma (n = 4), cervical cancer (n = 3), pharyngeal cancer (n = 3), breast cancer (n = 2), lung cancer (n = 1), rectal cancer (n = 1), maxillary cancer (n = 1), synovial sarcoma (n = 1), and benign neoplasms (n = 4). The histological diagnoses of RAS included osteosarcoma (n = 8), leiomyosarcoma (n = 3), undifferentiated pleomorphic sarcoma (n = 3), rhabdomyosarcoma (n = 1), angiosarcoma (n = 1), malignant peripheral nerve sheath tumor (n = 1), spindle cell sarcoma NOS (n = 1), and sarcoma not further specified (n = 2). The median survival time from the diagnosis of RAS was 26 months. Eleven patients underwent surgery. Five of these patients achieved a continuous disease free (CDF) status or showed no evidence disease. Four patients underwent CIRT. One of these patients with leiomyosarcoma achieved a CDF status, and the other patient with osteosarcoma achieved a partial response. On the other hand, 2 patients experienced grade 3 toxicities that required surgical treatment. CONCLUSION: RAS originates from various types of diseases that are treated by radiotherapy and shows diverse pathological features. Complete resection achieves a good prognosis. CIRT can be an effective and feasible option for unresectable RAS.

DOI： 10.1159/000521504

PubMed

国際・国内誌：国際誌  

Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid tumors. However, metachronous appearance of intra-abdominal desmoid tumor is rare, and its clinical course is not well known. Here, we report a case of spontaneous regression of metachronous intra-abdominal desmoid tumor in a 36-year-old man with FAP. The patient was diagnosed with FAP and underwent laparoscopic total colorectomy. Intra-abdominal desmoid tumor appeared 2 years later and progressed despite treatment with tamoxifen and sulindac. He received four cycles of combinatory therapy with dacarbazine and adriamycin, resulting in shrinkage and stabilization of the desmoid tumor even after cessation of chemotherapy. A new intra-abdominal desmoid tumor developed 2 years later at a different site from the first lesion and progressed from 65 mm to 70 mm in diameter within a month. The size of the first lesion, however, remained unchanged. We prepared for chemotherapy because the second lesion progressed, but follow-up computed tomography showed spontaneous shrinkage of the second lesion. The patient still has not needed additional therapy as of more than 4 years after the appearance of the second lesion. Immunohistochemical staining showed the presence of macrophages in the second lesion. Although metachronous intra-abdominal desmoid tumor is rare and management protocols have yet to be established, this case suggests that an active surveillance approach may be applicable under careful follow-up in asymptomatic patients.

DOI： 10.1159/000521920

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Malignant peripheral nerve sheath tumor (MPNST) is a very aggressive peripheral nerve sheath-derived sarcoma, which is one of the most difficult tumors to diagnose due to its wide spectrum of histological findings and lack of specific immunohistochemical markers. Recently, it has been reported that losses of expression of H3K27me3 and H3K27me2 caused by PRC2 dysfunction may be useful diagnostic markers for MPNST, but there is no consensus on their clinicopathological significance. Here, we investigated the relationship between loss of H3K27 methylation and various parameters and clarified the clinicopathological significance of such loss. We analyzed the clinicopathological and immunohistochemical features in 84 MPNST cases. Complete losses of H3K27me3 and H3K27me2 were observed in 37 (44%) and 29 (35%) cases, respectively. Losses of H3K27me3 and H3K27me2 were significantly correlated with myogenic immunopositivity (H3K27me3 vs. desmin, P = 0.0051; H3K27me3 vs. myogenin, P = 0.0009; H3K27me2 vs. myogenin, P = 0.042). Meanwhile, there were significant correlations between preservation of immunohistochemical neurogenic markers and intact H3K27me3 and H3K27me2 (H3K27me3 vs. S-100 protein, P = 0.0019; H3K27me3 vs. SOX10, P = 0.014; H3K27me2 vs. S-100 protein, P = 0.0011; H3K27me2 vs. SOX10, P = 0.0087). In multivariate analysis, local recurrence, distant metastasis, high FNCLCC grade, and loss of SOX10 expression were independent prognostic factors for overall survival. H3K27me3 and H3K27me2 expression was retained in all 26 cases of rhabdomyosarcoma non-alveolar subtype. In conclusion, we suggest that H3K27me3 and H3K27me2 immunonegativity is useful but not definitive for diagnosing MPNST. Complete loss of H3K27 methylation may be involved in aggressive transdifferentiation from neural differentiation to skeletal muscle differentiation in MPNST.

DOI： 10.1007/s00428-021-03189-0

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Synovial sarcoma (SS) is a malignant soft tissue neoplasm harboring SS18-SSX fusion gene and is histologically characterized by spindle cells and epithelial components. Some investigations have demonstrated that desmoplastic reaction (DR) is an independent prognostic factor of cancers. However, it remains unknown whether DR is of predictive value for the prognosis of synovial sarcoma patients. Here, we reviewed the clinical and histological findings of 88 patients with SS. We defined DR as hyalinized collagenous structures and classified the degree of DR as follows: none, mild, moderate, and severe. Overall, 23 SS cases (24%) showed moderate or severe DR histologically. Statistically, the cases with moderate or severe degree of DR showed poorer prognosis than those with no or mild DR (local recurrence: P = 0.0059, distant metastasis: P = 0.0002, tumor death: P = 0.0382). The findings of the study suggest that the DR of synovial sarcoma could be an important prognostic factor.

DOI： 10.1016/j.prp.2021.153668

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Pancreatic undifferentiated carcinoma (UDC) is a rare tumor with a worse prognosis than pancreatic ductal adenocarcinoma (PDAC). Recent study showed that UDC exhibits loss of SMARCB1, which is one of the subunits of the SWI/SNF complex. However, whether there are abnormalities of other SWI/SNF complex subunits in UDC has remained unknown. In this study, we attempted to clarify whether the loss of SWI/SNF complex subunits is related to the pathogenesis of UDC by comparing undifferentiated component (UC) and ductal adenocarcinoma component (DAC). METHODS: Genetic analysis of the ten UCs and six DACs was performed. The expression of ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCC1, and SMARCC2 in formalin-fixed, paraffin-embedded tumor tissues collected by surgical resection from 18 UDC patients was evaluated immunohistochemically. Moreover, two pancreatic cell lines were evaluated for the effects of siARID1A on the mRNA and protein expression of E-cadherin, vimentin, and epithelial-mesenchymal transition (EMT)-related markers by qRT-PCR, western blotting, and immunofluorescence staining. RESULTS: UCs tended to have a higher frequency of mutation in ARID1A, SMARCA4, and SMARCC2 than DACs. Immunohistochemically, UCs revealed reduced/lost expression of ARID1A (72%), SMARCB1 (44%), SMARCC1 (31%), and SMARCC2 (67%). Reduced/lost expression of ARID1A, SMARCB1, and SMARCC2 was significantly more frequently observed in UCs than in DACs. In the pancreatic cell lines, western blotting and qRT-PCR showed that the downregulation of ARID1A increased the expression of vimentin and EMT-related markers. CONCLUSION: Our results suggest that the abnormality of SWI/SNF complex subunits, especially ARID1A, is one of the factors behind the morphological change of UDC.

DOI： 10.1007/s00432-021-03860-8

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIM: Amyloidosis is a systemic or localized disease of protein deposition characterized by amorphous eosinophilic morphology and positivity of Congo Red staining. The typing of amyloidosis is becoming increasingly important because therapeutic agents for each amyloidosis type have been developed. Herein, the authors review the autopsy cases at an institution to reveal the putative Japanese characteristics of each amyloidosis type and evaluate the clinicopathological significance of each type. MATERIALS AND METHODS: A total of 131 autopsy cases of systemic and localized amyloidosis were retrieved for classification by immunohistochemistry. Immunohistochemistry for transthyretin, amyloid A (AA), immunoglobulin light-chain kappa and lambda, and β2-microglobulin was performed for all cases. RESULTS: The 131 amyloidosis cases were classified as follows: 71 cases (54.2%) of transthyretin amyloidosis, 32 cases (24.4%) of AA amyloidosis, 8 cases (6.1%) of light-chain amyloidosis, and 5 cases (3.8%) of β2-microglobulin amyloidosis, along with 15 equivocal cases (11.5%). All cases showed myocardial involvement of amyloidosis. Histopathologically, the transthyretin type was significantly associated with the interstitial and nodular patterns, and with the absence of the perivascular and endocardial patterns. The AA type was significantly associated with the perivascular and endocardial patterns, and with the absence of the nodular pattern. CONCLUSION: The authors revealed the putative characteristics of cardiac amyloidosis in Japan by using autopsy cases. About 90% of amyloidosis cases were successfully classified using only commercially available antibodies.

DOI： 10.1016/j.prp.2021.153635

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

DOI： 10.3390/jcm10214972

PubMed

背景 非骨化性線維腫は小児から若年成人の長管骨の骨幹端から骨幹部の移行部に好発する良性腫瘍である。今回、左脛骨遠位骨幹部に発生し、骨巨細胞腫との鑑別が困難であった非骨化性線維腫の1例を経験したので報告する。症例 10代女性、2年前から運動後に左踵部からアキレス腱部に疼痛を自覚し、近医にて左脛骨遠位部の骨皮質欠損を指摘され当院紹介。掻把標本の圧挫細胞診では、破骨様多核巨細胞と異型に乏しい単核の紡錘形細胞から構成されており、孤在性、束状から花筵様構造を示した。単核細胞の核は卵円形から短紡錘形で細顆粒状のクロマチンを有し、核小体は不明瞭ないし小型であった。ヘモジデリンの沈着が目立ち、壊死や核分裂像、類骨は認められなかった。以上の細胞所見から非骨化性線維腫や骨巨細胞腫等が鑑別に挙げられた。組織診では細胞診と同様の像を呈しており、免疫染色ではヒストンH3F3A遺伝子変異を認識する特異的なH3G34W、H3G34R、H3G34Vに陰性で、FISHでUSP6 split signalは認められず、Direct SequencingにてKRAS遺伝子変異(p.G12D)が認められたことから非骨化性線維腫と診断された。結語 骨巨細胞腫との鑑別が臨床情報、細胞像からは困難であった非骨化性線維種の1例を経験した。小児から若年成人の骨腫瘍において、破骨様多核巨細胞を伴い単核細胞の束状から花筵様配列が目立つ場合は細胞検体においても形態での鑑別が困難なため、非骨化性線維腫を常に念頭に置き、免疫染色やFISHをはじめとする分子生物学的検索をもって慎重な診断がなされるべきである。(著者抄録)

肝内胆管癌(ICC)患者の転帰と、腫瘍の局所的な免疫状態を反映する炎症マーカーであるリンパ球/C反応性タンパク比(LCR)との関係を検討した。1998～2018年にICCに対して外科的切除を受けた患者78例を、高LCR群(44例)と低LCR群(34例)に分類した。低LCR群では、高LCR群と比較して血清CA19-9値が有意に高く(中央値:20.6 vs.77.3U/mL、p=0.0017)、腫瘍サイズが大きかった(中央値:3.5 vs.5.5cm、p=0.0018)。また、LCRは、腫瘍微小血管密度(r=0.369、P=0.0009)およびCD8+Tリンパ球浸潤(r=0.377、P=0.0007)と有意に相関していたが、FOXP3+Tリンパ球浸潤や腫瘍PD-L1発現とは相関していなかった。さらに、多変量解析により、低LCRは全生存率の悪化と有意に関連していた(p=0.0348)。以上より、低LCRは抗腫瘍免疫反応の低下を反映しており、ICC患者の予後不良を予測することが示唆された。

症例は5ヵ月女児で、生後1ヵ月から両親が腹部膨張を観察しており、生後4ヵ月の定期健康診断で腹部膨張を指摘されていた。自動車事故に遭い、二次救急病院へ搬送され、外傷性腎傷害による出血性ショックが疑われた。その後、当院の三次救急病院に搬送された。腎臓からの出血により出血性ショックとなったため、経カテーテル的動脈塞栓術により止血を行った。外傷の超音波検査やCT検査で左腎に腫瘍と疑われる異常域が認められため、止血術の10日後に潜在的悪性腫瘍と左腎臓を摘出した。病理診断は混合型Wilms腫瘍であった。リンパ節転移や遠隔転移がなかったことから、米国National Wilms Tumor Study Groupの病期分類ステージ1と判断した。そこで、術後化学療法として、ビンクリスチン+アクチノマイシンDを処方した。化学療法による合併症はなかった。治療終了後1年半以上経過した時点で再発はなかった。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

BACKGROUND: Changes in immune cell and inflammation-associated protein levels, either independently or in combination, are commonly used as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of LCR and its relationship to various aspects of the tumor immune microenvironment in patients with intrahepatic cholangiocarcinoma (ICC). METHODS: This was a single-center, retrospective study of patients who underwent surgical resection for ICC between 1998 and 2018. Patients were dichotomized into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. Tumor-infiltrating CD8+ and FOXP3s+ lymphocytes and tumor expression of CD34 and programmed death-ligand 1 were evaluated by immunohistochemical staining of resected tumors. RESULTS: A total of 78 ICC patients were enrolled and assigned to the high (n = 44)- and low (n = 34)-LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly higher serum CA19-9 level (median 20.6 vs. 77.3 U/mL, P = 0.0017) and larger tumor size (median 3.5 vs. 5.5 cm, P = 0.0018). LCR correlated significantly with tumor microvessel density (r = 0.369, P = 0.0009) and CD8+ T lymphocyte infiltration (r = 0.377, P = 0.0007) but not with FOXP3+ T lymphocyte infiltration or tumor PD-L1 expression. Low-LCR status was significantly associated with worse overall survival by multivariate analysis (P = 0.0348). CONCLUSIONS: Low-LCR status may reflect a poor anti-tumor immune response and predict worse outcomes in ICC patients.

DOI： 10.1007/s10147-021-01962-4

PubMed

国際・国内誌：国際誌  

When a tumor and trauma coexist, the treatment strategy must be established while considering their interaction. We herein report a 5-month-old girl with Wilms tumor complicated by blunt renal trauma. She was involved in a traffic accident and had hemorrhagic shock due to renal bleeding. We performed hemostasis by transcatheter arterial embolization. Ten days later, we extirpated the potential malignant tumor and left kidney. We were able to complete the surgery without rupture or major bleeding. Postoperative histopathology confirmed Wilms tumor. In the year since she received postoperative chemotherapy, there has been no recurrence. When we were deciding the treatment strategy, we first had to determine how much the renal trauma had affected the tumor staging. The second issue was when to extirpate the tumor after managing the trauma. There are no standard criteria for such situations at present, so we referred to the criteria concerning the bed rest period in cases of traumatic kidney injury and previous case reports and decided to wait over a week from the injury treatment to perform surgery. As a result, we were able to remove the tumor completely without any rupture or major bleeding.

DOI： 10.1007/s13691-021-00496-w

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity. METHODS AND RESULTS: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases. CONCLUSION: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours.

DOI： 10.1111/his.14393

PubMed

2014年1月～2016年12月にアセチルコリンエステラーゼ(AChE)染色によりヒルシュスプルング病と診断された患者177例のうち、同時にホルマリン固定パラフィン包埋HE染色が行われた患者90例(男性46例、3～73歳)を対象とした後向き研究を実施した。評価項目は病理組織学的所見および診断能とした。その結果、感度、特異度、正確度、kappa indexはAChE染色で94.1%、100%、98.9%、0.964、HE染色で76.5%、84.9%、83.3%、0.530であった。AChE染色では、HE染色と比較して、特異度、正確度、kappa indexが有意に高かった(P<0.001、P<0.001、P<0.05)。HE染色は、初回生検にてtotal colon aganglionosisが疑われた症例の診断に役立った。さらに、HE染色は神経節細胞と肥大した神経束の区別に有用であった。以上のように、ヒルシュスプルング病の診断においてAChE染色はHE染色と比較して優れた正確度を有する診断ツールであることが再確認された。また、HE染色は、診断能力には限界があるが、補助的な方法として有用であった。以上から、AChE染色とHE染色の同時実施が望ましいと考えられた。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

We report the peculiar case of a parosteal osteosarcoma arising beneath the periosteum in a 12-year-old boy. He complained of difficulty in left knee flexion. Plain radiography showed a uniformly dense mineralized mass in the bone cortex and parosteal ossified nodules at the metaphysis and diaphysis of the left distal femur. Periosteal reaction was not evident. Uniquely, plain radiography had a smooth outline and revealed gradually thickening mass toward the center. Histologically, the tumor showed a proliferation of spindle-shaped cells with parallel-oriented dense bone trabeculae and hyaline cartilaginous tissue disclosing mild atypia. The periosteum was inverted along the polypoid mass, but there was no periosteum at the top. Immunohistochemically, the spindle cells, including those at the top of the polypoid mass, and cartilaginous cells were positive for MDM2 and CDK4. MDM2 gene amplification was detected in these cells by fluorescence in situ hybridization. Despite the peculiar feature of plain radiography, the lesion was diagnosed as parosteal osteosarcoma. This case report presents a case of parosteal osteosarcoma arising beneath the periosteum, although it is postulated to arise in the outer layer of the periosteum. The unique radiographic findings in this case suggest an association of parosteal osteosarcoma with vigorous bone growth before closure of the growth plate.

DOI： 10.1007/s00256-021-03747-2

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Acetylcholinesterase (AChE) histochemistry has been widely performed for the histopathological diagnosis of Hirschsprung's disease (HD). However, we occasionally come across diagnostic difficulties. We conducted concurrent AChE histochemistry and hematoxylin and eosin (HE) staining to validate the ancillary value of this technique. METHODS: Of 177 patients diagnosed using AChE histochemistry from January 2014 to December 2016, 90 patients underwent formalin-fixed paraffin-embedded HE staining. The histopathological findings and diagnostic abilities were investigated and compared retrospectively. RESULTS: The sensitivity, specificity, accuracy, and kappa index of AChE histochemistry and HE staining were 94.1%, 100%, 98.9%, and 0.964 and 76.5%, 84.9%, 83.3%, and 0.530, respectively. The specificity, accuracy and kappa index of AChE histochemistry were significantly higher than those of HE staining (P < 0.001, <0.001, and <0.05). Hematoxylin and eosin staining supported the suspected diagnosis of total colon aganglionosis at the initial biopsy; furthermore, HE staining helped confirm the distinct shape of ganglion cells and hypertrophic nerve bundles. CONCLUSION: We re-confirmed that AChE histochemistry is an excellent method for diagnosing HD. Although the diagnostic ability of HE staining is limited, it has acceptable utility as an ancillary method. Thus, AChE staining is a useful test and it should be performed together with HE staining.

DOI： 10.1111/ped.14596

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Graft loss characterized by sudden deterioration after initial favorable recovery of the allograft function within the first week after liver transplantation was reported as "seventh-day syndrome." The outcome of seventh-day syndrome is extremely poor, and its etiology and management are not still established. We herein reported a seventh-day syndrome case who was successfully managed by immediate desensitization after liver retransplantation and reviewed by English literature. A 19-year-old woman who had underwent the first liver transplantation when she was 2-year-old. She developed graft failure due to chronic rejection and was on the waiting list for retransplantation. An evaluation of panel-reactive antibody showed high positivity, but there were no preformed donor-specific antibodies. Plasma exchange was performed one-time just before retransplantation and the mean fluorescence intensity significantly decreased. The second liver was successfully transplanted, and post-operative course was uneventful. However, on post-operative day 5, her body temperature elevated and thereafter, her liver enzymes dramatically elevated. We immediately started a desensitization consisted of plasma exchange, intravenous immunoglobulin, and anti-CD20 antibody. The peak level of AST and ALT was 5799 IU/L and 3960 IU/L, respectively. The pathological findings of liver biopsy revealed some central venous endotheliitis and massive centrilobular hemorrhagic hepatocellular necrosis. These findings were not typical for antibody-mediated rejection, but the desensitization was effective and liver graft was successfully rescued. The only way to prevent early graft loss due to seventh-day syndrome is thought to be an immediate decision to start intensive desensitization.

DOI： 10.1111/petr.13907

PubMed

掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s42399-021-00860-0

その他URL： https://link.springer.com/article/10.1007/s42399-021-00860-0/fulltext.html

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Giant cell tumor of bone (GCTB) is an intermediate malignant bone tumor that is locally aggressive and rarely metastasizes. Denosumab, which is a receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor, can be used to treat GCTB. We focused on potential immunotherapy for GCTB and investigated the tumor microenvironment of GCTB. Programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression and signal-regulatory protein alpha (SIRPα), forkhead box P3 (FOXP3), and cluster of differentiation 8 (CD8) infiltration were assessed by immunohistochemical studies of 137 tumor tissues from 96 patients. Of the naive primary specimens, 28% exhibited PD-L1 expression and 39% exhibited IDO1 expression. There was significantly more SIRPα+, FOXP3+, and CD8+ cell infiltration in PD-L1- and IDO1-positive tumors than in PD-L1- and IDO1-negative tumors. The frequency of PD-L1 expression and SIRPα+ cell infiltration in recurrent lesions treated with denosumab was significantly higher than in primary lesions and recurrent lesions not treated with denosumab. PD-L1 expression and higher SIRPα+ cell infiltration were significantly correlated with shorter recurrence-free survival. PD-L1 and SIRPα immune checkpoint inhibitors may provide clinical benefit in GCTB patients with recurrent lesions after denosumab therapy.

DOI： 10.1038/s41598-021-94022-w

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

We evaluated the prognostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in hepatocellular carcinoma (HCC). Their association with programmed death ligand 1 (PD-L1) expression and vascular formation was further investigated. In this retrospective study, using a database of 418 patients who had undergone 18F-FDG PET/CT before hepatic resection for HCC, immunohistochemical staining of PD-L1, clusters of differentiation (CD) 8, CD68, and CD34 was performed. Patients with a high maximum standardized uptake value (SUVmax) on 18F-FDG PET/CT showed a significantly worse recurrence-free survival (RFS) (hazard ratio [HR]: 1.500; 95% confidence interval [CI]: 1.088-2.069; P = 0.0133) and overall survival (OS) (HR: 2.259; 95% CI: 1.276-4.000; P = 0.0052) than patients with a low SUVmax. Logistic regression analysis showed that a high SUVmax in HCC was significantly associated with PD-L1-positive expression (odds ratio: 4.407; 95% CI: 2.265-8.575; P < 0.0001). SUVmax values of HCC were associated with intratumoral CD8-positive T-cell counts (P = 0.0044) and CD68-positive macrophage counts (P = 0.0061). Stratification based on SUVmax, PD-L1 expression, and the vessels that encapsulate tumor clusters (VETC) status was also significantly associated with RFS and OS. SUVmax, VETC, and PDL1 expression were independently predictive of survival on multivariable analysis. Conclusion: Our large cohort study showed that a high SUVmax on 18F-FDG PET/CT is associated with a poor clinical outcome and PD-L1 expression in patients with HCC. Additionally, stratification of patients based on the combination of SUVmax, PD-L1 expression, and the VETC status predicts poor clinical outcome.

DOI： 10.1002/hep4.1715

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometimes strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was thus to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6 in this disease. MATERIALS AND METHODS: Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. RESULTS: TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had a worse prognosis for overall survival. CONCLUSIONS: UPS showed variation in CMTM6 copy number and CMTM6 expression. CMTM6 expression was significantly correlated with PD-L1 expression, especially with strong PD-L1 expression.

DOI： 10.1007/s00432-021-03616-4

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.

DOI： 10.1016/j.humpath.2021.03.001

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Papillary renal neoplasm with reverse polarity (PRNRP) is a recently proposed entity of renal tumor. It shows a far better prognosis than papillary renal cell carcinoma (PRCC) and frequently has KRAS missense mutation. In this study, we compared 14 cases of PRNRP and 10 cases of PRCC type 1 (PRCC1) and type 2 (PRCC2) from clinical, morphological, immunohistochemical, and molecular biological perspectives. We subjected all PRNRP and PRCC cases to immunohistochemical analysis. Whole-exome sequencing using next-generation sequencing (NGS) was performed for six cases of PRNRP, three cases of PRCC1, and four cases of PRCC2. A search for KRAS gene mutation in the remaining eight cases of PRNRP was performed by polymerase chain reaction (PCR) sequencing. The results showed that all cases of PRNRP were pT1N0M0, none of which followed a course of recurrence or tumor-related death. Immunohistochemical analysis revealed diffuse staining of CK7, EMA, PAX8, and GATA3 but weak or negative staining of CD10, CD15, and AMACR in PRNRP. By NGS and PCR, KRAS missense mutation was detected in 11 of 14 PRNRP cases, although pathogenic KRAS mutation was not observed in PRCC1 and PRCC2. NGS analysis revealed less tumor mutation burden in PRNRP than in PRCC. PRNRP also showed no specific chromosomal copy number abnormalities, including gains of 7 and 17. In conclusion, we propose that PRNRP is a distinct condition from PRCC.

DOI： 10.1016/j.humpath.2021.03.009

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Therapies targeting the immune checkpoint molecules programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) have been explored in various malignant tumours. In this study, we examined the relationship between PDL-1, IDO1 and JAK2 expression and the roles of these signal pathways in soft tissue leiomyosarcoma (LMS). METHODS: The next-generation sequencing data of 53 patients with LMS were obtained from an online public database and were used to assess PD-L1, IDO1 and JAK2 gene amplification and mRNA expression. Then, we determined the relationship between JAK-STAT pathway activation and PD-L1 and IDO1 expression in a LMS cell line. In addition, immunohistochemical staining of 69 cases of LMS was performed for PD-L1, IDO1, TDO2 and phosphorylated JAK2 (pJAK2). RESULTS: Comprehensive gene expression analysis using microarray and RNA-Seq data revealed that PD-L1 and IDO1 mRNA expression positively correlated with JAK2 and STAT1 mRNA expression. Two of the 53 cases exhibited PD-L1 and JAK2 gene amplification; however, they were not related to their gene expression. LMS cell line analysis revealed that IFN-γ supplementation induced IDO1 and PD-L1 expression; these effects were suppressed by JAK inhibition. Immunohistochemical analysis of the resected specimens revealed that TDO2 expression positively correlated with pJAK2 (P = 0.0490) and IDO1 expression (P < 0.0001). PD-L1-positive specimens tended to express pJAK2; however, the relationship did not reach statistical significance (P = 0.1477). CONCLUSION: The results suggest the possible feasibility of the combined inhibition of PD-1/PD-L1 or IDO1 with IFN-γ-JAK-STAT pathway inhibition to treat soft tissue LMS.

DOI： 10.1007/s00432-020-03390-9

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Malignant rhabdoid tumor (MRT) is a rare, highly aggressive sarcoma with an uncertain cell of origin. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is very poor. Novel antitumor agents are needed for MRT patients. Forkhead box transcription factor 1 (FOXM1) is overexpressed and is correlated with the pathogenesis in several human malignancies. In this study, we identified the clinicopathological and prognostic values of the expression of FOXM1 and its roles in the progression of MRT. METHODS: We investigated the FOXM1 expression levels and their clinical significance in 23 MRT specimens using immunohistochemistry and performed clinicopathologic and prognostic analyses. We also demonstrated correlations between the downregulation of FOXM1 and oncological characteristics using small interfering RNA (siRNA) and FOXM1 inhibitor in MRT cell lines. RESULTS: Histopathological analyses revealed that primary renal MRTs showed significantly low FOXM1 protein expression levels (p = 0.032); however, there were no significant differences in other clinicopathological characteristics or the survival rate. FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to chemotherapeutic agents, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines. A cDNA microarray analysis showed that FOXM1 regulated FANCD2 and NBS1, which are key genes for DNA damage repair. CONCLUSION: This study demonstrates that FOXM1 may serve as a promising therapeutic target for MRT.

DOI： 10.1007/s00432-020-03438-w

PubMed

国際・国内誌：国際誌  

DOI： 10.1007/s00432-020-03466-6

PubMed

症例は56歳男性で、腹部超音波検査で偶然発見された、肝腫瘤の精査治療目的で受診した。腹部CT検査で、右胆管に沿った多嚢胞性病変が認められた。内視鏡的胆管膵管造影検査では、総胆管から右胆管まで、鋸歯状の変化が認められた。好酸球増多症はなく、腫瘍マーカーは正常であった。胆管再建を伴う肝右葉切除を施行した。組織学的には、寄生虫卵様構造とシャルコー-ライデン結晶と共に、炎症性細胞浸潤を伴う胆管炎が認められた。追加して施行した血清学的検査で、Fasciola hepatica抗体が陽性であった。以上より、肝蛭症による肝腫瘤と診断した。

症例は72歳女性で、15年前にS状結腸癌および多発性肝転移に対して、切除を受けた既往がある。術後6ヵ月間、補助化学療法が施行された。CEA値が高値であるため施行したCT検査で、肝前区域に70mm、左葉外側区域に6mmの腫瘍が認められた。肝中央2区域切除及び肝部分切除を施行した。病理学的には高分化から中分化腺癌で、CK20陽性、CDX2陽性、CK7陰性であった。更に、免疫組織化学染色により、癌幹細胞マーカーであるCD44およびCD133陽性であることが示された。術後経過は良好であった。

症例は72歳で、炭素イオン線治療後に再発した前立腺癌に対するサルベージ療法を受けるために当院に紹介された。局所再発を確認するため経会陰前立腺生検を行ったところ、13個のコア(左葉)のうち5個にグリソンスコア4～5の腺癌を検出した。外腸骨部と大腿骨部のリンパ節郭清を伴う手術映像を用いたロボット支援によるサルベージ根治的前立腺摘除術を行った。尿道を切開し、神経を温存せずに前立腺を切除した。前立腺摘出後、直腸に損傷はなく、膀胱-尿道吻合を行った。炭素イオン線治療後の癒着や変性にも拘わらず、術前術後の重篤な合併症なく、手術を行うことができた。術後7日目に膀胱造影を行ったところ、膀胱-尿道吻合部からの漏れはなく、尿道カテーテルを抜去した。術後10日目に退院した。

3歳8ヵ月男児。出生時より開口障害を認めた。頭頸部CT・MRI、PET、病理組織各所見より、右側頭下窩のデスモイド型線維腫症(本疾患)と診断した。手術の侵襲の大きさ、放射線治療のリスクを考慮し、定期的な画像検査と慎重な経過観察を行った。1年後のMRIで腫瘍の著明な退縮を認め、開口障害は改善した。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

The clinicopathological features of carcinomas expressing AT-rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD-L1) in HCC are poorly understood. Here, we examined ARID1A and PD-L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD-L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor-associated CD68-positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD-L1, and CD68 was performed. We also analyzed the expression PD-L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha-fetoprotein, high des-gamma-carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD-L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence-free survival, overall survival, and positive PD-L1 expression. Stratification based on ARID1A and PD-L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD-L1 protein expression levels were increased through phosphoinositide 3-kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A-low expression was significantly correlated with high levels of tumor-associated CD68-positive macrophage. Conclusion: Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD-L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti-programmed death 1/PD-L1 antibody therapy.

DOI： 10.1002/hep4.1659

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

Fascioliasis is a parasitic infestation caused by the digenetic trematodes Fasciola hepatica and F. gigantica. It is not commonly seen in developed countries, so diagnosis there is always difficult as a result of confusion with other hepatic or biliary disorders. A 56-year-old man presented at our hospital with a hepatic mass that had been inadvertently discovered by ultrasonography. Abdominal computed tomography revealed a multi-cystic lesion distributed along the branch of the right bile duct. Endoscopic retrograde cholangiopancreatography showed serrated changes ranging from the upper level of the common bile duct to the right hepatic bile duct. Eosinophilia was not observed and tumor marker levels were within normal ranges. Following right lobectomy combined with bile duct reconstruction, a histological examination revealed cholangitis with inflammatory cell infiltration accompanied by parasite egg-like structures and Charcot-Leyden crystals. An additional serologic test was positive for F. hepatica antibodies. A diagnosis of fascioliasis was thus confirmed by histopathology and serology. Fascioliasis should be suspected if imaging findings such as multiple small hypodense lesions in the liver are observed, and serologic tests can be useful for differential diagnosis.

DOI： 10.1007/s12328-021-01339-0

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Salvage radical prostatectomy is a therapeutic option for the biochemical recurrence of prostate cancer after radiotherapy. However, only one case report of salvage radical prostatectomy after carbon ion radiotherapy has been reported. We report a case of salvage robot-assisted radical prostatectomy for local recurrence of prostate cancer after carbon ion radiotherapy with surgical video. Owing to adhesion and degeneration after radiotherapy, difficulties in surgery and post-operative complications have been anticipated. However, surgery was feasible without severe peri- and post-operative complications. Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy may be a reasonable therapeutic option. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-020-00464-w.

DOI： 10.1007/s13691-020-00464-w

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Tumor microvessel density (MVD) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (ICC). Tumor-infiltrating lymphocytes (TILs) are also key components of the tumor microenvironment that play important roles in ICC progression. This study aimed to clarify the relationships between the MVD and immune status and prognosis in patients with ICC. Immunohistochemical staining for cluster of differentiation 34 (CD34), cluster of differentiation 8 (CD8), forkhead box protein P3 (Foxp3), and programmed death-ligand 1 (PD-L1) was performed. The relationships between the MVD and clinicopathological characteristics and outcomes were analyzed. Additionally, the correlations between the MVD, CD8+ and Foxp3+ TIL counts, and PD-L1 expression were evaluated. One hundred ICC patients were classified into high (n = 50) and low (n = 50) MVD groups. The serum platelet and carbohydrate antigen 19-9 levels were higher in the low MVD group than in the high MVD group (P = 0.017 and P = 0.008, respectively). The low MVD group showed a significantly larger tumor size (P = 0.016), more frequent microvascular invasion (P = 0.001), and a higher rate of intrahepatic (P = 0.023) and lymph node (P < 0.001) metastasis than the high MVD group. Moreover, the MVD showed a high positive correlation with CD8+ TILs (r = 0.754, P < 0.001) and a negative correlation with Foxp3+ TILs (r = -0.302, P = 0.003). In contrast, no significant correlation was observed between the MVD and PD-L1 expression in cancer cells (P = 0.817). Patients with low MVDs had a significantly worse prognosis than those with high MVDs. Furthermore, multivariable analyses revealed that a low MVD influenced recurrence-free survival. A decreased intratumoral MVD might predict ICC patient outcomes. Tumor microvessels might be associated with ICC progression, possibly by altering TIL recruitment.

DOI： 10.1038/s41379-020-00702-9

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

No cases of late recurrence of colorectal cancer liver metastasis (CRLM) over 10 years have been reported in the literature. A 72-year-old woman had a surgical history of sigmoid colectomy and partial hepatic resections for sigmoid colon cancer and multiple liver metastases 15 years previously. The patient had been postoperatively treated with chemotherapy for 6 months and was observed regularly with no recurrence. Computed tomography (CT) performed due to high carcinoembryonic antigen (CEA) revealed a tumor of 70 mm in diameter at the anterior segment of the liver and a 6-mm nodule at the left lateral segment. There was no other malignant finding. We performed central bisegmentectomy and partial resection of the liver. Pathological findings showed the tumors to be well to moderately differentiated adenocarcinoma, and positive cytokeratin 20 (CK20) and caudal-type homeobox transcription factor 2 (CDX2) expression with negative expression of cytokeratin 7 (CK7). In addition, the tumors showed cluster of differentiation 44 (CD44) and 133 (CD133) positive signified cancer stem cell immunohistochemically. The postoperative diagnosis was recurrence of hepatic metastasis of sigmoid colon cancer. We report a rare case of late recurrence of CRLM more than 15 years after the primary diagnosis.

DOI： 10.1007/s12328-020-01330-1

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI < 25.0 kg/m2, n = 48) and obesity groups (BMI ≥ 25.0 kg/m2, n = 26), respectively. Serum carbohydrate antigen 19-9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on 18F-FDG PET/CT (n = 46, r = 0.5152). Patients with high 18F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8 + tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3 + TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.

DOI： 10.1038/s41598-021-85186-6

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Synovial sarcoma (SS) is a malignant soft tissue neoplasm that occurs in various parts of the human body, but most commonly affects the extremities. Its diagnosis of synovial sarcoma often requires adjunctive techniques such as immunohistochemical staining and molecular studies, especially for synovial sarcoma at unusual locations. SS at a gastrointestinal location is exceedingly rare. We report here three cases of primary gastric synovial sarcoma. Malignant gastric mesenchymal tumor has many differential diagnoses other than synovial sarcoma, such as gastrointestinal stromal tumor (GIST), leiomyosarcoma, schwannoma, malignant peripheral nerve sheath tumor (MPNST) and so on. In our three cases, using reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing, we detected an SS18-SSX1 fusion gene, which is specific to synovial sarcoma. In addition, we found the reduced expression of SMARCB1/INI1 in the tumor cells in two of the three cases. Through histopathological, immunohistochemical, and molecular analyses, we confirmed the diagnosis of primary gastric synovial sarcoma.

DOI： 10.1016/j.prp.2021.153352

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Hepatocellular carcinoma (HCC) is a common and deadly cancer. The prognosis of HCC is poor and is related to tumor progression. The malignant potential of HCC is regulated by the tumor microenvironment (TME). As cancer-associated fibroblasts (CAFs) help regulate tumor progression, understanding how they function in HCC could improve patient outcomes. The aim of this study was to determine whether specific microRNAs (miRNAs) in exosomes derived from CAFs might be involved in HCC progression. METHODS: MiRNA microarray assay was used to analyze miRNA profiles of exosomes derived from CAFs and normal fibroblasts (NFs) in HCC. Migration and invasion assays were performed to examine the effects of miR-150-3p on HCC in vitro. In addition, the relationships between prognosis of HCC patients and miR-150-3p expression in HCC tissues and plasma exosomes were retrospectively analyzed. RESULTS: MiR-150-3p was significantly reduced in CAFs-derived exosomes, and inhibited HCC migration and invasiveness. MiR-150-3p was transferred from CAFs transfected miR-150-3p to HCC cells through exosomes, and abrogated HCC migration and invasiveness. Furthermore, low miR-150-3p expression in HCC tissues was a significant risk factor for recurrence in HCC patients. More importantly, survival rate in patients with low miR-150-3p levels in plasma exosomes was significantly poor compared with that in patients with high miR-150-3p levels. CONCLUSIONS: Overall, our findings suggest that the loss of antitumoral miR-150-3p in CAFs-derived exosomes greatly promotes HCC progression. Exosomal miR-150-3p is a potential prognostic biomarker, and transferring miR-150-3p-loaded exosomes to HCC cells might become a novel therapeutic option.

DOI： 10.1016/j.ejso.2020.08.002

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a regulator of programmed death ligand 1 (PD-L1), which induces antitumor immunity in several cancers. This study aimed to clarify the relationship between CMTM6 and PD-L1 expression and clinical outcomes in patients with hepatocellular carcinoma (HCC). In total, 259 patients with HCC who had undergone hepatic resection were enrolled. Immunohistochemical staining for CMTM6 and PD-L1 was performed. The relationships between CMTM6 expression and the clinicopathological characteristics and outcomes were analyzed. Additionally, the stabilization of PD-L1 expression and regulation of malignant activities by CMTM6 were examined in vitro. Our patients were divided into high (n = 65, 25.1%) and low (n = 194, 74.9%) CMTM6 expression groups. High CMTM6 expression was significantly associated with malignant aggregates, including poor differentiation (P < 0.0001), microscopic intrahepatic metastasis (P = 0.0369), and multiple intrahepatic recurrences (P = 0.0211). CMTM6 expression was significantly correlated with PD-L1 expression in HCC tissues (P < 0.0001). The patients were classified into three groups: high CMTM6/PD-L1 positive (n = 21), high CMTM6/ PD-L1 negative (n = 44), and low CMTM6 (n = 194) expression pattern groups. Overall survival was significantly different among the three groups (P < 0.0001). Additionally, immunohistochemical double staining revealed that CMTM6 and PD-L1 were co-expressed on HCC cells. In vitro, PD-L1 expression was enhanced at late time points in the presence of CMTM6 expression. CMTM6 also regulated epithelial-to-mesenchymal transition and stemness phenotypes in HCC cells. Conclusion: Our large cohort study found that CMTM6 co-expressed with PD-L1 was strongly associated with the clinical outcome in patients with HCC. The evaluation of CMTM6 combined with PD-L1 in HCC might be useful for patient selection in immune checkpoint therapy.

DOI： 10.1002/hep4.1643

PubMed

症例は60歳男性で、術後再発した肺多形癌に対し、ペムブロリズマブ(200mg/body)+カルボプラチン(AUC5)+ペメトレキセド(500mg/m2)による第一選択治療を受けた。ペムブロリズマブの投与開始から2週間後、手足の指に色の変化が見られ、レイノー現象を示唆する局所的な虚血が認められた。血管拡張薬を処方したが、症状が悪化したため、免疫関連有害事象と判断した。その後、プレドニゾロン(60mg/day)を経口投与したところ、症状は徐々に改善した。その後、両足の皮膚生検を行った。病理学的には、血管周囲にわずかなリンパ球浸潤を伴う動脈血栓症と内皮下に核崩壊を伴う好中球浸潤が認められ、血管炎が示唆された。約3週間後、プレドニゾロン(55mg/day)を経口投与したところ、四肢の動脈血栓症の症状がやや悪化した。さらに、急性腎機能低下(BUN:124.4mg/dl、Cre:7.82mg/dl)が起こり、尿中のβ2-ミクログロブリンが極めて高値となった。その後、3回の血液透析を受け、腎機能は改善した(BUN:30.8mg/dl、Cre:1.32mg/dl)。全身状態も改善し、BUNとCreの値が正常化した後に退院した。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors are becoming more common; however, irAEs involving blood vessels are rare. We report a patient with limb arteriolar vasculitis induced by pembrolizumab plus chemotherapy. He was 60-year-old man who received first-line treatment with pembrolizumab plus chemotherapy for postoperative lung cancer recurrence. Two weeks after the first administration, he experienced Raynaud's phenomenon. We initiated a vasodilator, but his symptoms worsened, and we considered an irAE. We initiated oral prednisolone, and his symptoms gradually improved. A few weeks later, we performed skin biopsies of both of the patient's feet, and pathological examination revealed arteriolar thrombosis with slight perivascular lymphocytic infiltration. Infiltration of neutrophils with karyorrhexis in the subendothelium was also seen. He also developed acute kidney injury, likely owing to thrombosis. Physical examination of bilateral fingers and toes in patients with lung cancer should be performed carefully after administering pembrolizumab therapy.

DOI： 10.1007/s13691-020-00454-y

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Dedifferentiated liposarcoma (DDLPS) is a relatively common soft tissue sarcoma that results from the progression of well-differentiated liposarcoma (WDLPS). This study aimed to investigate the progression process and to clarify the pathological and genetic factors related to poor prognosis in DDLPS. In 32 DDLPS cases and five WDLPS cases, genetic factors were analyzed by custom comparative genomic hybridization (CGH) array, which was designed to densely cover gene regions known to be frequently amplified in WD/DDLPS. The analyses comparing primary and metastatic lesions and those comparing histologically different areas in the same tumor revealed intra-tumoral genetic heterogeneity and progression. According to a prognostic analysis comparing the good-prognosis and the poor-prognosis groups, we selected MDM2 and HMGA2 as candidate genes associated with poor and good prognosis, respectively. The ratios of the amplification or gain levels of MDM2 and HMGA2 expressed in log ratios (log[MDM2/HMGA2] = log[MDM2]-log[HMGA2]) were significantly associated with prognosis. An amplification or gain level of MDM2 that was more than twice that of HMGA2 (MDM2/HMGA2 > 2, log[MDM2/HMGA2] > 1) was strongly related to poor OS (P < .001) and poor distant metastasis-free survival (DMFS) (P < .001). In the pathological analysis of 44 cases of DDLPS, histological tumor grade, cellular atypia, and MDM2 immunoreactivity were related to overall survival (OS), while HMGA2 immunoreactivity tended to be associated with OS. Cellular atypia was also associated with DMFS. In conclusion, histological grade and MDM2 expression were determined to be prognostically important, and the MDM2/HMGA2 amplification or gain ratio was found to have significant prognostic value by the custom CGH array analysis.

DOI： 10.1002/gcc.22899

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

The prognosis of undifferentiated pleomorphic sarcoma (UPS) is generally unfavorable. Recently, clinical trials such as SARC028 demonstrated the utility of cancer immunotherapy for soft tissue sarcomas. The aim of the present study was to assess the expression of PD‑L1 and IDO‑1 as prognostic factors and therapeutic targets. A total of 52 primary UPS cases were retrieved and two UPS cell lines were utilized for supplementary analysis. Immunohistochemical staining of anti‑PD‑L1 (28‑8), IDO‑1, CD8, CD4, CD3, HLA class I, MSH2, MSH6, MLH1 and PMS2 was carried out. Immunohistochemically, 19 of 52 (36.5%) cases showed PD‑L1 expression at least focally (≥1%) and 5 of 52 (9.62%) showed strong PD‑L1 expression (≥50%). Overall, 25 of 52 (48.1%) cases expressed IDO‑1 (≥1%). Two tumors were evaluated as having deficient mismatch repair and six tumors as having the loss of HLA class I. PD‑L1 expression (≥1%) was significantly related to the infiltration of CD8‑ and CD3‑positive lymphocytes, but strong PD‑L1 expression (≥50%) did not present a significant relationship with tumor‑infiltrating lymphocytes. IDO‑1 expression was also associated with CD8‑, CD4‑, and CD3‑positive lymphocytes. In vitro, both PD‑L1 and IDO‑1 were induced by IFN‑γ stimulation. In survival analysis, strong PD‑L1 expression (≥50%) was a significant poor prognostic factor, while IDO‑1 expression (≥1%) was a favorable one. In conclusion, UPS was shown to frequently express PD‑L1 and IDO‑1. It was suggested that PD‑L1 expression (≥50%) and IDO‑1 expression are poor and favorable prognostic factors of UPS patients, respectively.

DOI： 10.3892/or.2020.7837

PubMed

国際・国内誌：国際誌  

We describe a Case of a 74-year-old Japanese man with poorly differentiated carcinoma of the anterior mediastinum. The patient underwent anterior mediastinal tumor resection through median sternotomy. The tumor, 7.0 × 5.0 cm, had invaded surrounding tissues (pericardium, right lung, right and left brachiocephalic veins, and superior vena cava). Complete resection of the tumor was not performed. One month after the operation, the patient developed multiple pulmonary metastases, right pleural dissemination, and carcinomatous pleurisy. He was treated with lenvatinib, a novel multi-kinase inhibitor, to which the metastasis responded favorably. This case reports for the first time the clinical usefulness of lenvatinib for poorly differentiated carcinoma of the anterior mediastinum. Management of side effects by several methods, including suspending use of medication on weekends (called a weekends-off strategy), is another strong argument to continue lenvatinib administration.

DOI： 10.1016/j.rmcr.2021.101477

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND AND AIMS: We investigated the prognostic value of programmed death ligand 1 (PD-L1) expression, tumor-infiltrating CD8-positive T-cell status, and their combination in hepatocellular carcinoma (HCC). Their association with PD-L1 expression and vascular formation was further explored. APPROACH AND RESULTS: Using a database of 387 patients who underwent hepatic resection for HCC, immunohistochemical staining of PD-L1, CD8, and CD34 was performed. Additionally, we undertook an enzyme-linked immunosorbent assay for soluble PD-L1. Compared with patients with HCC and PD-L1-negative expression (n = 311), patients with HCC and PD-L1-positive expression (n = 76) showed significantly worse overall survival (OS; multivariate hazard ratio, 2.502; 95% confidence interval [CI], 1.716-3.649; P < 0.0001). The presence of tumor-infiltrating CD8-positive T cells was significantly correlated with longer OS (multivariate hazard ratio, 0.383; 95% CI, 0.274-0.537; P < 0.0001). Stratification based on PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status was also significantly associated with OS (log-rank, P < 0.0001). HCC with PD-L1-positive expression was significantly correlated with positivity for vessels that encapsulated tumor clusters. Serum PD-L1 levels were significantly higher in the group of patients who had PD-L1-positive expression than in the group of patients who had PD-L1-negative expression (P = 0.0158). CONCLUSIONS: PD-L1 expression in cancer cells was associated with a poor clinical outcome and vascular formation in patients with HCC. Additionally, the combination of PD-L1 expression with tumor-infiltrating CD8-positive T-cell status enabled further classification of patients based on their clinical outcome. Thus, PD-L1 expression in cancer cells and tumor-infiltrating CD8-positive T-cell status might serve as predictive tissue biomarkers.

DOI： 10.1002/hep.31206

PubMed

症例は11歳男児で、急性骨髄性白血病(AML)と診断された。化学療法後に完全寛解し、兄弟から造血幹細胞移植(HCT)を受けたが、5ヵ月後にAMLが再発した。エトポシド、シタラビン、ミトキサントロンから成る導入療法を開始した。15日後に発熱と腹痛が発現した。腹部は柔らかく膨満はみられなかったが、右下腹部に圧痛が認められた。血液検査で好中球減少が確認されたが、CRP、β-Dグルカン、プロカルシトニン値に異常は認められなかった。造影CTにより隣接組織の炎症を伴う虫垂腫大が明らかになった。緊急虫垂切除術後も腹痛は持続した。虫垂病巣には血管と筋層に沿って多くの真菌の菌糸形成が認められた。中隔と分岐角の形態はアスペルギルス属に特徴的であった。先行する真菌感染の証拠はなかったが、病巣の血管に糸状真菌が特定されたことから抗真菌薬をフルコナゾールから治療量のアムホテリシンBリポソーマル製剤に切り替えた。腹痛は消失したが好中球減少は持続した。抗真菌薬をボリコナゾールに変更した。汎真菌プライマーを用いたPCRとシーケンス解析でAspergillus nigerと同定された。抗真菌治療中に症例は2回目のHCTを受け成功した。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

The presence of sarcomatoid or rhabdoid features (which are associated with advanced disease and poor prognosis) is rarely observed in the subtypes of renal cell carcinoma (RCC). The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits including SMARCB1/INI1 (SMARCB1), SMARCA4/BRG1 (SMARCA4), SMARCC1/BAF155 (SMARCC1), and SMARCC2/BAF170 (SMARCC2), can be regarded as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. We analyzed the histological, immunohistochemical, and clinicopathological status in 72 cases of RCC with sarcomatoid or rhabdoid features, focusing on the expression status of the subunits of SWI/SNF chromatin-remodeling complex proteins. Cases with lost or reduced expression were defined as showing aberrant expression. The frequency of aberrant SMARCA4 immunoexpression of a sarcomatoid or rhabdoid component in clear cell RCC (ccRCC) (47/50, 94%) was significantly higher than that in non-ccRCC (4/9, 44%) (p < 0.001). In ccRCC without sarcomatoid or rhabdoid features, aberrant SMARCA4 immunoexpression was observed in 33 of 48 (67%) cases. Immunoreactivities for SMARCB1, SMARCA2, and SMARCC2 were retained in almost all subtypes of RCC. The patients with aberrant SMARCA4 expression in RCC with sarcomatoid or rhabdoid features achieved shorter progression-free survival compared with the patients with retained SMARCA4 expression (all subtypes of RCC, p = 0.0212; ccRCC, p = 0.0265). These results suggest that in ccRCC, aberrant SMARCA4 expression is one of the adverse prognostic factors or a high-grade malignant transforming factor. The evaluation of SMARCA4 immunoexpression may be a useful diagnostic tool to help distinguish ccRCC from non-ccRCC.

DOI： 10.1007/s00428-020-02839-z

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Treatment options for patients presenting with life-threatening splanchnic ischemia, including that of the intestine and liver, could previously only receive salvage surgery and attempted medical revascularization. We propose that urgent liver transplantation (LT) for acute liver failure (ALF) due to massive liver necrosis should be considered as a life-saving treatment. We successfully performed urgent living donor LT for nonocclusive hepatic ischemia accompanied by nonocclusive mesenteric ischemia (NOMI). CASE: An 11-month-old boy with biliary atresia whose jaundice was re-elevated after Kasai portoenterostomy underwent cysto-jejunostomy. Three hours after the uneventful operation, tachycardia, hypotension, and unconsciousness suddenly occurred. Computed tomography revealed whole-liver and massive splenic and focal intestinal ischemia without any vessel occlusion. Urgent LT was performed on postoperative day 3 because intensive therapies, including prostaglandin E1 administration, blood transfusion, and continuous hemodiafiltration, were not effective and the patient had developed life-threatening bradycardia and hypotension. Intraoperative findings included whole-liver necrosis and splenic ischemia and segmental ileal necrosis without any vessel thrombus. LT and necrotic intestinal resections by end-to-end anastomosis were performed. Massive liver necrosis with Gram-positive cocci was histopathologically identified, indicating bacterial translocation due to NOMI. The post-LT course was uneventful, and the neurologic outcomes were uncomplicated. CONCLUSIONS: Urgent LT was successfully completed for ALF with NOMI. LT is the sole treatment for the refractory ALF, and undelayed determination is important to rescue.

DOI： 10.1016/j.transproceed.2020.06.010

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND/AIM: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. MATERIALS AND METHODS: Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen's disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. RESULTS: We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRH-MPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. CONCLUSION: MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.

DOI： 10.21873/anticanres.14642

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Aspergillus is a widespread fungus in the environment, usually invades through the respiratory tract. Invasive aspergillosis is a fatal disseminated infection in immunocompromised hosts. Appendicitis occurs scarcely in patients with leukemia. We report a case of Aspergillus appendicitis that underwent an urgent appendectomy. An 11-year-old boy received the diagnosis of acute myeloid leukemia, because of the bone pain and results of the bone marrow study. He obtained a complete remission after cancer chemotherapy and received peripheral blood stem cell transplantation from a histocompatible sibling. Leukemia relapsed 5 months post-transplant. Induction therapy with etoposide, cytarabine and mitoxantrone was started on Candida prophylaxis. Fifteen days after the end of chemotherapy, he presented with febrile neutropenia and abdominal pain, that did not respond to broad-spectrum antibiotics. Serum levels of C-reactive protein, β-D-glucan and procalcitonin were unremarkable. Computed tomography scan revealed a swollen appendix and the adjacent tissue inflammation. An urgent appendectomy led to a tentative diagnosis of Aspergillus appendicitis based on the histopathological findings of many fungal hyphal forms. Panfungal polymerase chain reaction using DNA extracted from the lesion determined the pathogen of Aspergillus niger. There was no evidence of invasive aspergillosis. During the prolonged anti-fungal therapy, he achieved a remission of leukemia and underwent the second hematopoietic cell transplantation. To our knowledge, Aspergillus appendicitis was reported to occur in 5 leukemia patients. Four of them survived after appendectomy and one died from intestinal perforation. Early surgical intervention is mandatory for a cure of Aspergillus appendicitis in neutropenic patients on Candida prophylaxis.

DOI： 10.1016/j.jiac.2020.07.016

PubMed

症例は75歳男性で、食道癌の治療目的で当院入院となった。上部消化管内視鏡検査ではBarrett型、表在型(0-IIc型)の遠位食道癌として観察され、その生検から食道腺癌であることが明らかになった。CT検査ではリンパ節転移は認められなかったものの、膀胱の右側に19mm大の腫瘍が発見された。そのため膀胱癌も疑い、食道癌に対しては内視鏡的粘膜下層剥離術を、膀胱腫瘍に対しては経尿道的切除術(TURBT)を施行した。切除した食道癌の病理診断は中分化型～低分化型の腺癌(tub2, pT1b(SM), ly0, v0)とされた。その水平方向の断端は陰性、垂直方向断端は陽性であった。この結果から、根治を目指すためには食道切除術とリンパ節郭清を追加施行する必要があることが示されたものの、患者には重症の循環器疾患も存在していたため食道切除術は困難であり、経過観察が選択された。また切除された膀胱腫瘍は尿路上皮癌(Ta, Ly0, v0)に分類された。TURBTから32ヵ月後、膀胱内に多発する腫瘍が発見され膀胱癌再発が疑われた。7個の腫瘍に対しTURBTを再度施行し、その病理診断は低分化型腺癌(tub2)とされた。免疫組織化学の所見は以前に切除された食道癌のものに適合した。食道癌の膀胱内転移と診断し、一次治療としてS-1とオキサリプラチンの併用化学療法を開始した。

小児陰茎尖圭コンジローマの症例を経験したので報告する。症例は6歳男児。外尿道口部の腫瘤を主訴に当科紹介受診された。亀頭先端に乳頭状の腫瘤を認め泌尿器科、皮膚科コンサルトするも、確定診断に至らず、手術目的に入院となり、膀胱鏡検査および腫瘤切除術を施行された。膀胱及び尿管に異常所見を認めず、病理組織検査で尖圭コンジローマの診断となった。術後合併症なく経過していたが、術後4ヵ月経過時に再発を認め、近医で凍結療法が追加された。小児尖圭コンジローマの報告は稀であり、小児外科医にとっては診断が難しい疾患である。小児尖圭コンジローマは悪性腫瘍との鑑別が必要となり得るが、非腫瘍性病変であり、過大な外科療法は不要である。よって、陰茎の腫瘤を認めた際は尖圭コンジローマも鑑別疾患に挙げつつ診断・治療を行い、過剰な侵襲を回避することが望まれる。(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

A 75-year-old man was admitted to our hospital for treatment of esophageal cancer (EC) in March 2017. Esophagogastroduodenoscopy revealed Barrett's esophagus and superficial, distal EC (type 0-IIc). Tumor biopsy showed esophageal adenocarcinoma. Computed tomography revealed no lymph node metastasis but did reveal a 19-mm tumor on the right side of the urinary bladder. Bladder cancer (BC) was also suspected, and the patient underwent endoscopic submucosal dissection for EC and transurethral resection of the bladder tumor. The pathological diagnosis of EC was moderately to poorly differentiated adenocarcinoma (tub2), pT1b (SM), ly0, v0. The pathological horizontal margin was negative and the vertical margin was positive. Additional esophagectomy and lymph node dissection were indicated for curability. Esophagectomy was difficult because the patient had severe cardiovascular disease, so follow-up observation was adopted. BC was classified as urothelial carcinoma Ta, ly0, v0. After 32 months, multiple tumors were found in the bladder, and BC recurrence was suspected. Transurethral resection of the bladder was performed again for seven tumors, and pathological diagnosis was poorly differentiated adenocarcinoma (tub2). The immunohistochemical features matched those of EC. We diagnosed EC metastasis in the urinary bladder. Bladder adenocarcinoma is difficult to distinguish from metastasis from other organs, especially the upper gastrointestinal tract, and cytomorphological features and appropriate clinical history are required.

DOI： 10.1007/s13691-020-00434-2

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: Programmed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunosuppressive proteins known to be associated with poor prognosis in various cancers. However, their expression and clinical relevance in osteosarcoma remain unknown. In this study, the relationships of PD-L1 and IDO1 expression with clinicopathological features and prognosis were explored. METHODS: The expression of PD-L1, IDO1, CD3, CD4, and CD8 in 112 formalin-fixed, paraffin-embedded tumor tissues collected by biopsy or surgical resection from 56 osteosarcoma patients was evaluated immunohistochemically. Moreover, four osteosarcoma cell lines were evaluated for the effects of IFNγ on PD-L1 and IDO1 mRNA expression by real-time reverse-transcription polymerase chain reaction. RESULTS: In pre-neoadjuvant chemotherapy (NAC) primary specimens, 10 cases (17%) showed PD-L1 expression and 12 (21%) showed IDO1 expression. Six of ten cases (60%) with PD-L1 positivity co-expressed IDO1. In post-NAC metastatic lesions, the frequency of immunoexpression of PD-L1 and IDO1 was increased compared with that in pre-NAC specimens. PD-L1 and/or IDO1 expression was not associated with poor prognosis. PD-L1 immunoexpression was significantly associated with the infiltration of CD3+ T cells, CD4+ T cells, and CD8+ T cells; while, IDO1 immunoexpression was significantly associated with the infiltration of CD3+ T cells and CD4+ T cells. In all osteosarcoma cell lines, PD-L1 and IDO1 expression was upregulated by stimulation with IFNγ. CONCLUSION: Our results suggest that the PD-L1 and IDO1 immune checkpoint inhibitors may provide clinical benefit in osteosarcoma patients with metastatic lesions after conventional chemotherapy.

DOI： 10.1007/s00432-020-03242-6

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

PURPOSE: This study examined the expression of programmed cell death-ligand 1 (PD-L1), programmed cell death-ligand 2 (PD-L2), and indoleamine 2,3-dioxygenase-1 (IDO1) in tumor cells and cluster of differentiation 8 (CD8)-positive tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma according to histological subtypes. METHODS: We evaluated PD-L1, PD-L2, and IDO1 expression in tumor cells and CD8-positive TILs in surgically resected specimens from 196 stage 0 or I lung adenocarcinoma patients by immunohistochemical staining. We also examined the relationships between the expression of PD-L1, PD-L2, and IDO1 in tumor cells and the density of CD8-positive TILs and clinical factors. Patients were divided into three groups: A, adenocarcinoma in situ and minimally invasive adenocarcinoma (N = 32); B, lepidic predominant invasive adenocarcinoma (IAD; LPA; N = 66); and C, IAD except for LPA (N = 98). RESULTS: PD-L1 was expressed only in Group C, but not in Groups A or B. The positive ratio of PD-L2 was significantly higher in Group C (63.3%), and that of IDO1 was also significantly higher in Group C (65.3%). The density of CD8-positive TILs was significantly higher in Group C (45 ± 2.4). There was no significant difference between the positive ratios of PD-L2 and IDO1 and the density of CD8-positive TILs in Group A (50.0%, 21.9%, and 36 ± 4.1, respectively) or Group B (60.6%, 25.8%, and 44 ± 3.0, respectively). CONCLUSIONS: No cases in Groups A and B expressed PD-L1. The expression of immune-related factors, especially PD-L1 and IDO1, was significantly associated with Group C. This is the first report of the detailed examination of PD-L1, PD-L2, IDO1, and CD8 expression in lung adenocarcinoma subtypes with lepidic predominant components. Our results could help identify patients who would benefit from perioperative immunotherapy.

DOI： 10.1007/s00432-020-03250-6

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND/OBJECTIVES: 8-Hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and causes transversion mutations and carcinogenesis. 8-OHdG is excision repaired by 8-OHdG DNA glycosylase 1 (OGG1), which is classified as nuclear and mitochondrial subtypes. We aimed to clarify the role of OGG1 in pancreatic ductal adenocarcinoma (PDAC). METHODS: Ninety-two patients with PDAC who had undergone surgical resection at multiple institutions were immunohistochemically analyzed. The OGG1 and 8-OHdG expression levels were scored using the Germann Immunoreactive Score. The cutoff values of OGG1, as well as that of 8-OHdG, were determined. RESULTS: The low nuclear OGG1 expression group (n = 41) showed significantly higher carbohydrate antigen (CA)19-9 (p = 0.026), and higher s-pancreas antigen (SPAN)-1 (p = 0.017) than the high expression group (n = 51). Nuclear OGG1 expression has no effect on the prognosis. The low mitochondrial OGG1 expression group (n = 40) showed higher CA19-9 (p = 0.041), higher SPAN-1 (p = 0.032), and more histological perineural invasion (p = 0.037) than the high expression group (n = 52). The low mitochondrial OGG1 expression group had a significantly shorter recurrence-free survival (p = 0.0080) and overall survival (p = 0.0073) rates. The Cox proportional hazards model revealed that low mitochondrial OGG1 expression is an independent risk factor of the PDAC prognosis. OGG1 expression was negatively correlated with 8-OHdG expression (p = 0.0004), and high 8-OHdG expression shortened the recurrence-free survival of patients with PDAC. CONCLUSIONS: Low mitochondrial OGG1 expression might aggravate the PDAC prognosis.

DOI： 10.1016/j.pan.2020.07.011

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Rectal endometriosis is a rare disease. A definitive diagnosis prior to surgery is often difficult. We encountered a patient with rectal sub-obstructive endometriosis that was treated by robot-assisted laparoscopic low anterior resection. CASE PRESENTATION: A 43-year-old woman visited our hospital with suspected stenosis caused by upper rectal cancer. She had a 2-year history of constipation. We were unable to confirm the diagnosis through detailed examinations, including laparoscopy. Robot-assisted laparoscopic low anterior resection with D3 lymph node dissection was performed for both diagnosis and treatment. The postoperative specimen showed a submucosal tumor. The pathological examination confirmed rectal endometriosis. CONCLUSIONS: We herein describe a rare case of obstructive rectal endometriosis that we were unable to diagnose preoperatively. Robotic surgery was useful in this case, which involved extensive pelvic adhesion.

DOI： 10.1186/s40792-020-00977-9

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国内誌  

An asymptomatic 47-year-old woman was admitted with pleural effusion and pulmonary infiltrates 1 month after ingesting raw wild boar and deer meat. Both her blood and pleural fluid were eosinophilic. Thoracoscopy revealed multiple nodules of the pleura, and biopsy samples of the nodules showed necrosis with epithelioid cell granulomas. An enzyme-linked immunosorbent assay was positive for antibodies against Paragonimus westermani, and the patient was successfully treated with praziquantel. This is the first reported case of pulmonary or pleuropulmonary paragonimiasis where several pleural nodules were observed. The detection of pleural nodules on thoracoscopy can contribute to the prompt and accurate diagnosis of paragonimiasis.

DOI： 10.2169/internalmedicine.4457-20

PubMed

症例は47歳女性で、人間ドックで行ったCTで右肺上葉の浸潤を伴う右胸水を認めたため来院した。1ヵ月前に野生のイノシシと鹿の生肉を摂取していた。海外渡航歴はなかった。血液検査では、好酸球増多と血清免疫グロブリンE高値が判明した。酵素結合免疫吸着法(ELISA)では、Paragonimus westermaniが弱陽性であった。吸引胸水でも好酸球増多を認めた。気管支鏡検査を行ったが、気管支洗浄液中に病原菌は検出されなかった。胸腔鏡検査では、多発性胸膜結節が判明した。結節の生検標本では、類上皮細胞肉芽腫を伴う壊死が認められた。生検標本に卵はなかったが、マイクロプレートELISAでP.westermani抗体が検出されたことから、胸膜肺吸虫症と診断した。胸水ドレナージとプラジカンテル治療が成功した。3ヵ月後、胸水と肺浸潤は改善しており、臨床状態も安定していた。

肝細胞癌(HCC)進行における酸化ストレスとDNA修復機構との関連性について解明するため、HCC切除検体86検体を用いて、免疫化学組織学的に、8-ヒドロキシ-デオキシグアノシン(8-OHdG)ならびにDNA修復酵素である8-OHdGDNAグリコシラーゼ(OGG1)発現を評価した。その結果、8-OHdG高発現が認められた検体では、低発現を示した検体と比べ、血清アスパラギン酸トランスアミナーゼ値と総ビリルビン値が高く、血小板数では低値が示され、組織学的肝硬変や低分化度が高率に認められた。また、肝硬変患者では、8-OHdGおよびOGG1発現において負の相関性が示され、さらに、低OGG1/高8-OHdG発現群患者の予後は、他の発現群患者に比べ予後不良であったことから、低OGG1/高8-OHdG発現が、HCC患者予後に影響を与える因子と考えられた。本報からOGG1と8-OHdG発現パターンを評価することにより、HCC患者予後に関わる重要なバイオマーカーが検出されることが示された。

症例は43歳女性で、上部直腸癌による狭窄疑いにて当院を紹介された。2年前から便秘を呈しており、下血や腹痛はみられず、未経産であり、月経周期は安定していた。臨床検査では貧血や炎症反応はみられず、腹部X線検査で大量の腸内ガス、結腸鏡検査にて上部直腸に全周性の隆起性病変を認めた。隆起した病変部はHouston下弁まで広がり、正常粘膜に覆われていた。内視鏡下生検では非特異的炎症がみられ、注腸造影で表面平滑な狭窄が認められたことから、壁外腫瘤が疑われた。さらに診断的腹腔鏡を行ったところ、腹膜播種や肝転移はみられず、左卵巣にチョコレート嚢胞が生じており、直腸に軽度癒着を認めたが直腸表面や腹壁に子宮内膜は認められなかった。悪性疾患の可能性を否定できず、ロボット補助腹腔鏡下低位前方切除術+D3リンパ節郭清術を行った。術中所見では、直腸左壁は左卵巣および骨盤腔と強固に癒着しており剥離は困難であり、肛門縁から3cmの部位を吻合し、一時的回腸瘻造設術を行った。術後に吻合部漏を生じたが保存的療法にて軽快し、37日目に自宅退院となった。切除標本の組織病理診では多数の子宮内膜腺を有する肥厚した直腸壁の伸展が認められ、粘膜下から漿膜下にかけて間質が存在していた。免疫染色の結果、腺細胞、間質細胞ともにエストロゲン受容体とプロゲステロン受容体に陽性であり、直腸子宮内膜症と診断した。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Hepatocellular carcinoma (HCC) has a poor prognosis in the setting of chronic inflammation and fibrosis, both of which promote nuclear DNA oxidative damage. 8-hydroxy-deoxyguanosine (8-OHdG) DNA glycosylase (OGG1) enhances the repair of 8-OHdG, which is the primary oxidative stress-induced mutation that leads to malignant alterations. This study aims to clarify the relationships between oxidative stress-induced factors and HCC progression. The clinicopathological factors were compared with immunohistochemistry OGG1 and 8-OHdG expressions in 86 resected HCC specimens. High 8-OHdG expression was associated with high serum aspartate transaminase and total bilirubin levels, as well as a low platelet count, compared with low 8-OHdG expression. Histological liver cirrhosis and poor differentiation were more frequent in patients with high 8-OHdG expression than in those with low 8-OHdG expression. The 8-OHdG was negatively correlated with OGG1 expression in HCC patients. Therefore, we classified the patients into two groups, low OGG1/high 8-OHdG group and the other group. The patients with low OGG1/high 8-OHdG expressions had worse prognosis than those with the other expressions. Our results showed that low OGG1/high 8-OHdG expressions in nuclei influence HCC patient outcomes. Evaluating the patterns of OGG1 and 8-OHdG expressions might provide pivotal prognostic biomarkers in patients with HCC.

DOI： 10.1111/pin.12952

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Renal cell carcinoma (RCC) with sarcomatoid changes and rhabdoid features has shown poor outcomes. Several immune checkpoint inhibitors including programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors have been approved for the treatment of RCC. Combination therapy using PD-1/PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors has also been used to treat various malignancies. However, little is known about IDO1 expression and therapeutic effects of the IDO1 inhibitor in RCC. Herein, we retrospectively analyzed the expression of PD-L1/IDO1 and examined its relationship with tumor-infiltrating lymphocyte (TIL) status and prognostic effect. We investigated the PD-L1, IDO1, CD3+, CD4+, and CD8+ immunoexpression status in 60 cases of sarcomatoid/rhabdoid RCC. The PD-L1 and IDO1 results were defined by the tumor proportion score. For the evaluation of TIL status, we counted the number of lymphocytes located in the tumor and averaged the numbers over five high-power fields for each case. The results revealed PD-L1 and IDO1 expression was observed more frequently in the sarcomatoid/rhabdoid component than in the nonsarcomatoid/nonrhabdoid component. The correlation between PD-L1 and IDO1 expression was significant (P = 0.0076). PD-L1 expression and coexpression of PD-L1 and IDO1 were correlated with a high density of CD3+, CD4+, and CD8+ T cells. There was no significant difference in overall survival among the patients with PD-L1 and/or IDO1 expression, but PD-L1 expression and coexpression were related to poor progression-free survival. Our results suggest that combination therapy using the PD-1/PD-L1 inhibitor and IDO1 inhibitor may be effective for treating sarcomatoid/rhabdoid RCC.

DOI： 10.1016/j.humpath.2020.04.003

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

The Akt/mammalian target of rapamycin (mTOR) pathway, which plays an important role in regulating cellular functions including proliferation, motility, and invasion, is known to be activated in many cancers. Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) (cHCC-CC) has wide histological diversity characterized by relatively poor prognosis. Because of a lack of investigation into its molecular mechanisms, no effective systemic therapy is currently available for unresectable cHCC-CC tumors. Here, we retrospectively examined the clinicopathological and activation statuses of the Akt/mTOR pathway in 89 cases of cHCC-CC. Expression levels of molecular markers associated with this signaling pathway, including phosphatase and tensin homologue deleted on chromosome 10 (PTEN), phosphorylated Akt (p-Akt), p-mTOR, p-ribosomal protein S6 (p-S6RP), and p-eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (p-4E-BP1), were measured by immunohistochemical staining. In addition, such activation in different cHCC-CC morphological categories was compared by dividing cases into those with HCC (n = 86), CC (n = 78), and intermediate components (n = 60). Comparison of prognosis among these groups revealed that p-4E-BP1 immunopositivity in cHCC-CC cases containing CC a component was a significant risk factor for poorer overall survival (P = 0.041). By evaluating factors in p-4E-BP1 expression in 78 cHCC-CC cases with a CC component, only lymph node metastasis was significantly correlated with positive immunostaining for p-4E-BP1 (P = 0.0222). In conclusion, p-4E-BP1 expression, especially in cHCC-CC cases with a CC component, was a notable Akt/mTOR pathway-related factor associated with poor prognosis. Assessing histological structure and p-4E-BP1 expression in cHCC-CC may be helpful for both predicting prognosis and using molecular targeted therapy.

DOI： 10.1007/s00428-019-02741-3

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

DOI： 10.1016/j.prp.2020.152969

PubMed

川崎病は,主に乳幼児が罹患する中型血管炎を特徴とする全身性の血管炎である。また,冠動脈瘤を形成することによって予後不良となりうる疾患である。症例は心肺停止にて搬送された6ヵ月,男児。病理解剖の結果,全身の広範な血管炎および冠動脈瘤を認め,川崎病血管炎による突然死と診断した。急激な経過をたどった川崎病血管炎の一剖検例を経験したので報告する。(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND: Liver fibrosis and cancer are serious hepatic complications for patients with congenital heart diseases. We present a rare case of combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) (cHCC-CCA) after the repair of tetralogy of Fallot (TOF). CASE PRESENTATION: A 54-year-old Japanese woman had undergone biventricular repair for TOF at 7 years old. She presented with abdominal distension. Abdominal CT revealed ascites and a 90-mm tumor involving the liver's left lobe. Tumor marker values were: alpha-fetoprotein, 16,208 ng/mL and des-gamma-carboxy prothrombin, 33,920 mAU/mL. The preoperative diagnosis was malignant tumor of the liver (e.g., HCC or intrahepatic CCA). We performed a left lobectomy of the liver. Histopathologically, the tumor was composed of two components growing in trabecular and irregular tubular patterns accompanied by a transitional area; the tumor was diagnosed as cHCC-CCA. The non-cancerous area showed fibrous change mainly surrounding a central vein and sinusoid, expanding toward the portal area without inflammation. CONCLUSIONS: We provide the details of our patient's cHCC-CCA that developed from fibrous congestive liver associated with right-sided heart failure after TOF repair, diagnosed based on histopathological features. We discuss liver fibrosis as a hepatic complication and a careful follow-up maneuver for improving the outcomes of patients with chronic hepatic congestion.

DOI： 10.1016/j.prp.2020.152908

PubMed

症例は13歳女性で、左上背部の腫瘍に気づいて来院した。血液検査およびCT検査にて低リン血症性くる病が判明、血清intact fibroblast growth factor 23(FGF23)は高値を示した。腫瘍切除後、病理組織所見から非悪性のphosphaturic mesenchymal tumor, mixed connective tissue variant(PMT-MCT)に関連した腫瘍性骨軟化症と診断された。その後、血清intact FGF23値に急激な変化は認めなかった。17歳時、左下肢の腫瘍増大により再入院となった。病理組織所見はpleomorphic sarcomaの特徴を示し、リアルタイムPCRにてFGF23陽性、DNAシーケンシングにてTP53変異陽性であった。患肢切断を施行したものの多発転移をきたし、18歳時に死亡に至った。

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

AIMS: Inflammatory myofibroblastic tumour (IMT) is a spindle cell neoplasm of intermediate malignancy, and the diagnosis is often challenging due to the morphological overlap with other spindle cell neoplasms and reactive lesions. More than half of IMTs have the ALK gene rearrangement, and a minor subset have ROS1, NTRK3 or RET gene rearrangements. We sought to determine the potential diagnostic utility of pan-Trk immunohistochemistry for IMTs. METHODS AND RESULTS: We retrospectively examined 40 cases of IMT using immunohistochemistry with a rabbit monoclonal pan-Trk antibody. Gene rearrangement was confirmed by fluorescence in-situ hybridisation and/or reverse transcription-polymerase chain reaction. The IMTs were classified as the ALK (n = 29), ROS1 (n = 2), NTRK3 (n = 2), RET (n = 0) and 'quadruple-negative' (n = 7) genotypes by molecular analyses. Both of the ETV6-NTRK3 fusion-positive cases showed nuclear and cytoplasmic staining for pan-Trk in the majority of tumour cells. None of the ALK, ROS1 or quadruple-negative-type IMTs showed nuclear staining for pan-Trk, but approximately one-third of these IMTs showed focal and weak cytoplasmic staining. One exceptional case of a RANBP2-ALK-positive epithelioid inflammatory myofibroblastic sarcoma (an aggressive variant of IMT) showed moderate cytoplasmic staining for pan-Trk. CONCLUSIONS: These results suggest that pan-Trk immunoreactivity with a nuclear and cytoplasmic staining pattern may be useful to identify ETV6-NTRK3-positive IMTs and may be helpful in selecting patients for Trk-targeted therapy.

DOI： 10.1111/his.14010

PubMed

【はじめに】悪性黒色腫はメラノサイト由来の癌であるが,メラノサイトは発生学的に神経堤由来であることから,神経堤から発生する神経系にもごく稀に悪性黒色腫が発生する.今回,極めて稀な脊髄原発悪性黒色腫の症例を経験したため,報告する.【症例】43歳男性.1年前に歩行不安定感で近医受診するも原因を特定できず,排尿困難が出現し前医を受診.MRIでT1/2高位の硬膜内にT1WIで高信号,T2WIで低信号の腫瘍性病変による脊髄の圧迫を認め,当科紹介となった.排尿障害,左下肢の痛覚低下,軽度の筋力低下による歩容不安定を認めており,腫瘍摘出術(後方固定術併用)を行った.腫瘍は黒色の腫瘍で,脊髄や硬膜,くも膜,神経根に播種と思われる黒い色素沈着を認めたこと,全切除により脊髄損傷の可能性もあるため可及的切除とした.病理診断は悪性黒色腫であり,術後ニボルマブによる化学療法を開始した.術後1年,MRIで腫瘍の増大なく経過している.(著者抄録)

胃癌のうち充実性の低分化型腺癌(PDA)に注目し、ミスマッチ修復(MMR)蛋白質(MLH1、PMS2、MSH2、MSH6)、SWI/SNF複合体サブユニット(ARID1A、INI1、BRG1、BRM、BAF155、BAF170)、EBERの発現状態、およびKRAS、BRAF両遺伝子の変異状態を調べた。充実性PDAの胃癌患者から成るPDA群54名(男性35名、55～90歳)と、その他の組織型の胃癌であった対照群40名(男性34名、53～84歳)について後方視的に比較解析した。対照群に比べてPDA群ではMMR機能の欠乏、およびSWI/SNF複合体サブユニットのうちARID1A、BRG1、BRM、BAF155の欠損がみられた頻度が有意に高かった。その他にも上記の発現状態・変異状態に関し詳細な所見を多く得た。結論として、充実性PDAではMMR蛋白質の欠乏とSWI/SNF複合体の欠乏が頻繁にみられていた。SWI/SNF複合体が欠乏していることで形態的に分化型腺癌から充実性PDAへと遷移する現象が引き起こされる可能性が示唆された。

【背景】Chronic Expanding Hematoma(CEH)はしばしば悪性腫瘍との鑑別が困難となる.今回悪性腫瘍を疑い広範切除術を施行したCEHの一例を経験したので報告する.【症例】50歳男性で,既往歴に特記事項なく,3年前より右大腿外側の腫瘤を自覚した.徐々に増大し,自壊・出血をきたしたため近医を受診し,右大腿部悪性軟部腫瘍が疑われ,当科紹介となった.MRIでT1・2共に低～高信号が混在し,辺縁が不均一に造影されていた.FDG-PETでは辺縁にのみ軽度集積していた.針生検で壊死組織のみを認めたが,経過より悪性腫瘍を疑い広範切除術を行った.切除により広範な皮膚欠損を生じたため,人工真皮で被覆し,術後5週で分層植皮を行った.病理診断はCEHであった.【考察】悪性腫瘍の中には血腫を伴うものも存在し,CEHとの鑑別が困難となる場合が多い.病歴と画像所見をもとに総合的に判断する必要がある.(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid-type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid-type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid-type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid-type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid-type PDAs. In the MMR-deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR-proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid-type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated-type adenocarcinoma to solid-type PDA.

DOI： 10.1111/cas.14301

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Skeletal muscle tumors are classified into rhabdomyoma and embryonal, alveolar, spindle cell/sclerosing and pleomorphic rhabdomyosarcoma according to WHO classifications of tumors. These tumors arise mostly in the head and neck and, in childhood, represent the largest subset of soft tissue tumors. Although these skeletal muscle tumors show common immunoexpression of two myogenic regulatory factors, MyoD1 and myogenin, their molecular biological backgrounds are quite different. Therefore, treatment regimens vary a great deal depending on the histological subtype. Histopathologically, rhabdomyoma is characterized by well-demarcated lesions with no invasion of the surrounding tissue. Embryonal rhabdomyosarcoma is composed of primitive mesenchymal cells in various stages of myogenesis and shows heterogeneous nuclear staining for myogenin. Alveolar rhabdomyosarcoma, on the other hand, shows a proliferation of uniform primitive round cells arranged in alveolar patterns. The tumor cells at the periphery of alveolar structures adhere in a single layer to the fibrous septa. Diffuse and strong nuclear immunoexpression for myogenin is observed. In genetic backgrounds, almost all alveolar rhabdomyosarcomas contain a characteristic fusion gene such as PAX3/7-FOXO1. Spindle cell/sclerosing rhabdomyosarcoma is characterized by fascicularly arranged spindle-shaped cells or dense hyalinized collagenous matrix. NCOR2- or VGLL2-related gene fusions or MYOD1 (p.L122R) mutation is commonly recognized. Epithelioid rhabdomyosarcoma is a rare variant of rhabdomyosarcoma that shows a proliferation of epithelioid tumor cells having large vesicular nuclei, prominent nucleoli, and amphophilic to eosinophilic cytoplasm arranged in sheets. As these characteristic histological and molecular features are present in each subtype, it is possible to diagnose skeletal muscle tumors accurately.

DOI： 10.1007/s12105-019-01113-2

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

BACKGROUND/AIM: Yolk sac tumour (YST) is a rare malignant ovarian germ cell tumour that often occurs in young women or adolescents and exhibits an unfavourable outcome. To evaluate the biological behavior of carcinomas in vitro, permanent tumour cell lines are required. However, previously, only a few human YST cell lines have been established. Therefore, we aimed to establish a novel YST cell line. MATERIALS AND METHODS: We established a novel YST cell line, TC587, from an adolescent patient with ovarian YST. RESULTS: The cell line expressed AFP and SALL4, the characteristics of YST. In addition, we evaluated somatic mutations using next-generation sequencing and revealed some pathogenic variants, including mutations in the NRAS, KIT, KMT2C, RSF1, and TP53 genes. CONCLUSION: The newly established TC587 cell line may represent an effective tool for developing treatments and conducting molecular analyses for YST.

DOI： 10.21873/anticanres.14007

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Sinusitis is a serious infectious complication of allogeneic hematopoietic stem cell transplantation. Schizophyllum commune (S commune) is a common basidiomycete fungus that is rarely involved in human disease. We report herein a case of S commune sinusitis after allogeneic bone marrow transplantation. A 66-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation and developed maxillary and ethmoid sinusitis. The sinusitis did not improve with liposomal amphotericin B after neutrophil engraftment, so we considered that surgical intervention was needed for the recovery of sinusitis. Endoscopic sinus surgery was performed. In the debridement tissue of paranasal mucosa, filamentous fungal elements were observed. Moreover, genetic analysis of the tissue revealed the presence of S commune. Schizophyllum commune should be recognized as a fungal pathogen that causes sinusitis after allogeneic hematopoietic stem cell transplantation. This case suggests the effectiveness of prompt surgical intervention with liposomal amphotericin B treatment for S commune sinusitis and the usefulness of genetic diagnosis for cases under antifungal treatment. (160 words).

DOI： 10.1111/tid.13205

PubMed

47歳、男性。右尿管結石を契機に偶発的に左腎腫瘍を指摘された。左腎腫瘍は造影CTで、早期相で濃染し排泄相で低吸収を呈した。ロボット支援腎部分切除術が施行された。摘出腎に径6.4cmの乳白色を呈する充実性腫瘤を認め、組織学的に淡明細胞型腎細胞癌に類似した領域の他に、好酸性細胞の島状増殖や球状基底膜様物質を認めた。免疫染色で腫瘍細胞はメラノサイトマーカーの他、Cathepsin KやTFEBに陽性であった。さらにFISHでTFEB遺伝子領域の転座が検出された。以上の所見よりTFEB転座型腎細胞癌と診断した。(著者抄録)

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Myxofibrosarcoma (MFS) is a malignant fibroblastic/myofibroblastic neoplasm with the prominent myxoid area. It has the clinical features of frequent local recurrence and occasional distant metastasis. Morphologically, MFS is occasionally difficult to distinguish from undifferentiated pleomorphic sarcoma (UPS), especially in the case of high-grade MFS. Here, we reviewed clinical and histologic data of 162 MFS cases and 43 UPS cases. MFS was distinguished from UPS with the criterion of 10% myxoid area as a cutoff value. Overall, 52 MFS (34.4%) and 9 UPS (20.9%) cases showed local recurrence, 18 MFS (12.2%) and 19 UPS (44.2%) cases developed distant metastasis, and 13 MFS (9.5%) and 14 UPS (32.6%) cases resulted in tumor-related death. Statistically, MFS had a better prognosis than UPS. Moreover, MFS with less myxoid area had a tendency to present a poorer prognosis. FNCLCC grade was a statistically significant prognostic factor (distant metastasis: P=0.0021, tumor-related death: P=0.0021). Cellularity and nuclear atypia had only a statistical tendency for associations with a poorer prognosis. The overall survival rate of MFS after transformation into a UPS-like condition (<10% myxoid area) was close to that of UPS. It was suggested that MFS is a biologically distinct tumor from UPS, and MFS with less myxoid area had a tendency to present a poorer prognosis. We considered that evaluation of the amount of myxoid area, cellularity, and nuclear atypia may be important as prognostic predictors. MFS may become similar to histologic malignancy of UPS in terms of morphology and biology via local recurrence.

DOI： 10.1097/PAS.0000000000001389

PubMed

国際・国内誌：国内誌  

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the TP53 mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.

DOI： 10.1297/cpe.29.69

PubMed

掲載種別：研究論文（学術雑誌）   国際・国内誌：国際誌  

Although hepatoblastoma is the most common pediatric liver cancer, its genetic heterogeneity and therapeutic targets are not well elucidated. Therefore, we conducted a multiomics analysis, including mutatome, DNA methylome, and transcriptome analyses, of 59 hepatoblastoma samples. Based on DNA methylation patterns, hepatoblastoma was classified into three clusters exhibiting remarkable correlation with clinical, histological, and genetic features. Cluster F was largely composed of cases with fetal histology and good outcomes, whereas clusters E1 and E2 corresponded primarily to embryonal/combined histology and poor outcomes. E1 and E2, albeit distinguishable by different patient age distributions, were genetically characterized by hypermethylation of the HNF4A/CEBPA-binding regions, fetal liver-like expression patterns, upregulation of the cell cycle pathway, and overexpression of NQO1 and ODC1. Inhibition of NQO1 and ODC1 in hepatoblastoma cells induced chemosensitization and growth suppression, respectively. Our results provide a comprehensive description of the molecular basis of hepatoblastoma and rational therapeutic strategies for high-risk cases.

DOI： 10.1038/s41698-020-0125-y

PubMed

難治性小児固形腫瘍患者を対象にNCCV Cocktail-1ワクチンの安全性と有効性を評価する非無作為化非盲検第I相臨床試験を行った。本ワクチンは、難治性小児固形腫瘍患者における癌抗原のKOC1、FOXM1、KIF20Aに由来した癌ペプチドのカクテルワクチンである。対象患者12名(男性7名、年齢7～32歳)に皮内接種を毎週実施した。主要評価項目は安全性、副次評価項目は免疫応答(インターフェロン-γを酵素結合免疫スポットアッセイにて評価)および臨床成績(腫瘍縮小と無増悪生存期間)とした。本ワクチンの忍容性は良好であった。臨床的反応としては8週後に患児4名で安定判定が得られ、2名では11ヵ月よりも長く寛解が維持された。

77歳女。既往歴として糖尿病・骨粗鬆症・子宮脱などがあり、近医内科で施行された腹部エコーで膀胱内の腫瘍を指摘され、当科に紹介された。腹部造影CTで膀胱頸部から左側壁にかけて造影効果のある隆起性病変を認めた。骨盤部MRIで膀胱頸部に広基性腫瘍を認め、DWIで高信号、T2WIで低信号を呈した。膀胱鏡検査で膀胱頸部8時に3cm大の隆起性腫瘍を認めた。これらの所見から、膀胱癌の診断で経尿道的膀胱腫瘍切除術を施行し、病理組織所見から膀胱原発MALTリンパ腫と診断した。追加治療は行わず、術後8ヵ月の現在まで転移や再発を疑わせる所見は認めていない。

大腸癌と食道癌の患者を対象とするHLA-A24拘束性およびHLA-A2拘束性の熱ショック蛋白質(HSP)105ペプチドワクチンに関する第I相臨床試験を施行した。今回、その追加研究として、当ワクチンの免疫学的有効性について検討した。大腸癌または食道癌の患者のHLA型に適合するよう上記のいずれかのワクチンを用いた治療を15名ずつに行った。ex vivoおよびin vitroにて酵素結合免疫スポットアッセイを適用し、インターフェロン(IFN)-γを検出することで、誘導されたHSP105特異的な細胞傷害性Tリンパ球(CTL)の評価を行い、その結果と患者の予後との相関性を解析した。その結果、本ワクチンにより全患者30名中15名でHSP105特異的CTLが誘導されたことが確認された。同CTLの誘導は無増悪生存率(ハザード比3.03、95%CI 1.34～6.85)および全生存率(ハザード比2.72、95%CI 1.13～6.52)に対する予測バイオマーカーの候補となることが示された。さらに同CTLは注射された部位(皮膚)だけでなく腫瘍組織でもサイトカインを産生していたことから、同CTLはワクチン接種部位に集積するのみならず腫瘍に浸潤してゆくことも示唆された。

35歳男。10年間嗄声であった。わずかな呼吸困難から近くの病院を受診し、声帯病変が検出された。肉眼的検査では、ポリープ状病変が左声帯に広く付着しており、声腔の2/3を占めていた。窒息を防ぐために病変は内視鏡的に切除され、4ヵ月後には無かった。声帯ポリープが最初に疑われたが、鑑別診断には高分化脂肪肉腫と炎症性筋線維芽細胞腫瘍(IMT)が含まれていた。腫瘍細胞は未分化リンパ腫キナーゼ(ALK)、カルポニンおよびビメンチンに陽性で、他の平滑筋マーカーに陰性であった。蛍光in situハイブリダイゼーションによりALK遺伝子再構成が検出され、5'RACE(rapid amplification of cDNA ends)によりTIMP3-ALK融合が確認された。病変をIMTと診断し、ALKが再構成された星細胞腫瘍と考えられた。

肝臓の孤立性線維性腫瘍(SFT)症例および文献考察を行った。20年前に頭蓋内血管周皮細胞腫に対する手術を受けた49歳女性症例について検討した。倦怠感を主訴とした。腹部CT検査から大型の境界明瞭な腫瘤が肝臓の前区域に示された。腫瘍マーカーの値は基準範囲内であった。肝中央二区域切除術後、試料の組織検査から腫瘍が紡錘細胞および線維芽細胞様の細胞から構成されており、collagenous stromaを伴うことが認められた。免疫組織化学検査で、紡錘細胞はCD34に陰性であったが、STAT6には陽性であった。NAB2-STAT6融合遺伝子が逆転写PCRによって検出された。SFTの診断が組織病理的および遺伝学的に確認された。

症例は2歳男児。小腸型ヒルシュスプルング病の診断で、人工肛門を造設し、在宅静脈栄養管理中であった。2歳6ヵ月時に発熱を主訴に受診しカテーテル関連血流感染の診断で入院した。入院3日目に突然の顔面蒼白、脈拍上昇、腹部膨満を認め出血性ショックとなった。腹部超音波検査で腹水貯留を認め、腹部造影CT検査にて脾破裂と診断し、同日脾動脈塞栓術を施行した。その後、被膜下血腫の増大を認めたため、塞栓術施行後8日目に脾臓摘出術を施行し、脾下極部の被膜裂傷を認めた。経過良好で術後32日目に退院したが、術後3ヵ月時に乏尿、活気不良にて受診した。脾摘後重症感染症の疑いで入院・加療を開始したが、2歳10ヵ月で永眠された。本症例は、小腸型ヒルシュスプルング病に非外傷性脾破裂を併発した稀な症例である。その経過についてまとめ、原疾患と脾破裂の関連やその成因、急変後の初期対応などについて考察し、報告する。(著者抄録)

30歳、男性。急性膵炎の診断で前医に入院し、第2病日に低血糖が出現したが、第4病日より高血糖となりCTで膵全体にまだらな低吸収域が出現した。第8病日に当院に転院となり、ケトアシドーシス発症を契機に劇症1型糖尿病と診断されたが、その際のCTでは低吸収域は消失していた。膵生検では膵島は認められなかった。急性膵炎と低血糖が先行し、膵CT所見の経時的変化を観察しえた非常にまれな劇症1型糖尿病の1例を経験した。(著者抄録)

骨軟部腫瘍や小児がんなどの希少がんは,正確かつ迅速な病理診断が行われていないことが多々ある.一般病理が見慣れない希少がんに遭遇した際には,専門家にコンサルテーションせざるを得ないのが現状である.欧州では,軟部肉腫の病理診断の集約化が確立されている.一方,本邦では人手不足のため,軟部肉腫領域での中央病理診断体制の導入は非現実的であるが,代替案として非定型例や診断困難例のみを肉腫専門病理医にコンサルトするというシステムが提唱されている.また,一般病理医を対象に希少がんの病理診断医の育成事業も行われており,後継者の育成が求められている.(著者抄録)

小児軟部腫瘍は稀なため、病理医・臨床医ともにその診断や治療法の選択に難渋することも少なくない。そのため、病理組織診断の概念や枠組み、それを取り巻く分子生物学的背景についてよく理解しておくことが必要である。現在広く用いられているWHO分類は細胞の分化に基づく組織分類であり、12の項目と3つの悪性度により分類されている。また、解析系の発達により様々な遺伝子異常が判明しており、組織分類に反映されている。しかし、悪性度が異なる腫瘍が同一のキメラ遺伝子を有する例や腫瘍特異的と考えられた遺伝子異常がその他の腫瘍群でも見つかるなど、すべての症例で1対1対応しているわけではない。分子生物学的解析についても、検体採取や解析上のエラーが一定の割合で生じうる。病理診断は時間と戦いでもあるため、解析の妥当性について長時間の検討を許されず、日々の精度管理が重要である。したがって現状では、組織診断を基本線として、分子生物学的解析結果によりエビデンスを補強するというスタイルが大切となる。また、現在小児腫瘍はほぼ全例が中央病理診断されているが、標本の回覧や各施設で行われなかった解析を実施するなど、時間がかかってしまうことも多い。速やかな治療のためには、臨床医が自施設でどの程度の病理学的分子生物学的検討が実施できるかを理解したうえで、どの範囲まで求めるかを病理医と検討しておくことが重要となる。(著者抄録)