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Objective HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. Methods We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. Results We found both IgG-RF(+) and IgG-RF(–) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (–) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(–) subset. We confirmed that these associations were irrespective of ACPA presence. Conclusion We found a unique genetic architecture for IgG-RF(–) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

Objectives Although the SLE Disease Activity Score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs. Methods We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the lupus patient-reported outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA) and physician global assessment (PhGA). Results Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike information criterion, and Bayesian information criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission and categories of disease activity (remission, mild and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC and PhGA, but not SF-36 or PtGA. Conclusion No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs.

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.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.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).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.

Pancreatic fistula is one of the most common and potentially fatal surgical complications after radical gastrectomy. The purpose of this study was to assess the validity of extrapolating the definition of pancreatic fistula by the International Study Group on Pancreatic Surgery to include situations surrounding gastric cancer surgery.The clinicopathological data of 443 patients who underwent elective gastrectomy with suprapancreatic lymph node dissection (D1+, D2, or D2+ dissection) without pancreatic resection were reviewed. The relationship between postoperative pancreas-related complications (PPRC) and laboratory data, including drain fluid amylase levels on postoperative day 1 (dAmy1) and day 3 (dAmy3), were investigated.Twenty-four patients (5.4%) developed PPRC of ≥ grade II according to Clavien-Dindo classification. Among them, 15 patients had dAmy3 levels ≥ 375 IU/L, while all 24 patients had dAmy1 levels ≥ 375 IU/L. None of the patients with dAmy1 levels 375 IU/L developed PPRC. The area under the curve of dAmy1 and dAmy3, calculated by drawing receiver operating characteristic curves, were 0.896 and 0.791, respectively. Univariate and multivariate analyses demonstrated that both dAmy1 and dAmy3 were significant predictors of PPRC; however, dAmy1 (p 0.001) was more strongly correlated with PPRC than dAmy3 (p = 0.049).DAmy1 is more sensitive than dAmy3 as an indicator of pancreatic fistula after gastric cancer surgery.

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.

A 58-year-old man who underwent lower lobectomy of the right lung for primary pulmonary leiomyosarcoma (PPL) 4 years ago presented with epigastric pain and was diagnosed with small bowel intussusception caused by an intestinal mass. Partial resection of the small intestine was performed, and pathological examination revealed metastatic leiomyosarcoma. Masses in the left adrenal gland, subcutaneous tissue of the left upper arm, right pleura, jejunum, right trapezius muscle, and right adrenal gland were subsequently detected in the following 4 years. Resection was performed for each tumor, which was histologically confirmed as metastatic leiomyosarcoma. However, 1 month after the last surgery, multiple systemic metastases were found, thus, he is currently undergoing chemotherapy. The patient has been alive for 8 years and 4 months after the first operation for PPL. PPL is an extremely rare disease with no established treatment strategy for recurrences. Aggressive metastasectomy may be beneficial in selected cases.

Introduction: The drain amylase concentration (dAmy-C) is a useful marker for predicting pancreatic fistula after gastric cancer surgery. However, dAmy-C might be reduced in cases of high drainage volume. Therefore, we hypothesized that we could accurately assess the amount of amylase leaked from the pancreas by multiplying dAmy-C by the daily drainage volume. In this study, we investigated the clinical utility of the amount of drain amylase (A-dAmy: concentration × volume) for predicting pancreatic fistula. We investigated the clinical utility of the combination of dAmy-C and A-dAmy for predicting pancreatic fistula. Methods: We investigated patients who underwent gastrectomy for gastric cancer at Yodogawa Christian Hospital between 2012 and 2020. The optimal cutoff levels of dAmy-C and A-dAmy on postoperative day 1 for predicting Clavien-Dindo (CD) grade II or higher pancreatic fistula was calculated using receiver operating characteristic (ROC) curves. We calculate the positive predictive value and negative predictive value for predicting pancreatic fistula using these cutoff levels. Results: A total of 448 patients were eligible for analysis. Twenty-two patients experienced CD grade II or higher pancreatic fistula. ROC curves identified 1,615 IU/L as the optimal cutoff level of dAmy-C, predicting pancreatic fistula. When the simple cutoff level of dAmy-C was 1,600 IU/L, the positive predictive value for was 22.8%, and the negative predictive value was 99.7%. ROC curves identified 177.52 IU as the optimal cutoff level of A-dAmy predicting pancreatic fistula. When the simple cutoff level of A-dAmy was 177 IU, the positive predictive value was 21.2%, and the negative predictive value was 99.7%. Using these two cutoff levels together, the positive predictive value was 34.4%, and the negative predictive value was 99.7%. Conclusion: A-dAmy could predict and exclude pancreatic fistula after gastrectomy as with dAmy-C. The combination of dAmy-C and A-dAmy predict pancreatic fistula more accurately than dAmy-C alone.

Objectives Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index in SLE patients. Methods This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral bone mineral density was measured with dual-energy X-ray absorptiometry, and the presence of vertebral fractures was determined using X-ray, computed tomography, or magnetic resonance imaging. Results On multiple regression analysis, both high lumbar and femoral T-scores were associated with the concomitant use of hydroxychloroquine (P = .018 and P = .037, respectively), no use of bisphosphonate or denosumab (P = .004 and P = .038, respectively), high body mass index (P Conclusion Vertebral fracture was associated with SLE-associated organ damage, and serum bone-specific alkaline phosphatase level is a potentially useful marker for osteoporosis monitoring in SLE patients.

The application of a load on the internal fixation of a trochanteric fracture exerts a moment along the lag screw, causing the proximal bone fragment to slide along the lag screw, allowing contact between the proximal and distal bone fragments, which promotes healing. However, excessive sliding is related to poor postoperative outcomes. We aimed to identify the risk factors for excessive sliding.We conducted a multicenter retrospective study including 115 trochanteric fractures sustained through low-energy trauma in 19 male and 96 female patients aged 60 years or older (mean age: 82.9 years) between September 2013 and December 2014. We measured the postoperative sliding distance after osteosynthesis using a sliding hip screw or intramedullary nailing, and classified participants with ≥8 mm of sliding into the excessive sliding group (ESG) and with8 mm into non-ESG. Finally, we investigated the risk factors of excessive postoperative sliding.Fifty participants were classified into the ESG and 65 participants into the non-ESG. Female sex (p = 0.0264), an A3 fracture type (p = 0.0003), greater tip-apex distance (p = 0.0250), and poor reduction in either the anteroposterior or lateral radiographic views (p = 0.0156) were identified as risk factors for excessive sliding by multivariate regression analysis.Female sex, an unstable fracture type, a greater tip-apex distance, and a poor reduction, in either the anteroposterior or lateral views, are associated with excessive postoperative sliding. Therefore, surgery should aim to achieve good reduction and stabilization from both radiographic views.

Objectives The present study aimed to clarify comprehensive relationships among the clinical variables of systemic lupus erythematosus (SLE). Methods We retrospectively surveyed 32 clinical variables in 581 patients and conducted comprehensive association studies among SLE clinical phenotypes. A univariate analysis of all possible combinations was performed, and the results of phenotypic correlations were reduced into two dimensions. We also created a regression formula using L1 regularisation (LASSO) to calculate the probability of exhibiting each phenotype. Results The univariate analysis identified 26 correlations, including multiple phenotypes with low complement. Some unpredicted correlations were identified, including fever and the anti-Sm antibody (odds ratio; OR = 2.3, p = 1.6 × 10–5) or thrombocytopenia and psychosis (OR = 3.7, p = 3.2 × 10–5). The multivariate analysis accurately estimated the probability of exhibiting each phenotype (area under the curve > 0.7) in 10 out of 20 phenotypes. Conclusions The present results show the phenotypic architecture of SLE and represent a model for estimating the probability of exhibiting each phenotype. They also offer insights into the pathology of SLE and estimating the probability of the onset of new phenotypes in clinical practice.

HLA-B*52 is an established genetic factor in Takayasu arteritis (TAK). Recently, single nucleotide polymorphisms (SNPs) in IL12B (rs6871626) and LILRA3 (rs103294) were newly identified as non-HLA susceptibility loci in TAK. Here, we examined how these SNPs contribute to clinical characteristics and vascular damage in TAK. We retrospectively reviewed the medical records of 99 TAK patients enrolled in our previous genome-wide association study, and whose genotypes for IL12B rs6871626, LILRA3 rs103294, and HLA-B*52 were available. Incidence of aortic regurgitation (AR) was significantly associated with the A allele (risk allele) of IL12B rs6871626 (CC 42%, AC 61%, AA 81%; p = 0.0052; odds ratio [OR] 2.45), as well as with the incidence of hypertension (p = 0.049; OR 1.82) and the proportion of patients who underwent aortic valve replacement (p = 0.023; OR 3.64). Regarding vascular damage, there was positive correlation between the Takayasu Arteritis Damage Score and the A allele of IL12B rs6871626 (CC 3.42 ± 2.71, AC 4.06 ± 3.25, AA 6.00 ± 2.81; p = 0.0035; β = 1.35) and between the Vasculitis Damage Index and the A allele (CC 3.47 ± 1.98, AC 4.33 ± 2.40, AA 5.37 ± 2.22; p = 0.0054; β = 0.96). Contrarily, no correlation was found between LILRA3 rs103294 and vascular damage. In the present study, IL12B rs6871626 was associated with vascular damage in TAK, whereas LILRA3 rs103294 was not. Genotyping of IL12B rs6871626 may help to identify patients at risk of disease progression.

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.

AimsDedifferentiation 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.MethodsClinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed.ResultsThe 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%).ConclusionsThe 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.

AimsLiposarcoma 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.MethodsIn 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.ResultsOf 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 pConclusionsPLIN1 and ADRP expression is associated with poor prognosis in high-grade liposarcoma.

Objective The systemic lupus erythematosus (SLE) symptom checklist (SSC) is a patient-reported outcome measure consisting of 38 queries. We translated SSC into Japanese and attempted to validate its usefulness for evaluating the quality of life (QOL) of SLE patients and identify factors that affect QOL. Methods Data from the Medical Outcomes Study Short-form 36 questionnaire (SF-36), Japanese LupusPRO, the Japanese version of the SSC (SSC-J) questionnaire, SLEDAI-2k, and the physician global assessment (PGA) were obtained on the same day from 226 SLE outpatients of the Kyoto Lupus cohort at Kyoto University Hospital. Relationships between the total scores or each item of SSC-J and SF-36, Japanese LupusPRO, SLEDAI-2k, or PGA were analyzed by Spearman’s rank test. Results The total scores of SSC-J correlated with the scores of SF-36 and Japanese LupusPRO. In each item of SSC-J, all 38 items correlated with the physical component summary and mental component summary of SF-36 as well as the Health-Related QOL (HRQOL) scores of Japanese LupusPRO, but not with the non-HRQOL of LupusPRO. SSC-J scores correlated with age, PGA, and corticosteroid doses, but not with SLEDAI-2k. Conclusions SSC-J is suitable as a disease-specific QOL assessment tool for SLE.

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.

A 43-year-old woman was suffering from epigastric pain. Her gastroscopy revealed polyposis of the stomach, and her biopsy revealed a hyperplastic polyp. During the 18-month follow-up, the polyps proliferated, and the patient was referred to our institute for further investigation and treatment. A juvenile gastric polyposis diagnosis was made. She refused to have the surgery despite the fact that it was necessary due to the anemia and hypoalbuminemia she was experiencing. Endoscopic biopsy results revealed gastric cancer at a follow-up visit 2 years and 3 months later; thus, a laparoscopic total gastrectomy was performed. Pathological examination revealed adenocarcinomas that were scattered and well-differentiated, with hyperplastic polyps in the background. No lymph node metastasis was found. Despite the fact that juvenile gastric polyposis is a pathologically benign disease, there have been numerous case reports of surgery being performed due to anemia, hypoalbuminemia, or gastric cancer associated with the disease. When gastric cancers are discovered in cases of juvenile gastric polyposis, they are usually in an early stage, making them a good candidate for laparoscopic total gastrectomy.

Melanin influences light reflection and absorption and is known to be one of the elements producing structural color, such as that in the feathers of birds. In this study, we used polydopamine (PDA), an artificial melanin, as a light-absorbing material and examined in detail the effect of its composite method on the structural color. The following two composite methods were investigated using cerium(IV) oxide (CeO2) particles as a core particle: binary coassembly of CeO2 and PDA particles and unary assembly of CeO2@PDA core-shell particles. Although both methods dramatically improved the visibility of the structural color by suppressing the scattered light owing to the light absorption capability of the PDA, there was a difference in the particle arrangement, angle dependence of the structural color, and color tone change. By selecting the PDA composite method, the guidelines for providing high visibility and the desired structural color were presented.

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. 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. 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. 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.

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.

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7-30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and β-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not significantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.