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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.

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.

Objective eribulin, an anticancer agent that inhibits microtubule growth, along with trabectedin and pazopanib, has been approved for the treatment of advanced soft tissue sarcoma (STS). However, there has been no consensus on the optimal second-line therapy among these three agents following treatment failure with doxorubicin. Recently, the effects of eribulin on the tumor microenvironment and immunity have been reported in breast cancer, and peripheral blood immune markers have also been reported to be a predictor of eribulin efficacy, though this remains unverified in STS. We aimed to evaluate the predictive value of various peripheral blood immune markers in STS patients treated with eribulin. Methods we retrospectively reviewed the medical records of STS patients treated with eribulin and examined whether peripheral blood immune markers at different time points could be prognostic factors for STS patients treated with eribulin. Results several peripheral blood immune markers were significantly associated with progression-free survival (PFS), specifically neutrophil-to-lymphocyte ratio (NLR) prestart (NLR before the initial administration of eribulin) (P = 0.019) and absolute lymphocyte count (ALC)8D (ALC on Day 8 of the first administration of eribulin) (P = 0.037). NLR prestart (P = 0.001) was significantly associated with overall survival. The combination of NLR prestart and ALC8D determined the PFS of STS patients treated with eribulin. Conclusions the combined indicator of low NLR prestart and high ALC8D predicted the survival of patients treated with eribulin as well as the histology of L-sarcoma. Though further validation was needed, this finding would provide valuable prognostic factor that help treatment decision in the absence of consensus on the optimal second-line therapy following doxorubicin treatment in STS patients.

Giant cell tumour of bone (GCTB) is genetically characterised by an H3F3A mutation. GCTB is treated with curettage or resection, and denosumab may be administered. Herein, we retrospectively analysed a large cohort of GCTB and identified a previously uncharacterised distinct blue matrix. Among 127 archival GCTB cases positive for the H3F3A G34 mutation, a blue lacy matrix was observed in 10 cases (7.9%). Five patients were previously treated with denosumab. Although a focal observation, the matrix was multifocal or relatively conspicuous in a subset. It appeared as blue mottles or bands, in which a delicate meshwork of basophilic, focally calcified, lacy material intricately surrounded the H3.3 G34W-positive mononuclear cells. The matrix was associated with depletion of osteoclast-like giant cells and fascicular proliferation of spindle cells, regardless of the history of denosumab therapy. Recognising this unique matrix will help avoid confusion with other bone tumours with different clinical management.

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.

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.

Background We present a case of pancreatic and splenic metastases following alveolar soft part sarcoma (ASPS), which was successfully treated by surgery. Case presentation A 41-year-old male was referred to our hospital in 2012. Computed tomography (CT) showed the presence of a pancreatic tumor. In 2002, the patient had undergone surgical resection of an ASPS of the anal region. In 2009, during follow-up, CT revealed lung metastases, which prompted surgical resection of the lung, followed by resection of the head skin in 2011. Abdominal ultrasonography (US) revealed the presence of isodense masses sized 34 mm in the pancreatic head and 60 mm within the spleen. The contrast-enhanced US revealed a solitary lesion with enhancement. Contrast-enhanced CT revealed solitary lesions with enhancement within the pancreatic head, spleen, and liver. The patient underwent metastasectomies from the pancreas, spleen, and liver. The patient was discharged on postoperative day 22 without recurrence for 18 months after metastasectomy. Twelve years after primary resection and 2 years after metastasectomy, the patient died as a consequence of multiple metastases. Conclusions We have presented a rare case of pancreatic and spleen metastases from ASPS. Resection by radical metastasectomy was successful without morbidity. Thus, for improved survival of patients with multiple metastases from ASPS, metastasectomy may be indicated. If multiple metastases are resectable, surgical approaches may be the preferred treatment.

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.

Giant cell tumor of bone (GCTB) is a locally aggressive bone tumor that frequently shows local recurrence and occasionally shows malignant transformation to high-grade sarcoma. Histologically, conventional GCTB is composed mainly of three types of cells: mononuclear neoplastic cells with an osteoblastic precursor phenotype, mononuclear histiocytic cells, and osteoclast-like multinucleated giant cells. These cells interact with each other via the RANKL-RANK axis and other mechanisms for tumor formation. The vast majority of GCTBs were recently revealed to harbor H3F3A p.G34W mutation, and a minor subset have H3F3A p.G34L, p.G34M, p.G34R, or p.G34V mutation. H3.3 G34W mutant-specific immunohistochemistry is a highly sensitive and specific surrogate marker for H3F3A p.G34W mutation in GCTB and thus useful for differential diagnoses of histological mimics. H3.3 mutant-specific immunohistochemistry has also contributed to the understanding of the bone-forming ability of neoplastic cells of GCTB and the remarkable new bone formation after treatment with denosumab, an inhibitor of RANKL. In primary and secondary malignant GCTBs, the H3F3A gene allele can be preserved or lost with malignant transformation.

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.

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.

The yips, an involuntary movement impediment that affects performance in skilled athletes, is commonly described as a form of task-specific focal dystonia or as a disorder lying on a continuum with focal dystonia at one end (neurological) and chocking under pressure at the other (psychological). However, its etiology has been remained to be elucidated. In order to understand sensorimotor cortical activity associated with this movement disorder, we examined electroencephalographic oscillations over the bilateral sensorimotor areas during a precision force task in athletes with yips, and compared them with age-, sex-, and years of experience-matched controls. Alpha-band event-related desynchronization (ERD), that occurs during movement execution, was greater in athlete with yips as compared to controls when increasing force output to match a target but not when adjusting the force at around the target. Event-related synchronization that occurs after movement termination was also greater in athletes with yips. There was no significant difference in task performance between groups. The enhanced ERD is suggested to be attributed to dysfunction of inhibitory system or increased allocation of attention to the body part used during the task. Our findings indicate that sensorimotor cortical oscillatory response is increased during movement initiation in athletes with yips.

Solitary fibrous tumor (SFT) is a soft-tissue neoplasm of intermediate malignant potential, presenting a wide histopathological spectrum. Poorer prognosis of hemangiopericytoma of the central nervous system (CNS), hypoglycemic SFT, and dedifferentiation are well-known characters of SFT, but their clinical significance were not demonstrated enough by large-sized study. Here, the clinicopathological features of SFTs are reviewed and the relationship between genetics and clinicopathological features is examined using 145 SFT cases. All cases were STAT6 IHC-positive and/or NAB2-STAT6 fusion gene-positive. Tumor location was classified into three categories: 30 pleuropulmonary, 96 non-pleuropulmonary/non-central nervous system (CNS), and 18 CNS tumors. The tumor developed recurrence in 21 of 93 available cases (22.5%), metastasis in 11 of 93 (11.8%), and tumor death in 9 of 93 (9.6%). Hypoglycemia occurred in 2 primary tumors and 1 metastatic tumor among 63 reviewable cases, and dedifferentiation occurred in 10 cases (6.8%) including 6 primary tumors, 2 recurrent tumors, and 2 metastatic tumors. Recurrence was positively associated with CNS location (p = 0.0109) and hypoglycemia (p = 0.001); metastasis was positively associated with CNS location (p = 0.0231), hypoglycemia (p

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, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still 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 to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. 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 worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

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. 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. 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. 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.

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.

This paper proposes a method of underwater depth estimation from an orthographic multispectral image. In accordance with Snell’s law, incoming light is refracted when it enters the water surface, and its directions are determined by the refractive index and the normals of the water surface. The refractive index is wavelength-dependent, and this leads to some disparity between images taken at different wavelengths. Given the camera orientation and the refractive index of a medium such as water, our approach can reconstruct the underwater scene with unknown water surface from the disparity observed in images taken at different wavelengths. We verified the effectiveness of our method through simulations and real experiments on various scenes.

Objectives The multidrug regimen with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is widely used for recurrent pancreatic cancer after pancreatic resection. However, there are concerns about severe toxicities and poor tolerability of FOLFIRINOX in these patients because some suffer from surgery-associated malnutrition, weight loss, and diabetes mellitus. We evaluated the toxicity and tolerability of FOLFIRINOX in these patients. Methods This study was conducted as a secondary analysis of the Japan Adjuvant Study Group of Pancreatic Cancer 06 study, which was a multicenter observational study of FOLFIRINOX for pancreatic cancer in Japan. The toxicity and tolerability of FOLFIRINOX in recurrent disease correlated with those of both the locally advanced and the metastatic disease group. Results The major grades 3 and 4 toxicities observed in the recurrent and locally advanced or metastatic disease groups were neutropenia (68% vs 63%), febrile neutropenia (4% vs 15%, P = 0.007), thrombocytopenia (4% vs 3%), diarrhea (4% vs 8%), and sensory neuropathy (0% vs 2%). The dose modification and relative dose intensity did not differ markedly between the groups. Conclusions The toxicity and tolerability of FOLFIRINOX for recurrence after pancreatic resection were similar to those for locally advanced or metastatic disease with appropriate patient selection and dose modifications.

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.

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). 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). 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

Background Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study—a nationwide, multicenter, observational study—FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice. Methods We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings. Results Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients’ characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2–19.1) months and 6 cycles (range, 1–13 or more), respectively. The major grade 3/4 adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2–13.3), 4.1 (95% CI, 2.6–5.5) months, and 30%, respectively. Conclusion Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

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.

Summary 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.

BACKGROUND Lymph node metastasis is an important prognostic factor for distal bile duct cancer. The number of lymph node metastases was adopted for nodal classification. However, different cutoff values have been proposed, ranging from two to five. METHODS A total of 1748 cases who underwent curative surgery with pancreatoduodenectomy for distal bile duct cancer registered in the nationwide biliary tract cancer registry in Japan from 2008 to 2013 were included. Univariate Cox regression was performed to assess the effect of prognostic lymph node metastasis counts on mortality and to determine cutoff values. RESULTS The overall survival rate after resection was 47.4% at 5 years. Univariate and multivariate analysis found prognostic factors to include lymph node metastasis. The cutoff point was set to two lymph node metastases using the Cox model. There were significant differences in pairwise comparisons between three groups by the number of metastatic lymph node (P

The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 43 patients of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 19 (44.2%) complete and 12 (27.9%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased.

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.

This paper proposes a method to estimate depth from a single multispectral image by using a lens property known as chromatic aberration. Chromatic aberration causes light passing through a lens to be refracted depending on the wavelength. The refraction causes the angle of rays to vary depending on their wavelength and a change in focal length, which leads to a defocus blur for different wavelengths. We propose a theory to recover a continuous depth map from the blur in a single multispectral image that includes chromatic aberration. The proposed method needs only a standard wide-aperture lens, which naturally exhibits chromatic aberration, and a multispectral camera. Moreover, we use a simple yet effective depth-of-field synthesis method to calculate the derivatives and obtain all-in-focus images necessary to approximate spectral derivatives. We verified the effectiveness of the proposed method on various real-world scenes.

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 (

This paper proposes a method for depth estimation from a single multispectral image by using a lens property known as a chromatic aberration. The chromatic aberration cause that the light passing through the lens is refracted depending on the wavelength. The refraction cause that rays vary their angle depending on the wavelength and generate a change in focal length which leads to a defocus blur for different wavelengths.We show that the chromatic aberration provides clues to recover depth maps from a single multispectral image if we assume that the defocus blur is Gaussian. The proposed method needs only a standard wide-aperture lens which naturally exhibits the chromatic aberration and a multispectral camera. Moreover, we use a simple yet effective depth of field synthesis method to calculate the derivatives and obtain all-in-focus images necessary to approximate spectral derivatives. We verified the effectiveness of the proposed method on various real-world scenes.

Background The present study analyzed biliary tract cancer patients registered from 2008 to 2013 in Japan and evaluated the outcomes of biliary tract cancer. Methods A total of 18,606 patients were registered from 2008 to 2013. Cases were analyzed with regard to patient survival according to contiguous extent of the primary tumor (T), node metastasis, and tumor stage using the 3rd English edition of the Japanese classification of the biliary tract cancers. Results Five-year survival rates were 39.8% for gallbladder cancer, 24.2% for perihilar bile duct cancer, 39.1% for distal bile duct cancer, and 61.3% for ampullary region cancer. Significant differences were observed between newly introduced subdivisions in the new Japanese classification for all tumoral sites except gallbladder cancer. The survival rate in patients with #13a metastasis was significantly higher than in patients with distant lymph node metastasis. Conclusions The new Japanese classification adopted the 7th edition of staging system developed by the Union for International Cancer Control staging system. However, numerous aspects of these classification systems remain unvalidated. The present analysis demonstrated the significance of a proportion of T factor subdivisions and classifications of regional lymph nodes in cases of gallbladder cancer in the new Japanese classification.

Chemotherapywith TAS-102 with bevacizumab(Bmab)is a new treatment for metastatic colorectal cancer. A 67-year-old male patient with synchronous multiple liver metastases was treated with TAS-102 with Bmab as a fifth-line chemotherapy. It was demonstrated that liver metastases decreased in size by1 3%bycomputed tomography(CT)after 3 months of TAS-102 with Bmab therapy. The Grade 3 or worst adverse event that was experienced was neutropenia. The patient was able to continue treatment with TAS-102 with Bmab for 6 months. TAS-102 with Bmab treatment was safetyand efficacious as a late-line chemotherapytreatment for metastatic colorectal cancer.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. PBM can be diagnosed if the pancreaticobiliary junction outside the wall is shown in multi-planar reconstruction images provided by multidetector row computed tomography (MD-CT). A total of 29 cases were diagnosed with PBM by MD-CT. Three studies have investigated the capability of MD-CT to diagnose PBM, including the present study. These studies reported only a few cases ranging from 9 to 46 cases. The detection rate for PBM lesion is 100% in adults and 19.5% in children.

Phosphaturic mesenchymal tumour, mixed connective tissue variant (PMT-MCT), is a tumour of uncertain differentiation, characterised by 'smudgy/grungy' calcification and vitamin D-resistant phosphaturic osteomalacia. Fibroblast growth factor (FGF)23 is recognised as a reliable marker of PMT-MCT, but quantitative evaluation has never been performed. We reviewed cases of tumour-associated osteomalacia or histologically definitive PMT-MCT without osteomalacia using histological, immunohistochemical and genetic methods and evaluated the diagnostic significance of these findings.A total of 19 tumours from 14 cases diagnosed previously as PMT-MCT were retrieved, on which immunohistochemical staining, reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridisation (FISH) analysis were performed. Histologically, fibrous capsule, calcification and giant cell reaction tended to be observed in soft-tissue PMT-MCT, while PMT-MCT of bone and multiple PMT-MCT showed an infiltrative growth pattern. The immunohistochemical results were as follows: the tumour cells were positive for FGF23 (nine of 12, 75%), FGFR1 (11 of 11, 100%), CD56 (12 of 14, 85.7%) and E26 oncogene homologue (ERG) (5 of 13, 38.4%). The sole malignant tumour was positive for p53. FGF23 mRNA was detected in seven of 14 formalin-fixed paraffin-embedded (FFPE) specimens and all five frozen specimens by RT-PCR. The level of FGF23 mRNA, which was determined by real-time PCR, varied among the phosphaturic cases. Two of 17 tumours were positive for FGFR1 gene rearrangement.It was considered that PMT-MCT is a histopathological entity with or without phosphaturia, with varying levels of FGF23 mRNA, and with or without fibronectin 1 (FN1)-FGFR1 fusion gene. The authors propose that the histology of PMT-MCT differs depending on its location, such as bone or soft tissue, which could complicate the differential diagnosis.

Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. However, their limited in vitro lifespan in culture systems hinders their therapeutic application. Some somatic stem cells, including hADMPCs, are known to be localized in hypoxic regions; thus, hypoxia may be beneficial for ex vivo culture of these stem cells. These cells exhibit a high level of glycolytic metabolism in the presence of high oxygen levels and further increase their glycolysis rate under hypoxia. However, the physiological role of glycolytic activation and its regulatory mechanisms are still incompletely understood. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multipotency of hADMPCs. Intriguingly, these effects were not mediated by hypoxia-inducible factor (HIF), but rather by the Notch signaling pathway. Five percent O2 significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2 markedly increased glucose consumption and lactate production of hADMPCs, which decreased back to normoxic levels on treatment with a γ-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions and, thus, likely affects the cell lifespan via glycolysis.