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Giant cell tumors of soft tissue (GCT-ST) are rare low-grade neoplasms that were at one time thought to represent the soft tissue counterparts of GCT of bone (GCT-B) but are now known to lack the H3F3 mutations characteristic of osseous GCT. We present six distinctive giant cell-rich soft tissue neoplasms that expressed keratins and carried a recurrent HMGA2-NCOR2 gene fusion. Patients were five females and one male aged 14–60 years (median, 29). All presented with superficial (subcutaneous) masses that were removed by conservative marginal (3) or wide (2) local excision. The tumors originated in the upper extremity (2), lower extremity (2), head/neck (1), and trunk (1). Five patients with follow-up (median, 21 months; range, 14–168) remained disease-free. Grossly, all tumors were well-demarcated but not encapsulated with variable lobulation. Histologically, they were composed of bland plump epithelioid or ovoid to spindled mononuclear cells admixed with evenly distributed multinucleated osteoclast-type giant cells. Foci of stromal hemorrhage and hemosiderin were seen in all cases. The mitotic activity ranged from 2 to 14/10 high power fields (median: 10). Foci of necrosis and vascular invasion were seen in one case each. The mononuclear cells were immunoreactive with the AE1/AE3 keratin cocktail and less frequently/less diffusely for K7 and K19 but lacked expression of other lineage-associated markers. RNA-based next-generation sequencing revealed an HMGA2-NCOR2 fusion in all tumors. None of the keratin-negative conventional GCT-ST showed the HMGA2-NCOR2 fusion (0/7). Metaplastic bone (4/9) and SATB2 expression (3/4) were frequent in keratin-negative conventional GCT-ST but were lacking in keratin-positive HMGA2-NCOR2 fusion-positive tumors. The distinctive immunophenotype and genotype of these tumors strongly suggest that they represent a discrete entity, differing from conventional GCT-ST and other osteoclast-rich morphologic mimics. Their natural history appears favorable, although a study of additional cases and longer follow-up are warranted.

Background. Hyaline fibromatosis syndrome is a rare autosomal recessive disorder caused by ANTXR2 pathogenic variants. The disorder is characterized by the deposition of amorphous hyaline material in connective tissues. The hallmarks of the disease are joint contractures, generalized skin stiffness, hyperpigmented papules over extensor surfaces of joints, fleshy perianal masses, severe diarrhea, and gingival hypertrophy. The severity of the disease varies and prognosis is poor. No specific treatment is yet available. Most patients with the severe form of the condition pass away before the second year of age. In this study, we describe the clinical and molecular findings of a cohort of seven hyaline fibromatosis syndrome patients who were diagnosed and followed up at a single tertiary reference center in Turkey. Methods. Genomic DNA was extracted by standard salting out method from peripheric blood samples of three patients. In one patient DNA extraction was performed on pathology slides since peripheric blood DNA was not available. All coding exons of the ANTXR2 were amplified and sequenced on ABI Prism 3500 Genetic Analyser. Results. Sanger sequencing was performed in 3 patients and homozygous c.945T>G p.(Cys315Trp), c.1073dup p.(Ala359CysfsTer13), and c.1074del p.(Ala359HisfsTer50) variants were identified in ANTXR2. All patients passed away before the age of five years. Conclusions. HFS is a rare, progressive disorder with a broad phenotypic spectrum. HFS can be recognized easily with distinctive clinical features. Nevertheless, it has poor prognosis with increased mortality due to severe clinical decompensation.

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A , LOX and ITGA5 , causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients. The development of chemoresistance is a major hurdle in triple negative breast cancer (TNBC). Here, the authors show that lysyl oxidase (LOX) is overexpressed in chemoresistant TNBCs, and when inhibited reduces collagen cross-linking, fibronectin fibril assembly, and downstream integrin signalling, overcoming resistance.

Background Primary immunodeficiency disease (PID)/Inborn Errors of Immunity (IEI) with T-cell dysfunction is well-known for susceptibility to opportunistic/viral infections. Epstein–Barr virus-positive smooth muscle tumor (EBV-SMT) is a rare entity primarily seen in the setting of immunodeficiency, such as transplantation, HIV/AIDS, and IEI. Aim This study aimed to characterize patients’ clinical/immunologic/genetic features with EBV-SMT and assess their association with IEI. Methods We reviewed the medical records of patients with EBV-SMT in an outpatient immunology clinic and analyzed a total of 33 patients, including 24 identified from the literature. Results The study included nine patients (male/ female = 6/3). The median ages at the onset of symptoms, clinical diagnosis of PID, genetic diagnosis, and EBV-SMT diagnosis were 12 months (1–84 months), 6 years (2–15 years), 10 years (6–18 years), and 10 years (4–18 years), respectively. The parental consanguinity ratio was 7/9(78%). Four patients had combined immunodeficiency. Five out of nine patients (56%) received a genetic IEI diagnosis: JAK3 deficiency ( n  = 1), STAT1 GOF ( n  = 1), CARMIL2 deficiency ( n  = 1), DOCK8 deficiency ( n  = 1), and ITK deficiency ( n  = 1). Recurrent infections (100%), chronic diarrhea/colitis (78%), organomegaly (67%), and lymphadenopathy (56%) were prevalent among the patients. Six patients exhibited leiomyoma-like morphology, while three had leiomyosarcoma-like morphology. Five out of nine patients (55%) died, two of whom succumbed due to the complications of hematopoietic stem cell transplantation. Conclusion EBV-SMT may suggest an underlying immunodeficiency. Since the mortality is high, early genetic diagnosis of IEI, monitoring the patients with IEI for chronic EBV and cancer, and an individualized therapeutic approach will minimize complications. Highlights Epstein-Barr virus-positive smooth muscle tumor (EBV-SMT) is a rare entity mostly observed in cases of immunodeficiency, such as PID/IEI, transplantation, and HIV/AIDS. Since the diagnosis of EBV-SMT strongly suggests an underlying immunodeficiency, including PID, we did an immunological investigation, including genetic studies, and found documented IEI, especially combined immunodeficiency. This study increases the number of reported cases of a rare but potentially life-threatening IEI complication, EBV-SMT, suggesting the need for early hematopoietic stem cell transplantation.

To draw attention to the disregarded malignancy risk after ileocystoplasty, we present two cases of adenocarcinoma. The first case was metastatic at initial diagnosis. Despite chemotherapy, the condition progressed and the patient died at the 9th month. The second patient has received cystectomy followed by chemotherapy and radiotherapy. Although the second patient was an immunosuppressed renal transplant, she was disease-free at the 27th month. As the malignancy risk after bladder augmentation is a proven fact, until the discovery of a proper diagnostic method, we recommend doing routine annual cystoscopic biopsy starting after the 10th year of ileocystoplasty.

Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro . Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.

ObjectiveThe purpose of this study is to assess the ability of apparent diffusion coefficient (ADC) values in differentiating Ewing sarcoma and osteosarcoma.Materials and methodsThis retrospective cross-sectional observational study included a total of 35 patients with a recent diagnosis of Ewing sarcoma (n = 13) and osteosarcoma (n = 22) who underwent conventional MRI and diffusion-weighted imaging (DWI). Three ADC measurements from the areas of the lowest diffusivity in ADC maps (ADCmin), and other areas with low diffusivity (ADCother), were made independently by two observers on pre-treatment MRI, and the means of these measurements were compared using independent samples t-test. Intraclass correlation coefficient was calculated for inter-observer agreement.ResultsThere was a significant difference between the ADCmin (P < 0.001) and ADCother (P < 0.001) in Ewing sarcoma and osteosarcoma for both observers. For Ewing sarcoma and osteosarcoma, mean ADCmin was 0.566 ± 0.07 and 1.193 ± 0.33 × 10−3 mm2/s; 0.551 ± 0.08 and 1.182 ± 0.33 × 10−3 mm2/s; and mean ADCother was 0.813 ± 0.11 and 1.510 ± 0.35 × 10−3 mm2/s; 0811 ± 0.12 and 1.501 ± 0.33 × 10−3 mm2/s for observers 1 and 2, respectively. Inter-observer correlation coefficient for mean ADCmin was 0.994 and for mean ADCother was 0.995.ConclusionDiffusion-weighted imaging and ADC values could be used in the differentiation of Ewing sarcoma and osteosarcoma in borderline cases.

PurposeThe HER2-low breast cancer is a newly recognized entity with the clinical characteristics is yet to be defined. We hypothesized that HER2-low breast cancer could lead to an increased rate of brain metastases in patients with localized breast cancer. We tested this hypothesis in a large cohort of breast cancer patients with long follow-up.MethodsWe included 2686 adult breast cancer patients followed up in Hacettepe University Cancer Center. Patients with 1 + positive HER2 expression and 2 + HER2 expression with a negative FISH were categorized as HER2-low disease. We evaluated the brain metastasis risk with binary logistic regression analyses and reported odds ratios (OR) with 95% confidence intervals (CI).ResultsDuring a median 95.4 (IQR 72.6–123.1) month follow-up, 184 patients developed brain metastasis (6.9%). The brain metastases were developed in 5.1% of the patients with HER2-negative disease, 8.5% of the patients with HER2-low disease, and 10.1% of the patients with HER2-positive disease. A multivariable binary logistic regression model demonstrated an increased risk of brain metastasis in patients with HER2-low disease (OR: 1.611, 95% CI 1.055–2.460, p = 0.027) and in HER2-positive patients (OR: 1.837, 95% CI 1.308–2.580, p < 0.001). Additionally, HR + -HER2-low disease was associated with a decreased DFS compared to HR + -HER2-negative disease (p = 0.008).ConclusionIn this study, we observed an increased risk of brain metastasis in localized breast cancer patients with HER2-low disease. We think that a high level of vigilance and a low threshold for brain imaging could benefit HER2-low breast cancer patients similar to the patients with HER-positive disease.

Primary sclerosing epithelioid fibrosarcoma (SEF) of bone is a rare and scarcely reported neoplasm. We document clinicopathological and molecular features of 9 additional cases. Five males and 4 females had a mean age of 39 years (14–71 years). Most tumors affected flat/irregular bones; only 3 cases involved a long bone. By radiology, it has characteristic radiographic features of a predominantly lytic expansile lesion with a sclerotic rim. Referring diagnoses were SEF (n = 2), low-grade osteosarcoma (n = 2), chondrosarcoma (n = 1), and chondromyxoid fibroma (n = 1). Histologically, five cases revealed classical morphology of SEF of soft tissue. Remaining cases were classified as hybrid SEF/low-grade fibromyxoid sarcoma, characterized by spindle or stellate cells, prominent stroma, and giant hyalinized areas. Various morphological deviations such as prominent vasculature (n = 3), osteoid-like material (n = 4), or parallel bone trabeculae (n = 2) were observed. Immunohistochemically, all cases showed diffuse and strong MUC4 expression. SATB2 was observed in 5/8 cases. Using FISH, EWSR1, and FUS rearrangements were detected in 4 cases and 1 case, respectively. EWSR1-CREB3L1 fusion was identified in 1 additional case by next-generation sequencing. Recurrence and metastasis were observed in 1 case and 2 cases, respectively. All but one patient were alive with disease for a mean interval of 31 months. SEF of bone is a relatively indolent sarcoma of adults, most commonly located in the flat/irregular bones. Due to overlapping histological features, it is often misdiagnosed as osteosarcoma or a chondroid tumor. Most SEF of bone exhibit EWSR1 rearrangements, but rare cases may harbor a FUS gene fusion.

Background Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a “ hepatostat ” are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration. Methods Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA. Results Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1–3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1–7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation. Conclusions We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna , Vegf , endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor’s remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.