Mastocytosis is a heterogeneous group of disorders, characterized by accumulation of clonal mast cells which can infiltrate several organs, most often spine (70%). The pathogenesis of mastocytosis bone disease is poorly understood. The main aim of the study was to investigate whether neoplastic mast cells may be the source of sclerostin and whether there is an association between sclerostin and selected bone remodeling markers with mastocytosis related bone disease. We assessed sclerostin, bioactive sclerostin, and SOST gene expression in HMC-1.2 human mast cell culture supernatants and plasma of SM patients (n = 39). We showed that human mast cells can secrete sclerostin, and after their stimulation with IL-6, there is a significant increase in SOST gene expression. We observed significantly higher levels of sclerostin in patients diagnosed with more advanced disease. We observed a statistically significant correlation between concentations of sclerostin and its bioactive form and the concentration of alkaline phosphatase (ALP), and between sclerostin and interleukin-6 (IL-6). We observed that significantly higher sclerostin concentrations are present in patients with increased sclerosis of the spongy bone. Sclerostin may serve as a marker of more advanced disease and bone disease in mastocytosis. Further studies are justified to evaluate its role in mastocytosis.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8(+) T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4(+) breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4(+) cancer.

Granular cell tumour (GCT) or Abrikossoff tumour, is a rare submucosal neoplasm orginating from Schwann cells, and accounts for 0.03% of all submucusal tumours. Only 8% of GCTs occur in the gastrointestinal tract, mostly in the esophagus. Diagnosis of granular cell tumour is exceptionally rare. The case is presented of a 72-year-old female patient who underwent polypectomy of a colon polyp which, in the histopathology report, appeared to be a granular cell tumour. The possibility of granular cell tumour diagnosis which is extremly rare, is discussed. However, 2% of these tumours are malignant. It is very important to establish the diagnosis as early as possible. The patient was admitted to the Gastroenterology Outpatient Clinic due to a hepatic vascular lesion. She did not present any symptoms of granular cell tumour. A complete resection of the granular cell tumour fortunately confirmed it to be benign.

Vesicovaginal fistula is a cause of deterioration in the quality of life. It is a communication between the bladder and vagina resulting in the uncontrollable leakage of urine through the vagina. Recently, regenerative methods have been used more frequently, and platelet-rich plasma is one of these methods. The functional properties of platelet-rich plasma are based on the synthesis and secretion of multiple growth factors released after platelet activation. The aim of this study was to investigate how platelet-rich plasma influences the condition of the tissue and the healing ability of the urothelium, vaginal epithelium and tissues surrounding the fistulous canal. The study included eight patients who had undergone the Latzko procedure aimed at closing the vesicovaginal fistula. Samples were collected during primary surgery without platelet-rich plasma and after failed surgery, during a second attempt. The specimens were subjected to histological and immunohistochemical evaluation. The histology demonstrated that in platelet-rich plasma patients, greater vascularization and wider subepithelial mucosa layering was observed. Inflammatory infiltration in the subepithelial layer was increased in platelet-rich plasma patients. No localization differences in growth factor proteins were found in either group, but in platelet-rich plasma-patients, the reactions were stronger. It can be concluded that the use of platelet-rich plasma improves the morphological structure of the injected tissues.

The Grand Round concerns a 24-year-old man from Zimbabwe who was studying and living in Poland. The patient had been complaining of abdominal pain, fatigue, alternating diarrhoea and constipation, and presence of blood in his stool for 3 years. The patient had the following diagnostic tests: colonoscopy, CT scan, histopathology, and parasitological and molecular tests. Results of the examinations showed that the cause of the patient's complaints was chronic intestinal schistosomiasis due to the co-infection with Schistosoma intercalatum and Schistosoma mansoni. The patient had two cycles of praziquantel therapy (Biltricide) and responded well to the treatment. In the Grand Round, we describe full diagnostics as well as clinical and therapeutic management in the patient with S intercalatum and S mansoni co-infection. This case allows us to draw attention to cases of forgotten chronic tropical diseases (including rare ones) in patients from regions with a high endemic index staying in non-endemic regions of the world for a long time. Co-infection with S intercalatum and S mansoni should be considered as a very rare clinical case.

Melanoma is a highly malignant neoplasm with the most typical primary locations in the skin and eyeball and rarely reported in the other organs, including the gallbladder. More commonly metastases of melanoma of various primary sites to the gallbladder are observed. However, generally melanoma of the gallbladder is a rare entity with only 217 cases reported in the literature up to date. The paper summarizes knowledge on epidemiology, symptoms, laboratory and imaging findings, morphology, treatment options, and outcome of patients with both primary and metastatic melanoma to the gallbladder.

IntroductionBrain metastases (BM) severely affect the prognosis and quality of life of patients with NSCLC. Recently, molecularly targeted agents were found to have promising activity against BM in patients with NSCLC whose primary tumors carry “druggable” mutations. Nevertheless, it remains critical to identify specific pathogenic alterations that drive NSCLC-BM and that can provide novel and more effective therapeutic targets.MethodsTo identify potentially targetable pathogenic alterations in NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma and 18 patients with lung squamous cell carcinoma. In addition, we performed multiregion copy number profiling on 15 BM samples and whole-exome sequencing on 40 of 51 NSCLC-BM pairs.ResultsBM consistently had a higher burden of SCNAs compared with the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, suggesting BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified putative BM-driving alterations affecting multiple cancer genes, including several potentially targetable alterations in genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. Finally, we identified putative pathogenic alterations in multiple cancer genes, including genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples.ConclusionsOur study represents the most comprehensive genomic characterization of NSCLC-BM available to date, paving the way to functional studies aimed at assessing the potential of the identified pathogenic alterations as clinical biomarkers and targets.

Background Despite the fact that tumor microenvironment (TME) and gene mutations are the main determinants of progression of the deadliest cancer in the world – lung cancer, their interrelations are not well understood. Digital pathology data provides a unique insight into the spatial composition of the TME. Various spatial metrics and machine learning approaches were proposed for prediction of either patient survival or gene mutations from this data. Still, these approaches are limited in the scope of analyzed features and in their explainability, and as such fail to transfer to clinical practice. Methods Here, we generated 23,199 image patches from 26 hematoxylin-and-eosin (H&E)-stained lung cancer tissue sections and annotated them into 9 different tissue classes. Using this dataset, we trained a deep neural network ARA-CNN. Next, we applied the trained network to segment 467 lung cancer H&E images from The Cancer Genome Atlas (TCGA) database. We used the segmented images to compute human-interpretable features reflecting the heterogeneous composition of the TME, and successfully utilized them to predict patient survival and cancer gene mutations. Results We achieved per-class AUC ranging from 0.72 to 0.99 for classifying tissue types in lung cancer with ARA-CNN. Machine learning models trained on the proposed human-interpretable features achieved a c-index of 0.723 in the task of survival prediction and AUC up to 73.5% for PDGFRB in the task of mutation classification. Conclusions We presented a framework that accurately predicted survival and gene mutations in lung adenocarcinoma patients based on human-interpretable features extracted from H&E slides. Our approach can provide important insights for designing novel cancer treatments, by linking the spatial structure of the TME in lung adenocarcinoma to gene mutations and patient survival. It can also expand our understanding of the effects that the TME has on tumor evolutionary processes. Our approach can be generalized to different cancer types to inform precision medicine strategies.

Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). To identify targetable drivers of NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung squamous cell carcinoma (LUSC). BM consistently had a higher burden of SCNAs compared to the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, as revealed by multi-region SCNA profiling in 15 BM samples, suggesting that BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified BM driving alterations affecting multiple cancer genes, including several targetable genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. We explored the metastatic potential of CDK12 and DDR2 in vitro and in vivo and found that overexpression of either gene alone in murine lung cancer cells causes the induction of key genes involved in epithelial-mesenchymal transition. Finally, we performed whole-exome sequencing of 40 NSCLC-BM pairs and identified BM driver mutations in multiple cancer genes, including several genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples. Our study represents the most comprehensive genomic characterization of LUAD and LUSC BM available to date, uncovering potentially targetable NSCLC-BM drivers and inspiring the design of novel precision treatment strategies for NSCLC patients.

A 69-year-old patient was admitted to the Department of Cardiology due to an accidental finding on a chest X-ray, enlarged heart outline, accompanied by worsening of heart failure to NYHA II with LVEF, about 30%. In the X-ray description, an enlargement of the left atrium silhouette with local calcifications. The patient underwent TTE, confirming the presence of a pedunculated tumor of the left atrium attached to the ceiling measuring 3.5x3.5x2.2 cm. Due to the ischemic heart disease manifestation patient uderwent coronarography confirming the presence of single-vessel coronary artery disease with changes in the middle segment of the LAD. Patient was treated with CABG LIMA-LAD surgery and removeal the left atrial tumor. Post operation tissue material prooved the preseance of left atrium myxoma. The postoperative course was uneventful, the patient was discharged home.

High-grade pediatric glioma (p-HGG—WHO 2021, formerly GBM—WHO 2016), as a common, aggressive, and highly lethal primary brain malignancy in adults, accounts for only 3–15% of primary brain tumors in pediatric patients. After leukemia, brain malignancies are the second most common in the pediatric population and first in incidences concerning solid tumors. This study was designed on the basis of 14 pediatric patients hospitalized at Children’s Memorial Health Institute in Warsaw, Poland, due to p-HGG treatment. All the patients had a histopathological diagnosis performed by an experienced neuropathologist according to WHO guidelines (WHO 2016 Grade IV Glioblastoma). A significant correlation was found between the miR-155 concentration and the level of PD-L1 expression in p-HGG tumor tissue. Very few reports have indicated PD-L1 expression in pediatric patients.

Luteinizing hormone-releasing hormone receptor (LHRHR) expression has been reported in various cancers, including endometrial neoplasms. Thus, LHRHR provides a potential point for therapeutic approach using LHRH analogs as carrier molecules for chemotherapeutic agents in this cancer population. However, clinical data did not prove any potential benefits for patients. We decided to assess LHRHR expression in patients with endometrial cancer to explain possible lack of efficacy in previous clinical reports. LHRHR expression was assessed immunohistochemically in different anatomic and histogenetic compartments of female genital tract of patients with endometrial cancer. The study sample consisted of paraffin tissue blocks obtained from patients who has undergone primary surgery owing to endometrial cancer. Strong LHRHR expression was found in endometrial cancer, fallopian tube, and concurrent atypical hyperplasia. Interestingly, LHRHR expression showed significant differences depending on the respective compartment of the ovary analyzed. Level of LHRHR expression in patients with primary advanced and unresectable disease, particularly in certain ovarian compartments may be substantially lower, which may influence the use of new targeted therapy regimens. The studies on secondary Müllerian system compartment and its hormonal receptor status may be crucial to understand mechanisms of lack of efficacy of LHRH hybrid molecules anti-cancer treatment.

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.

There are several types of morphea with different levels of connective tissue involvement and morphological manifestations. In this mini review, it was pointed out the most important morphological and clinical aspects of localised scleroderma in the oral cavity. The case presented in this article supports the scientific information and is described with details. The morphea of mucous membrane which was clinically suspected, was proved by histopathological examination of the sample. The unusual location of the local findings posed a diagnostic challenge. The case history should be significant due to the low number of studies. The special attention should be taken to match the clinical with pathomorphological picture in localised scleroderma diagnosis and treatment when the involvement of skin and oral mucosa is.

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High-grade gliomas are infrequent in the pediatric population compared to adults, nevertheless, mortality and morbidity caused by malignant gliomas in this group of patients remain significant. PD-L1 and PD-1 Immune checkpoints (IC) molecules maintain immunological balance between activation and suppression. Eighteen patients with a histopathological diagnosis of pediatric glioblastoma multiforme (GBM, WHO IV) were studied. In total, PD-L1 expression was detected in 8 patients (44%). The molecular aspect of IC and immunotherapy targeted on PD-1/PD-L1 axis in pediatric population may be a promising adjuvant therapy in pediatric glioblastoma multiform treatment, however, this subject requires further investigation.

Angioimmunoblastic T-cell lymphoma (AITL) is an uncommon lymphoma of elderly adults with a poor prognosis. AITL patients show systemic symptoms, lymphadenopathy, and not infrequently, skin rash with various dysimmune phenomena rashes. The case is presented of a 68-year-old male with skin rash, lymphadenopathy and hypereosinophilia who, after investigations, was diagnosed with AITL. Despite the treatment used, the patient's condition gradually deteriorated and died due to heart and kidney failure. The diagnosis of AITL is often established only after several weeks or months because of transient physical findings, non-specific symptoms, and a broad range of serologic or radiologic abnormalities. Some patients with AITL experience non-specific dermatitis and eosinophilia. The presented case should raise awareness of the presentations of AITL which is important for physicians to reach an accurate diagnosis.