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Clear cell Renal Cell Carcinoma (ccRCC) is among the 10 most common cancers in both men and women and causes more than 140,000 deaths worldwide every year. In order to elucidate the underlying molecular mechanisms orchestrated by phosphorylation modifications, we per-formed a comprehensive quantitative phosphoproteomics characterization of ccRCC tumor and normal adjacent tissues. Here, we identified 16,253 phosphopeptides, of which more than 9000 were singly quantified. Our in-depth analysis revealed 600 phosphopeptides to be significantly differentially regulated between tumor and normal tissues. Moreover, our data revealed that significantly up -regu-lated phosphoproteins are associated with protein syn-thesis and cytoskeletal re-organization which suggests proliferative and migratory behavior of renal tumors. This is supported by a mesenchymal profile of ccRCC phos-phorylation events. Our rigorous characterization of the renal phosphoproteome also suggests that both epidermal growth factor receptor and vascular endothelial growth factor receptor are important mediators of phos-pho signaling in RCC pathogenesis. Furthermore, we determined the kinases p21-activated kinase 2, cyclin-dependent kinase 1 and c-Jun N-terminal kinase 1 to be master kinases that are responsible for phosphorylation of many substrates associated with cell proliferation, inflammation and migration. Moreover, high expression of p21-activated kinase 2 is associated with worse survival outcome of ccRCC patients. These master kinases are targetable by inhibitory drugs such as fostamatinib, min-ocycline, tamoxifen and bosutinib which can serve as novel therapeutic agents for ccRCC treatment., NO acknowledges the Royal Society Newton Advanced Fellowship (NA170389) .

Objective: to determine the frequency of granulomatous inflammation within hepatocellular carcinoma (HCC) and its clinicopathologic associations. Material and method: fifty-eight HCCs (51 explants, 3 lobectomies, and 4 segmentectomies) were reviewed. Results: five (8.6%) cases (F/M=1/4, mean age: 63.6) were identified with granulomas.1/5 had history of neoadjuvant therapy. 4/5 patients presented with early stage (pT1/2). All were well-differentiated (Grade1-2/4). The mean number of tumor foci was 3.6, with a median size of 2.2 cm. All of them had advanced fibrosis. No difference was identified from cases without granulomas (n=53) in terms of prognosis and aforementioned parameters (p> 0.05). Granulomas were mainly concentrated in peripheral parts of the tumors. One case with nodule-in-nodule formation had granulomas lined along the border of the inner nodule. In 2 cases, granulomas were identified in steatohepatitic areas, while another had clear cell change. Only 1 had necrotizing granulomas, none with acid resistant bacilli. Two cases revealed concomitant granulomas in the adjacent liver parenchyma in addition to the tumor stroma. Except for one with a history of tuberculosis, none of the cases had a granulomatous disease.Conclusion: this is the largest case series of HCCs with granulomas by far. Our data revealed neither clinicopathologic and prognostic difference nor definite etiology related to granulomas. Yet, association with steatotic and clear tumor cells suggests the role of cytoplasmic content, while distribution of granulomas points to host immune response., NA

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management.

Background: to investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function. Methods: four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning. Results: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05). Conclusion: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels.

Autoimmune hepatitis (AIH) is a chronic progressive autoimmune liver disease characterized by hypergammaglobulinemia, interface hepatitis, a female preponderance, and the presence of autoantibodies in most patients. The presence of HLA-DR3/DR4 and functional impairment in regulatory T cells are associated with AIH. However, AIH is a multifactorial complex disease. This report is a description of a case of seronegative AIH in a girl with chronic hepatitis, a high immunoglobulin E (IgE) level, perforating nodular dermatitis, and sheer eosinophilia. To re-evaluate the diagnosis, whole exon sequencing was performed. It was determined that the patient had ancestral haplotype A1-B8-DR3, which is associated with autoimmunity. Importantly, it was also noted that an undocumented point mutation (Ala627Thr) of the FMS-like tyrosine 3 kinase (FLT3) receptor was present. This FLT3 receptor gain-of-function mutation is associated with the activation of the mechanistic target of rapamycin (mTOR), and dendritic cell activation. In addition, a loss-of-function mutation in the melanocortin-3 receptor gene, which inhibits interleukin 4, was detected. The constellation of these immune deregulatory factors may have propagated auto-aggression of the liver, causing chronic hepatitis with AIH features. The findings of seronegativity with eosinophilia and a high IgE level led us to hypothesize that the pathognomonic mechanism in this case was unlike that of classic AIH pathophysiology. Since mTOR is constitutively activated, mTOR inhibitors may be a useful option to treat AIH and dermatitis., NA

Clear cell renal cell carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified four putatively secreted biomarker candidates, namely, PLOD2, FERMT3, SPARC, and SIRPa, as highly expressed proteins that are not affected by intratumor and intertumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of patients with ccRCC, making it a promising marker for the detection of the disease in body fluids. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared with cluster 2 tumors. Moreover, among the most significant dustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC. Implications: Our in-depth quantitative proteomics analysis of ccRCC tissues identifies the putatively secreted protein SPARC as a promising urine biomarker and reveals two molecular tumor phenotypes., NA

Background: to investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function. Methods: four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning. Results: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05). Conclusion: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels., University of Gottingen Open Access Publication Funds

We analyzed metastatic liver tumors received in the department of pathology in a tertiary care center over a 3-year period. There were 509 metastatic liver tumors; counterintuitively, there were as many resections (235 cases) as biopsies (274 cases). This unexpected finding reflects contemporaneous organ-specific paradigms for diagnosis and management of metastatic liver disease in oncologic practice, and the association of our practice with a National Cancer Institute-designated comprehensive cancer center with expertise and specialization in liver surgery. We receive a large number of resections for metastatic liver tumors because metastasectomy from a variety of primary tumors is associated with improved overall, and in many instances, disease-free, long-term survival. Metastatic colorectal carcinomas, metastatic neuroendocrine tumors, and metastatic gastrointestinal stromal tumors constituted 78% of resections because the largest body of literature and cumulative experience exists for these lesions. In contrast, breast carcinomas and pancreatic carcinomas, which are the next common metastatic liver tumors were biopsied but rarely resected, because metastasectomy is not the standard of care for these tumors. Immunohistochemistry was performed in less than a quarter of the total number of cases (23%), because the primary tumor site was known in the vast majority of cases. Of the 42 cases with unknown primary tumor, it was elucidated in 50% of the cases by immunohistochemical and clinical work-up. Of the cases with known primary tumor, immunohistochemistry was performed mostly in metastatic breast, colon, and lung carcinomas. In these cases, biomarker analyses provided additional information relevant to clinical management., NA

Background: this study aims to investigate the role of endobronchial ultrasonography elastography in predicting malignancy. Methods: between January 2016 and December 2016, a total of 221 lymph nodes were biopsied using the endobronchial ultrasonography-guided transbronchial needle aspiration from 119 consecutive patients (69 males, 50 females; mean age 63.2±12.4 years; range, 16 to 86 years) were included. Lymph nodes were scored by elastography according to their colors in four categories before the procedure. The strain ratio was calculated based on the region of interest after three measurements. Results: of the patients, 93 were diagnosed with a malignancy through endobronchial ultrasonography-guided transbronchial needle aspiration biopsy. The mean lymph node score of benign versus malignant lesions was 2.2±1.0 and 3.2±1, respectively (p<0.001). There was a positive correlation between the lymph node scores and lymph node diameter, strain ratio, and fluorodeoxyglucose uptake value (p<0.01). With a cut-off value of ?3 of lymph node scoring, the sensitivity for malignancy was 79% and specificity was 60%. The mean strain ratio for malignant and benign lymph nodes was 22.2±30.1 and 5.2±1.7, respectively (p<0.001). With a cut-off value of ?2.47 of strain ratio, the sensitivity for malignancy was 75% and specificity was 65%. The combined use of positron emission tomography and lymph node score or strain ratio yielded 80.4% and 61.2% sensitivity and 80% and 70.3% specificity for malignancy, respectively. Conclusion: endobronchial ultrasonography elastography is useful in predicting malignancy of the lymph nodes. When combined with positron emission tomography, specificity and positive predictive value for malignancy increase. / Amaç: bu çalışmada endobronşiyal ultrasonografi elastografinin maligniteyi öngörmedeki rolü araştırıldı. Çalışma planı: Ocak 2016 - Aralık 2016 tarihleri arasında, endobronşiyal ultrasonografi eşliğinde transbronşiyal iğne aspirasyon biyopsisi

Background: this study aims to investigate the role of endobronchial ultrasonography elastography in predicting malignancy. Methods: between January 2016 and December 2016, a total of 221 lymph nodes were biopsied using the endobronchial ultrasonography-guided transbronchial needle aspiration from 119 consecutive patients (69 males, 50 females; mean age 63.2±12.4 years; range, 16 to 86 years) were included. Lymph nodes were scored by elastography according to their colors in four categories before the procedure. The strain ratio was calculated based on the region of interest after three measurements. Results: of the patients, 93 were diagnosed with a malignancy through endobronchial ultrasonography-guided transbronchial needle aspiration biopsy. The mean lymph node score of benign versus malignant lesions was 2.2±1.0 and 3.2±1, respectively (p<0.001). There was a positive correlation between the lymph node scores and lymph node diameter, strain ratio, and fluorodeoxyglucose uptake value (p<0.01). With a cut-off value of ?3 of lymph node scoring, the sensitivity for malignancy was 79% and specificity was 60%. The mean strain ratio for malignant and benign lymph nodes was 22.2±30.1 and 5.2±1.7, respectively (p<0.001). With a cut-off value of ?2.47 of strain ratio, the sensitivity for malignancy was 75% and specificity was 65%. The combined use of positron emission tomography and lymph node score or strain ratio yielded 80.4% and 61.2% sensitivity and 80% and 70.3% specificity for malignancy, respectively. Conclusion: endobronchial ultrasonography elastography is useful in predicting malignancy of the lymph nodes. When combined with positron emission tomography, specificity and positive predictive value for malignancy increase. / Amaç: bu çalışmada endobronşiyal ultrasonografi elastografinin maligniteyi öngörmedeki rolü araştırıldı. Çalışma planı: Ocak 2016 - Aralık 2016 tarihleri arasında, endobronşiyal ultrasonografi eşliğinde transbronşiyal iğne aspirasyon biyopsisi, NA

Objective: the nature and clinicopathologic associations of Löwenstein-Buschke disease are unclear. Materials and methods: 78 anal condylomatous lesions (≥2 cm) were analyzed. Cases were classified based on size as "medium-large"(2-5 cm, n=59), "large" (5-10 cm, n=13) and "giant" ( > 10 cm, n=6). Results: patients were predominantly males (male/female=70/8). The mean age was 38 years (range:20-66). Two distinct lining types were recognized: 1) Epidermal type, typically lacking overt koilocytotic change, with associated invasive carcinoma in 8%; 2) Mucosal type, often manifesting koilocytotic change, with associated invasive carcinoma in 21%. Three types of high-grade dysplasia were discerned: 1) Basaloid, 8/9 showing high-grade dysplasia/carcinoma in-situ but non-invasive lesions; 2) Keratinizing, innocuous-appearing, but 5/6 was associated with invasion; 3) Giant cell, showing scattered individual bizarre cells, with 3/5 showing invasive carcinoma. Overall, invasion was found in 14% of the cases. The bulbous, broad-based destructive pattern characterizing verrucous carcinomas of the upper aerodigestive tract was not observed. A statistically significant trend existed between the incidence of invasion and size: 8.5% for medium-large, 23% for large, and 50% for giant (p=0.02). There was no discernable trend in the depth of invasion relative to condyloma size. Conclusions: our findings suggest that Löwenstein-Buschke lesions are mega versions of conventional condyloma. Being verrucoid, large and minimally invasive, they can be conceptually regarded as a form of verrucous carcinoma, but they do not display the histologic characteristics of verrucous carcinoma defined in the aerodigestive tract. They exhibit two types of linings: the mucosal type that often shows koilocytotic changes, and the epidermal type that can be difficult to recognize in biopsies. These lesions may be associated with invasive carcinoma, albeit limited in amount., NA

The effect of COVID-19 on the transplant recipients is not well-established. Many reports underestimate the effect of COVID-19 on the immunosuppressed population. Herein, we report on 3 pediatric liver transplant recipients who were transplanted at our center between February 11 and March 10, 2020-during the COVID-19 pandemic era. The 3 patients aged between 5 and 10 months, had a rapid and aggressive respiratory deterioration that necessitated mechanical ventilation and extracorporeal life support; and eventually died. The clinical and pathological pictures likely represent COVID-19 pneumonia. Chest x-rays showed progressive infiltrates. Lung autopsies showed diffuse alveolar damage in two cases. We concluded that COVID-19 is very likely to have catastrophic effects on transplant recipients., NA

Background: desmoplastic small round cell tumor (DSRCT) is a rare, aggressive neoplasm seen in children and young adults, usually manifested by involvement of abdominal serosa. Here, we present an unusual case of primary DSRCT of kidney. Case presentation: the patient was an 8-year-old girl with a large renal mass which was confused with primitive neuroectodermal tumor (PNET) in the needle biopsy. The tumor had a variegated histology revealing frequent pseudo-rosette formations, pseudopapillary architecture, rhabdoid, clear or pleomorphic cells in addition to typical small round cell morphology and desmoplasia. It showed immunohistochemical features of DSRCT, and EWSR1 re-arrangement. Conclusions: proffering this diagnosis is particularly difficult for tumors of viscera because of the incognizance of the entity in these locations. Moreover, DSRCT is a great mimicker and may get easily confused with more common kidney malignancies of childhood such as Wilms tumor, PNET/EWS, rhabdoid tumor, clear cell sarcoma, and other small round cell tumors as well as renal cell carcinomas. The distinction is critical as the accurate therapeutic approach will require correct diagnosis., NA

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