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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 SIRPα, 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 clustering 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.

Supplementary Figure from Quantitative Proteomics Identifies Secreted Diagnostic Biomarkers as well as Tumor-Dependent Prognostic Targets for Clear Cell Renal Cell Carcinoma

Supplementary Data from Quantitative Proteomics Identifies Secreted Diagnostic Biomarkers as well as Tumor-Dependent Prognostic Targets for Clear Cell Renal Cell Carcinoma

© 2021, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were

We evaluated and described the impact of prostatic indocyanine green (ICG) injection on extended pelvic lymph node (LN) dissection (ePLND) in robotic-assisted radical prostatectomy (RARP). Between January 2019 and December 2021, we included consecutive 50 PCa patients who underwent ePLND during RARP with (n = 25) or without (n = 25) prostatic ICG injection. ICG injection was performed during abdominal port placement and robot docking. Pelvic LNs reflecting green color were initially excised and then the template was completed. The outcomes of two groups were compared. Overall, nine (36%) and five (20%) of the patients had metastatic LN involvement in the ICG and non-ICG groups, respectıvely. Of the 509 dissected LNs in the ICG group, 122 (23.9%) were fluorescence active. 20 LNs (3.9%) were metastatic in this group, 9 (45%) of which were ICG+. 408 LNs were resected on the non-ICG group with 8(1.9%) being metastatic. Eight (88.9%) of nine pN+ patients were florescent positive in the ICG group. Out of six patients with pN+ disease, Ga68 PSMA-PET/CT detected positive LNs preoperatively. In addition to preoperative Ga68 PSMA-PET/CT investigation, ICG-guided ePLND might increase identification and removal of metastatic LNs duirng RARP. Improvements ın stagıng and oncologıc outcomes may also be seen ın intermediate- and high-risk patients.

The literature on liver cysts is highly conflicting, mostly owing to definitional variations. Two hundred and fifty-eight >= 1 cm cysts evaluated pathologically using updated criteria were classifiable as: I. Ductal plate malformation related (63%); that is, cystic bile duct hamartoma or not otherwise specified-type benign biliary cyst (35 with polycystic liver disease). These were female predominant (F/M=2.4), large (10 cm), often multifocal with degenerative/inflammatory changes and frequently misclassified as "hepatobiliary cystadenoma." II. Neoplastic (13%); 27 (10.5%) had ovarian-type stroma (OTS) and qualified as mucinous cystic neoplasm (MCN) per World Health Organization (WHO). These were female, solitary, mean age 52, mean size 11 cm, and 2 were associated with carcinoma (1 in situ and 1 microinvasive). There were 3 intraductal papillary neoplasms, 1 intraductal oncocytic papillary neoplasm, 1 cystic cholangiocarcinoma, and 2 cystic metastasis. III. Infectious/inflammatory (12%). These included 23 hydatid cysts (including 2 Echinococcus alveolaris both misdiagnosed preoperatively as cancer), nonspecific inflammatory cysts (abscesses, inflammatory cysts: 3.4%). IV. Congenital (7%). Mostly small (

Background Results from prospective trials have shown higher accuracy of prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) in detection of lymph node metastasis (LNM) compared to conventional imaging. Objective To evaluate the accuracy of 68Ga-PSMA-11 PET/CT for LNM detection in patients undergoing radical prostatectomy (RP) and extended pelvic lymph node dissection (PLND). Design, setting, and participants Between June 2014 and November 2020, 96 patients with 68Ga-PSMA PET/CT for primary staging underwent RP and extended PLND. Outcome measurements and statistical analysis The results from 68Ga-PSMA PET/CT were compared with histologic data from primary PLND in 96 patients. All 68Ga-PSMA PET/CT scans were centrally reviewed. Results and limitations Of 96 patients, 15.6% (n = 15) harbored LNMs. The median prostate-specific antigen at 68Ga-PSMA PET/CT was 8.0 ng/ml (interquartile range 5.5–11.7). The majority of patients had intermediate- (52.1%) or high-risk disease (41.7%). Biopsy grade group 4 and 5 was present in 22.9% and 15.6%, respectively. The 68Ga-PSMA PET/CT scans identified eight of 15 patients (53.3%) as LN-positive (true positive). The calculated per-patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 68Ga-PSMA PET/CT in the detection of LNM were 53.3%, 98.8%, 88.9%, 92.0%, and 91.7%, respectively. The per-patient sensitivity and specificity in the detection of LNMs larger than 2 mm were 61.5% and 98.8%, respectively. The main limitation is the retrospective design of the study. Conclusions 68Ga-PSMA PET/CT is accurate in lymph node staging and the results support its use for primary staging of prostate cancer. Patient summary We compared prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) findings with histopathology results after extended lymph node dissection and showed that it is accurate in detecting lymph node metastases. Our results support the use of PSMA PET/CT for primary staging of prostate cancer.

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) .

The cost-effectiveness and low rate of inadequate sampling with the use of rapid on-site evaluation (ROSE) along with endobronchial ultrasonography (EBUS) is well established. Our aim in this study was to evaluate the correlation of ROSE during EBUS and final cytologic diagnosis and also to see if ROSE might predict the subtype of lung cancer.All consecutive subjects who attended our clinic between January 2016 and January 2019 for the evaluation of pathologic mediastinal and/or hilar lymph nodes (LNs)/mass using EBUS were enrolled into our prospective study. ROSE was performed in the same operating room with EBUS. ROSE results during EBUS were recorded. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ROSE compared with the final cytologic diagnosis were evaluated.We enrolled 684 LN/mass lesions belonging to 328 patients into this study. When we compared ROSE results and final cytologic diagnosis, these procedures agreed on 91.6% of the LNs (P0.001). The sensitivity of ROSE and final cytologic diagnosis for granulomatous inflammation was 72.5%, and for lung cancer, it was 89.2% (P0.001). The sensitivity of ROSE for the adenocarcinoma subtype of lung cancer was 67.7%, and it was 70% for small cell lung cancer.ROSE may help to recognize non-small cell lung cancer during EBUS, especially the adenocarcinoma subtype of lung cancer, which will help ensure having sufficient material for molecular analysis.

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

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

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

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

To evaluate the additive role of Ga-68 PSMA PET as a primary staging tool in patients bearing prostate cancer in single PIRADS 4 or 5 index lesions. Eighty-one biopsy-naive patients with preoperative mpMRI and Ga-68 PSMA PET who underwent radical prostatectomy (RP) were evaluated retrospectively. Forty-nine patients had PIRADS 4 and 32 had PIRADS 5 index lesions. The localization, grade, and volumetric properties of dominant (DT) and non-dominant tumors (NDT) in RP were compared to the index lesions of mpMRI and Ga-68 PSMA PET. The median age and PSA level were 62 (IQR; 59–69) years and 7 (IQR; 2–8) ng/ml, respectively. Ga-68 PSMA PET detected DTs in 100% of the patients including 13 patients in whom mpMR failed. In 45 patients an NDT was reported in RP. Ga-68 PSMA PET accurately detected NDT in 24 of 45 (53.3%) patients. Six patients (12.2%) in PIRADS 4 and 8 (25%) in PIRADS 5 group showed upgrading. In PIRADS 4, Ga-68 PSMA PET localized DT in all patients with upgraded tumors whereas mpMRI missed exact location in 2 of 6 (33.3%). In PIRADS 5 both mpMRI and Ga-68 PSMA PET accurately located all DTs. Overall detection rates of extracapsular extension (ECE) and seminal vesicle invasion (SVI) by mpMRI were 51.1% and 53.8%, respectively. Ga-68 PSMA PET detected ECE and SVI in 27.9% and 30.7%, respectively. When mpMRI and Ga-68 PSMA PET were used in combination detection rates of ECE and SVI increased to 65.1 and 61.5%. Ga-68 PSMA PET-detected six of ten patients with positive lymph nodes whereas mpMRI could not identify any. Ga-68 PSMA PET has a better diagnostic accuracy in detecting DT, NDT, upgrading, adverse pathology in patients with PIRADS 4 index lesions. However, mpMRI better predicted ECE and SVI than Ga-68 PSMA PET.

Objective Lymph node metastasis occurs in a subset of papillary microcarcinoma patients. We aimed to analyze the differences between metastatic and non-metastatic papillary microcarcinomas in order to identify a high-risk subgroup that is likely to require more aggressive treatment. Materials and methods 126 thyroidectomies with lymph node dissections (central ± lateral), diagnosed as papillary microcarcinoma, were reviewed. Results Mean age of 126 patients (F/M = 3.3) was 42 years. Mean size of the largest tumor was 7 mm. Classical was the most frequently (89%) encountered subtype. Multiple histologic subtypes co-occurred in 19%. Lymphovascular invasion was present in 16% (n = 20). 55 (44%) and 71 (56%) cases were unifocal and multifocal, respectively. 90 cases (71%) were non-encapsulated with overall infiltrative tumor borders, whereas in 36 cases (29%), the tumor had a well-defined capsule. Among those, 23 (64%) had tumor capsule invasion. 47 (37%) cases had metastasis in lymph nodes. In univariate analysis, metastasis was associated with tumor size of >5 mm (p = 0.02), tumor burden of >5 mm (p = 0.03), lymphovascular invasion (p = 0.02) and non-encapsulation (p = 0.01). No associations were found regarding sex, age, histologic subtype, lymphocytic thyroiditis, tumor capsule invasion (in capsulated tumors), laterality and multifocality (p > 0.05). In multivariate analysis, lymphovascular invasion (p = 0.01, OR = 3.97, 95% CI 1.35–11.67), tumor size >0.5 cm (p = 0.031, OR = 2.92, 95% CI 1.10–7.71) and non-encapsulation (p = 0.033, OR = 2.85, 95% CI 1.08–7.51) were independent risk factors. Conclusion Size (largest tumor or sum of all foci) of >5 mm, non-encapsulation and lymphovascular invasion were independent predictors of LNM in PMs. Unifocal tumors metastasize the same as multifocal tumors, suggestive of the contribution of other factors. Patients with sporadically resected microcarcinomas should be carefully followed-up, especially those that harbor risk factors in histology.

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, NA

OBJECTIVE. The objective of our study was to evaluate the relationship between the tumor-capsule contact length, defined as tumor contact length (TCL), and extraprostatic extension (EPE) using the ...

Objectives To assess the most optimal multi-parametric magnetic resonance imaging sequence (Mp-MRI) in determining pathological length of capsular contact (LCC) for the diagnosis of prostate cancer extraprostatic extension (EPE). Methods 105 patients with prostate cancer who underwent Mp-MRI of prostate prior to radical prostatectomy were enrolled in this retrospective study. LCC was determined from T2-weighted images (T2WI), Apparent Diffusion Coefficient (ADC) map, dynamic contrast-enhanced MRI (DCE-MRI) separately by two blinded radiologists. The LCCs in patients with and without EPE were compared with Mann Whitney-U test. The relationship between pathological LCC and the LCC that was measured from each Mp-MRI sequences were calculated by using Spearman test. The ability of all individual Mp-MRI sequences in determining pathological LCC was calculated by drawing receiver operator characteristic (ROC) curves. The diagnostic accuracy of LCC based on each MRI sequences for EPE diagnosis was also calculated with ROC curve analysis. Results The patients with EPE had longer median LCC than patients without EPE for each Mp-MRI sequences and for both readers. In addition, the LCC showed a broader overlapping between patients with and without EPE on ADC map (reader-1, p = 0.01; reader-2, p = 0.01) when compared with T2WI (reader-1, p = 0.002; reader-2, p = 0.001) and DCE-MRI (reader-1, p = 0.001; reader-2, p = 0.001). LCC based on DCE-MRI showed the strongest correlation with pathological LCC. The area under the curve (AUC) based on LCC was higher when using the DCE-MRI (reader-1: 0.874, p = 0.030; reader-2: 0.862, p = 0.02) than when using T2WI and ADC map in predicting pathological LCC for both readers. While the LCC based on ADC map showed poor diagnostic accuracy, LCC based on T2WI and DCE-MRI had fair diagnostic accuracy for EPE diagnosis. Conclusion The contact between prostate tumor and capsule seems to be a useful and objective parameter for evaluating the EPE of prostate cancer with Mp-MRI. More specifically, LCC based on DCE-MRI has highest correlation with pathological LCC and has better ability to predict pathological LCC when compared with other Mp-MRI sequences. However, the performance of LCC based on T2WI and DCE-MRI was similar for EPE diagnosis. It seems measurement of LCC from DCE-MRI and measurement of LCC from T2WI does not show any difference in clinical EPE assessment.

Nasopharyngeal glial heterotopia is a mass composed of mature neural tissue occurring outside the central nervous system and is extremely rare. The preoperative diagnosis of such a mass in the head and neck region is challenging. In this study, we report a case of a 16-month-old patient presenting with respiratory distress and snoring caused by nasopharyngeal glial heterotopia. Radiologic imaging and histopathology are obligatory for the definitive diagnosis of glial heterotopia. Preoperative evaluation of an intracranial connection is one of the most essential issues in the presence of pediatric nasopharyngeal masses. The gold standard of treatment is surgical excision. Early recognition and early surgical excision by endoscopic or external approach are crucial to relieve respiratory distress and to maintain healthy growth and development.