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Introduction: IQGAP3 possesses oncogenic actions; its impact on prostate cancer (PC) remains unclear. Objective: We will investigate IQGAP3′s association with PC progression, key mechanisms, prognosis, and immune evasion. Methods: IQGAP3 expression in PC was examined by immunohistochemistry and using multiple datasets. IQGAP3 network was analyzed for pathway alterations and used to construct a multigene signature (SigIQGAP3NW). SigIQGAP3NW was characterized using LNCaP cell-derived castration-resistant PCs (CRPCs), analyzed for prognostic value in 26 human cancer types, and studied for association with immune evasion. Results: Increases in IQGAP3 expression associated with PC tumorigenesis, tumor grade, metastasis, and p53 mutation. IQGAP3 correlative genes were dominantly involved in mitosis. IQGAP3 correlated with PLK1 and TOP2A expression at Spearman correlation/R = 0.89 (p ≤ 3.069e-169). Both correlations were enriched in advanced PCs and Taxane-treated CRPCs and occurred at high levels (R > 0.8) in multiple cancer types. SigIQGAP3NW effectively predicted cancer recurrence and poor prognosis in independent PC cohorts and across 26 cancer types. SigIQGAP3NW stratified PC recurrence after adjustment for age at diagnosis, grade, stage, and surgical margin. SigIQGAP3NW component genes were upregulated in PC, metastasis, LNCaP cell-produced CRPC, and showed an association with p53 mutation. SigIQGAP3NW correlated with immune cell infiltration, including Treg in PC and other cancers. RELT, a SigIQGAP3NW component gene, was associated with elevations of multiple immune checkpoints and the infiltration of Treg and myeloid-derived suppressor cells in PC and across cancer types. RELT and SigIQGAP3NW predict response to immune checkpoint blockade (ICB) therapy. Conclusions: In multiple cancers, IQGAP3 robustly correlates with PLK1 and TOP2A expression, and SigIQGAP3NW and/or RELT effectively predict mortality risk and/or resistance to ICB therapy. PLK1 and TOP2A inhibitors should be investigated for treating cancers with elevated IQGAP3 expression. SigIQGAP3NW and/or RELT can be developed for clinical applications in risk stratification and management of ICB therapy.

Abstract Background PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9’s oncogenic roles in melanoma and other cancers remain unclear. Methods PCSK9’s association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9 −/− mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. Results PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the low-density lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9 −/− mice. Conclusions Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9’s oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.

Patients undergoing definitive surgery or ablative techniques for nonmetastatic kidney cancer have varying degrees of risk of recurrent disease post procedure. The ultimate goal of “adjuvant therapy” is to reduce the incidence of recurrent disease, and to cure more patients. We summarize the current state of perioperative therapy for kidney cancer and explore future directions to develop optimal adjuvant strategies. We define risk and risk of recurrence post-definitive therapy, describe the controversies surrounding the trial landscape of adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitors and immune checkpoint inhibitors. We review data on neoadjuvant therapy before advanced kidney cancer resection. Radiologic, ethnic, economic, and geographic considerations with respect to adjuvant therapy are highlighted, as well as adjuvant therapy issues especially pertinent to patients, future directions in adjuvant trial design specifically targeted to biomarkers and patient selection, and sequencing of treatment after adjuvant therapy in those patients with recurrence.

Abstract Background Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra‐cranial imaging for the screening of asymptomatic BM in mRCC. Aims To evaluate the potential utility of routine intra‐cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM. Methods and Results The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi‐square tests, analysis of variance, and Kaplan–Meier method to characterize survival outcomes. A p‐value of 1) BM (75%) with no significant differences noted in number of BM or BM‐directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32–62) for patients with asymptomatic BM, and 39 months (95% CI: 29–48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18–42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10–21) in the symptomatic BM group (p = 0.04). Conclusions Given a substantial proportion of patients may present with asymptomatic BM, limiting intra‐cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra‐cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

Background: Prostate Specific Membrane Antigen (PSMA) – positron emission tomography (PET) guides metastasis-directed radiotherapy (MDRT) in prostate cancer (PrCa). However, its value as a treatment response assessment tool after MDRT remains unclear. Importantly, there is limited understanding of the potential of radiotherapy (RT) to alter PSMA gene (folate hydrolase 1; FOLH1) expression. Methodology: We reviewed a series of 11 men with oligo-metastatic PrCa (25 metastasis sites) treated with MDRT before re-staging with 18F-DCFPyL (PSMA) PET upon secondary recurrence. Acute effects of RT on PSMA protein and mRNA levels were examined with qPCR and immunoblotting in human wild-type androgen-sensitive (LNCap), castrate-resistant (22RV1) and castrate-resistant neuroendocrine (PC3 and DU145) PrCa cell lines. Xenograft tumors were analyzed with immunohistochemistry. Further, we examined PSMA expression in untreated and irradiated radio-resistant (RR) 22RV1 (22RV1-RR) and DU145 (DU145-RR) cells and xenografts selected for survival after high-dose RT. Results: The majority of MDRT-treated lesions showed lack of PSMA-PET/CT avidity, suggesting treatment response even after low biological effective dose (BED) MDRT. We observed similar high degree of heterogeneity of PSMA expression in both human specimens and in xenograft tumors. PSMA was highly expressed in LNCap and 22RV1 cells and tumors but not in the neuroendocrine PC3 and DU145 models. Single fraction RT caused detectable reduction in PSMA protein but not in mRNA levels in LNCap cells and did not significantly alter PSMA protein or mRNA levels in tissue culture or xenografts of the other cell lines. However, radio-resistant 22RV1-RR cells and tumors demonstrated marked decrease of PSMA transcript and protein expression over their parental counterparts. Conclusions: PSMA-PET may be a promising tool to assess RT response in oligo-metastatic PrCa. However, future systematic investigation of this concept should recognize the high degree of heterogeneity of PSMA expression within prostate tumors and the risk for loss of PSMA expression in tumor surviving curative courses of RT.

Purpose: Our purpose was to evaluate intra-prostatic cancer volumes for salvage radiotherapy in men with recurrent prostate cancer confined to the prostate post-primary radiotherapy using mpMRI and 18F-DCFPyL PET/CT (PET). Methods: Men with biochemical failure post-primary radiotherapy were enrolled in a multi-centre trial investigating mpMRI and PET. All men with isolated intra-prostatic recurrence are included in this secondary analysis. The intra-prostatic gross tumour volume (GTV) was manually delineated on mpMRI and was also delineated on PET using three methods: 1. manually, 2. using a 30% threshold of maximum intra-prostatic standard uptake value (SUVmax), and 3. using a 67% threshold of this SUVmax. Clinical target volumes (CTV) including expansions on each GTV were generated. Conformity indices were performed between the mpMRI CTV and each PET CTV. Correlation with biopsy and clinical outcomes were performed. Results: Of the 36 men included, 30 (83%) had disease in two quadrants or less using the combination of mpMRI and PET. Mean target volume (union of CTV on mpMRI and CTV manually delineated on PET) was 12.2 cc (49% of prostate gland volume). 12/36 (33%) men had a biopsy. Per-patient sensitivity was 91% for mpMRI and 82% for PET. Conclusions: mpMRI and PET provide complementary information for delineation of intra-prostatic recurrent disease. Union of CTV on mpMRI and PET is often less than 50% of the prostate, suggesting this imaging could help define a target for focal salvage therapy.

Abstract Background Preservation of hamstring tendon insertion at the time of anterior cruciate ligament (ACL) reconstruction is a well-known technique; however, its effect on graft integration is not well studied. The present study was conducted to study the graft integration inside the tibial and femoral tunnels, respectively, after ACL reconstruction using hamstring tendon graft with preserved insertion. Methods Twenty-five professional athletes who underwent ACL reconstruction using hamstring tendon graft with preserved tibia insertion were enrolled in the study. Functional outcomes were checked at final follow-up using Lysholm score and Tegner activity scale. Magnetic resonance imaging (MRI) was done at 8 months and 14 months follow-up to study the graft tunnel integration of the ACL graft at both tibial and femoral tunnels. Results The mean Fibrous interzone (FI) score (tibial tunnel) decreased from 2.61 (1–5) at 8 months to 2.04 (1–4) at 14 months follow-up (p = 0.02). The mean FI score (femoral side) decreased from 3.04 (2–5) at 8 months to 2.57 (2–4) at 14 months (p = 0.02). Conclusions Graft integration occurs early in the tibial tunnel as compared with the femur tunnel with preserved insertion hamstring tendon autograft. Trial registration CTRI/2019/07/020320 [registered on 22/07/2019]; http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=33884&EncHid=&modid=&compid=%27,%2733884det%27

Objectives: Since the introduction of the first master–slave robotic platform for surgical procedures, there have been ongoing modifications and development of new platforms, but there is still a paucity of commercially available systems. Our study aims to identify all master–slave robotic surgical platforms currently commercially available or in development around the world with applications in urologic surgery. Methods: A scoping literature search was performed using PRISMA methodology to identify all relevant publications in English in PubMed, PubMed Central, and Embase, with additional information being obtained from official company websites. Results: Ten robotic platforms with either proven or potential application in urologic surgery were identified: the da Vinci surgical system (Intuitive), Senhance surgical system (Transentrix), Versius Surgical (CMR Ltd), Enos surgical system (Titan Medical), Revo –I (Meere Company), MiroSurge (DLR), Avatera System (Avatera Medical), Hugo Surgical Robot (Medtronic), Ottava (J&J, Ethicon, Areus), and Hinotori (Medicaroid Corporation). Conclusions: This review highlights the distinct features of emerging master–slave robotic platforms with applications in urologic surgery. Research and development are now focused on finding wider applications, improving outcomes, increasing availability, and reducing cost. Additional research is required comparing newly developed master–slave robotic platforms with those already well established.

Purpose: With the integration of immunotherapy (IO) agents in the management of metastatic renal cell carcinoma (mRCC), there has been interest in the combined use with radiation therapy (RT). However, real world data are limited. The purpose of this study was to evaluate outcomes in patients with mRCC receiving both RT and IO compared with IO alone. Methods and Materials: Data were collected from Canadian Kidney Cancer Information System from January 2011 to September 2019 across 14 academic centers. Patients with mRCC who received IO as first- or second-line therapy were included. RT was categorized as radical dose or palliative dose. Kaplan-Meier estimates were reported for overall survival (OS) and time to treatment failure. Cox proportional hazard models were used adjusted for age and International Metastatic RCC Database Consortium risk categories. Results: In total, 505 patients were included in the study: 179 received RT + IO and 326 received IO alone. Two-year OS for the RT + IO group was 55.0% compared with 66.4% in the IO alone cohort (adjusted hazard ratio [aHR], 1.38; P = .07). At 2 years, 12.2% of the RT + IO patients remained on therapy versus 30.9% in the IO alone group (aHR, 1.30; P = .02). For patients receiving first-line therapy, 2-year OS in the RT + IO group was 56.4% versus 78.4% in the IO alone arm, though this difference was not statistically significant (aHR, 1.23; P = .56). For patients receiving radical dose and palliative dose, 2-year OS was 57.0% and 53.9%, respectively (aHR, 0.86; P = .63). Conclusions: In this descriptive analysis, more than one-third of patients with mRCC received RT and demonstrated inferior outcomes compared with IO alone. Potential explanations include greater presence of adverse metastatic sites in those receiving RT. Prospective clinical trials evaluating potential benefits of RT in an IO era remain an important need.

Li-Fraumeni Syndrome (LFS) is defined by germline mutations of the p53 tumour suppressor gene. Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that is commonly associated with LFS. Most LFS-linked ACC cases occur in children, and limited research has been dedicated to the clinical outcomes and genomics of adult cases with LFS-linked ACC. We report on a 34-year-old female who was diagnosed with three separate malignancies: stage III invasive ductal carcinoma of the right breast, metastatic ACC from the right adrenal gland, and grade 2 pleomorphic sarcoma of the left hand. Her invasive breast ductal carcinoma was treated with neoadjuvant chemotherapy, and she received a bilateral mastectomy after her LFS was confirmed with genetic blood testing. Adrenal ACC was initially treated with a right nephrectomy and adrenalectomy, followed by adjuvant mitotane and two lines of chemotherapy after disease recurrence. Her hand sarcoma was treated by second ray amputation. Further, we conducted deep next-generation sequencing of each of her unique tumour tissue samples using FoundationONE CDx. A whole-genome shot capture followed by in vitro sequencing performed by the Illumina® HiSeq platform revealed a germline P191fs*18 TP53 mutation across all three tissue samples. This case provides insight into the genomics and clinical characteristics of LFS-linked adult-onset ACC and demonstrated that p53 mutations were preserved throughout each malignancy, without apparent treatment pressures on genomic profiling. This case reinforces the critical importance of adopting best practices for LFS, which include the implementation of highly vigilant screening and management of care in a multidisciplinary setting.

Abstract Background Bosniak III and IV cysts have a high risk of malignancy and have traditionally been managed surgically. However, growing evidence suggests that many can be managed by active surveillance. The main objective of this study was to characterize the use of surveillance in the management of complex renal cysts. Methods A web-based survey was sent to all registered, active members of the Canadian Urological Association (N = 583) in October 2018. Results The survey response rate was 24.7%. Management of Bosniak III cysts varied considerably. A large proportion of respondents (33.1%) offered active surveillance in > 50% of cases. Only 13.7% of respondents reported never or rarely ( 50% of cases. A significantly greater proportion of academic urologists, compared to non-academic urologists, viewed surveillance as a management option for patients with a Bosniak III or IV cyst. The most commonly reported barriers to a greater adoption of surveillance were concerns regarding its oncologic safety, the lack of data to support surveillance in this population, and the lack of triggers for discontinuation of active surveillance and intervention. Conclusions Despite active surveillance being included as a management option in guidelines, many Canadian urologists are reluctant to offer surveillance to patients with Bosniak III or IV cysts. Practice patterns are heterogeneous among those offering surveillance. High-quality studies are required to better define the benefits and risks of cystic renal mass surveillance.

INTRODUCTION: In metastatic renal cell carcinoma (mRCC), the bone is the second most common site of metastasis and is associated with increased morbidity and poorer quality of life. Bone-targeted therapies (BTTs) such as denosumab and zoledronic acid may prevent skeletal-related events (SREs). However, the benefit of BTTs in combination with tyrosine kinase inhibitors (TKIs) remains unclear. METHODS: We performed a retrospective chart review at the Urologic Cancer Centre for Research and Innovation. Patients with mRCC were included if they had bone metastases treated with TKIs between 2010 and 2017. Our primary outcome was overall survival (OS), defined as the time elapsed from clinical diagnosis of mRCC to death, and modelled using the Kaplan–Meier method. Secondary outcomes included the median time to SRE and the analysis of prognostic factors of OS using Cox proportional hazards regression. RESULTS: In total, 230 patients with mRCC were identified; of which, 46 had bone metastases treated with TKIs and were included in the study (TKI-only, n = 37; TKI + BTT, n = 9). In the TKI + BTT cohort, patients received either denosumab (n = 5) or zoledronic acid (n = 4). At the time of analysis, 63% of patients were deceased. We observed an OS trend favouring the TKI + BTT cohort (13.8 months [95% confidence interval {CI}: 12.3–15.2] vs. 29.6 months [95% CI: 7.2–51.9], hazard ratio [HR]: 1.66 (95% CI: 0.62–4.45), P = 0.31). When patients in the TKI + BTT cohort were stratified by type of therapy (denosumab or zoledronic acid), the median time to SRE was similar between the groups (4.2 months [95% CI: 2.28–6.14] vs. 2.2 months [95% CI: not available], P = 0.71]. On univariate or multivariate analysis, it was found that age, gender, comorbidities, International metastatic RCC database consortium (IMDC) prognostic group and pathologic tumour grade were not significant predictors of worse OS. Pathologic stage 3 or 4 was an independent predictor of worse OS (HR: 5.8, 95% CI: 1.41–24.03, P = 0.015). CONCLUSION: BTTs may have a continued role in the era of targeted therapy and immunotherapy. Further prospective data are required to validate our findings.

Background: COVID-19 pandemic has led to disruption of onsite teaching of medical students, necessitating faculty to start online teaching at a short notice. This faculty survey was conducted with an aim to identify their perceptions, preparations, and participation in online teaching-learning activities during early lockdown period in our medical college. Materials and Methods: A Google form for online survey using a peer-reviewed 27 item questionnaire was designed and the link was shared with all faculty from Dean's office through WhatsApp group and E-mail. Data gathered were analyzed quantitatively and qualitatively to identify the perceptions, challenges faced, and need for corrective actions. Results: Out of 136 faculty, 108 (79.4%) responded. Majority (93; 88.89%) had put efforts to develop their skills for online teaching after lockdown was imposed. Eighty faculty (74.07%) had taken online classes using online platforms, mainly WhatsApp (77.5%), Zoom (56.25%), and Google classroom (25%). Flexibility and convenience for students and teachers were perceived as most common advantages while missing eye contacts and in-depth discussions were perceived as the most common disadvantages. Teaching and assessing cognitive skills was perceived as most feasible and psychomotor skills as least feasible using online platform. Need for faculty training for online-teaching methodology was strongly expressed; a faculty development program for the same was designed and conducted. Conclusions: Majority of the faculty had put efforts to develop skills for online teaching and started taking online classes, mainly on WhatsApp and Zoom. They strongly perceived need for faculty-development for online teaching methodology; teaching and assessment of cognitive skills was perceived as most feasible as compared to other skills.

ObjectiveAssess the work environment of salaried pathologists via (1) the national workload system (L4E), (2) work distribution among/in three hospital groups, and (3) the frequency of significant absences or departures (SADs).MethodsAutomated analysis of pathology reports from a regional laboratory (accessioned 2011-2019) using validated computer code.ResultsThe study set contained 574,099 pathology reports, reported by 63 pathologists. The average yearly L4E workload units/full-time equivalent for three hospital groups were 8,101.6, 6,906.5 and 4,215.8. The average Gini coefficient for full-time pathologists in the three hospital groups were respectively 0.05, 0.16 and 0.23. The average yearly SADs rates were respectively 13%, 16% and 9%. The group with the highest SADs rate had the intermediate Gini coefficient and intermediate workload.ConclusionsHigh individual workload and work maldistribution appear to be associated with SADs. Individual workload maximums and greater transparency may be essential for limiting staff turnover, maintaining high morale, and efficient laboratory function with a high quality of care.

Background: Vitamin D deficiency is high in athletes and has an impact on athletes' performance. Introduction: Assessment of serum Vitamin D levels in healthy North Indian sportspersons and its correlation with serum parathyroid hormone (PTH) levels and bone mineral density (BMD). Materials and Methods: Three-hundred and sixty-nine healthy athletes' aged 18–45 years were enrolled. Depending upon Vitamin D levels athletes were categorized into three groups: deficient (30 ng/ml). BMD and serum PTH levels were assessed in all athletes and correlation was seen with Vitamin D levels. Results: Two-hundred and fifty-eight (69.9%) athletes were Vitamin D deficient, 51/369 (13.8%) were Vitamin D insufficient, and 60/369 (16.3%) athletes were Vitamin D sufficient. There was a direct correlation between low serum Vitamin D levels and low BMD (r = 0.473; P < 0.05). Overall, 114/369 (30%) athletes had low BMD and out of these 114 athletes, 108 (95%) were Vitamin D deficient. Serum PTH levels were found to have inverse relations with both Vitamin D (r= −0.629) and BMD (r=-0.267). Conclusions: Vitamin D deficiency is highly prevalent among the North Indian athletes and the presence of low Vitamin D (

The coronavirus disease 2019 (COVID-19) pandemic has been universal and swift in its spread. As orthopaedic surgeons, for the most of us this timeframe has reduced our activity to emergency and trauma cases only, with virtual outpatient clinics and no elective surgeries. With some of the common deformity problems including clubfoot etc, which comprises a large number of children in the developing world, the management has been deferred, without any regional and national guidelines being framed. Updated guidelines relating to the management of clubfoot patients, in which parents can safely consult with the orthopaedic surgeon and physical rehabilitation specialists will allow them to cope with this unprecedented situation. We revisit the current scenario and the possible management protocol in the context of COVID-19 pandemic.

Purpose: Our purpose was to investigate the effect of the addition of prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) in patients with recurrent prostate cancer post-primary radiation therapy. Methods and Materials: A prospective, multi-institutional clinical trial evaluated 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) PET/CT restaging in 79 men with recurrent prostate cancer post-primary radiation therapy. We report actual patient management and compare this with proposed management both before and after PSMA-targeted PET/CT. Results: Most patients (59%) had a major change in actual management compared with pre-PET/CT proposed management. The rate of major change was underestimated by immediately post-PET/CT surveys (32%). Eighteen patients with PSMA avidity in the prostate gland suspicious for malignancy had a prostate biopsy. Sensitivity, specificity, and positive predictive values of PSMA uptake in the prostate were 86%, 67%, and 92%, respectively. Thirty percent of patients had directed salvage therapy and 41% underwent systemic therapy. Eleven out of 79 patients (14%) had high-dose-rate brachytherapy alone for local recurrence, and 91% were free of recurrence at a median follow-up of 20 months. Conclusions: Most patients had a major change in actual management compared with pre–PSMA-targeted PET/CT planned management, and this was underestimated by post-PET/CT questionnaires.

ObjectiveQuantify changes in workload in relation to the anatomic pathologist workforce.MethodsIn house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy.ResultsThe study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x.ConclusionsWork by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce.

Introduction: The common practice prevalent in most of the Postgraduate (PG) teaching institutes is that while the PGs are clinically evaluating the patients for the traditional long case, they are mostly not directly observed by the faculty. The presentation of the case by PGs is the main focus of assessment. Workplace Based Assessment (WPBA) tools assess the clinical competence of students at the ‘does’ level of Miller’s pyramid, while they perform in a real setting. Aim: To assess the feasibility, acceptability and effectiveness of Mini-Clinical Evaluation Exercises (Mini-CEX) for the PGs in Surgery. Materials and Methods: This educational intervention study was conducted in the General Surgery Department, over a period of one year. Sixteen PGs of 1st, 2nd, and 3rd-year residency participated in the study, and 13 faculty as assessors. The MiniCEX was conducted and the abim.org proforma was used to record the observations by the faculty. The perceptions of the PGs and faculty were obtained at the end of the study using a predesigned validated feedback questionnaire. The change in the level of acquisition of clinical skills of the PGs was evaluated using the group mean, median and rank. The Friedman test was applied to calculate the statistical significance at p

Abstract Background Succinate dehydrogenase (SDH)- deficient renal cell carcinoma (RCC) is a newly identified rare subtype of RCC, having only gained acceptance from the World Health Organization in 2016. To the best of our knowledge, there are only 55 reported cases worldwide. Here, we report a new case of SDH-deficient RCC. Case presentation A 49-year-old male patient was incidentally found to have a large right renal mass. He had no personal or family history of paragangliomas (PGL), pheochromocytomas (PC), or gastrointestinal stromal tumors (GIST). The neoplasm was unilateral and unifocal. He underwent an open partial nephrectomy. Detailed pathological analysis was conducted to confirm the diagnosis. Genetic testing revealed a pathogenic mutation in the SDHB gene. He has been followed for 24 months now and has remained well without any evidence of local or distant recurrence. In this report we describe our experience with this diagnosis and review the relevant clinical, pathological, and genetic features. Conclusions Without the identification of SDHB deficiency, this patient’s personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis. When faced with an eosinophilic RCC, pathologists should routinely search for vacuoles or flocculent cytoplasmic inclusions. When these are present, or in cases of difficult eosinophilic renal tumors, staining for SDHB is recommended. For tumours without adverse pathologic features (i.e. high nuclear grade, coagulative necrosis, or sarcomatoid differentiation) excision alone may be a reasonable option, with the addition of regular surveillance for PC and PGLs in those found to harbor germline SDH mutations.

Butyrylcholinesterase (BChE) is a plasma enzyme that hydrolyzes ghrelin and bioactive esters, suggesting a role in modulating metabolism. Serum BChE is reduced in cancer patients. In prostate cancer (PC), the down-regulation is associated with disease recurrence. Nonetheless, how BChE is expressed in PC and its impact on PC remain unclear. We report here the biphasic changes of BChE expression in PC. In vitro, BChE expression was decreased in more tumorigenic PC stem-like cells (PCSLCs), DU145, and PC3 cells compared to less tumorigenic non-stem PCs and LNCaP cells. On the other hand, BChE was expressed at a higher level in LNCaP cells than immortalized but non-tumorigenic prostate epithelial BPH-1 cells. In vivo, BChE expression was up-regulated in DU145 xenografts compared to LNCaP xenografts; DU145 cell-derived lung metastases displayed comparable levels of BChE as subcutaneous tumors. Furthermore, LNCaP xenografts produced in castrated mice exhibited a significant increase of BChE expression compared to xenografts generated in intact mice. In patients, BChE expression was down-regulated in PCs (n = 340) compared to prostate tissues (n = 86). In two independent PC populations MSKCC (n = 130) and TCGA Provisional (n = 490), BChE mRNA levels were reduced from World Health Organization grade group 1 (WHOGG 1) PCs to WHOGG 3 PCs, followed by a significant increase in WHOGG 5 PCs. The up-regulation was associated with a reduction in disease-free survival (P = .008). Collectively, we demonstrated for the first time a biphasic alteration of BChE, its down-regulation at early stage of PC and its up-regulation at advanced PC.

Objective: The purpose of this study is to assess the impact of spaced learning in an undergraduate teaching and learning program in pediatrics. Methodology: Analytical study involving the final year medical students posted in the Department of Pediatrics. “Spaced” learning opportunities were provided in addition to the conventional didactic lectures over 8 weeks for the assigned topics. The scores obtained before and after the spaced learning were analyzed using “t”-test. Results: A total of 37 students who underwent the spaced learning initiative and participated in both the tests (before and after spaced learning) were included in the analysis. There was significant positive correlation between the scores of the two groups r = 0.526 (P < 0.001). Paired sample “t”-test showed that there was a statistically significant difference between the test scores with a mean of 11.23, t = 7.434 (P < 0.001). Conclusion: Spaced learning had a significant impact on the students in their learning and recall, leading to better performance in their examination.

Renal cell carcinoma (RCC) in transplanted kidneys has been reported sporadically with incidence of about 0.5%. There are currently no standard guidelines on the management of allograft RCC in renal transplant recipients. Our objective was to study effectiveness of nephron-sparing surgery (NSS) for allograft RCC. We performed a retrospective analysis of patients with RCC in renal allografts managed with NSS in our institution from January 2000 to December 2015. Patient demographics, interval between transplant and RCC diagnosis, operative parameters, perioperative complications, final pathology, and renal function were evaluated. Three females underwent successful NSS for allograft RCC. Cause of end-stage renal disease was IgA nephropathy in all; mean time between renal transplant and diagnosis of RCC was 23 years. We were able to stay extraperitoneal in all the cases. In the final pathology, two had papillary and one had clear cell RCC. One patient developed pyelocutaneous fistula which was managed by stenting. Long-term functional outcomes of NSS are excellent; none of our patients is dialysis dependent.

We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN−/− mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n = 300), testing (n = 185), and validation (n = 194) cohort. Using the Cox model, a nine-gene signature was derived, including eight genes from a MUC1-related network (APC, CTNNB1/β-catenin, GALNT10, GRB2, LYN, SIGLEC1, SOS1, and ZAP70) and FAM84B. Genomic alterations in these genes reduce disease-free survival (DFS) in the training (P = .00161), testing (P = .00699), entire (training + testing, P = 5.557e-5), and a validation cohort (P = 3.326e-5). The signature independently predicts PC recurrence [hazard ratio (HR) = 1.731; 95% confidence interval (CI): 1.104-2.712; P = .0167] after adjusting for known clinical factors and stratifies patients with high risk of PC recurrence using the median (HR 2.072; 95% CI: 1.245-3.450, P = .0051) and quartile 3 (HR 3.707, 95% CI: 1.949-7.052, P = 6.51e-5) scores. Several novel β-catenin mutants are identified in PCs leading to a rapid onset of death and recurrence. Genomic alterations in APC and CTNNB1/β-catenin reduce DFS in two independent PC cohorts (n = 485, P = .0369; n = 84, P = .0437). The nine-gene signature also associates with reductions in overall survival (P = .0458) and DFS (P = .0163) in melanoma patients (n = 367). MUC1 upregulation is associated with CRPC and bone metastasis. A nine-gene signature derived from a MUC1 network predicts PC recurrence.

Background: The aim of this study was to investigate the contributions of FAM84B in prostate tumorigenesis and progression. Methods: A FAM84B mutant with deletion of its HRASLS domain (ΔHRASLS) was constructed. DU145 prostate cancer (PC) cells stably expressing an empty vector (EV), FAM84B, or FAM84B (ΔHRASLS) were produced. These lines were examined for proliferation, invasion, and growth in soft agar in vitro. DU145 EV and FAM84B cells were investigated for tumor growth and lung metastasis in NOD/SCID mice. The transcriptome of DU145 EV xenografts ( n = 2) and DU145 FAM84B tumors ( n = 2) was determined using RNA sequencing, and analyzed for pathway alterations. The FAM84B-affected network was evaluated for an association with PC recurrence. Results: FAM84B but not FAM84B (ΔHRASLS) increased DU145 cell invasion and growth in soft agar. Co-immunoprecipitation and co-localization analyses revealed an interaction between FAM84B and FAM84B (ΔHRASLS), suggesting an intramolecular association among FAM84B molecules. FAM84B significantly enhanced DU145 cell-derived xenografts and lung metastasis. In comparison with DU145 EV cell-produced tumors, those generated by DU145 FAM84B cells showed a large number of differentially expressed genes (DEGs; n = 4976). A total of 51 pathways were enriched in these DEGs, which function in the Golgi-to-endoplasmic reticulum processes, cell cycle checkpoints, mitochondrial events, and protein translation. A novel 27-gene signature (SigFAM) was derived from these DEGs; SigFAM robustly stratifies PC recurrence in two large PC populations ( n = 490, p = 0; n = 140, p = 4e −11 ), and remains an independent risk factor of PC recurrence after adjusting for age at diagnosis, Gleason scores, surgical margin, and tumor stages. Conclusions: FAM84B promotes prostate tumorigenesis through a complex network that predicts PC recurrence.

We have recently reported that CYB5D2 plays a role in suppression of cervical cancer tumorigenesis, “CYB5D2 displays tumor suppression activities towards cervical cancer” [1]. We provide the accompany data here describing the effects of CYB5D2 overexpression and addition of recombinant CYB5D2 on HeLa cell cycle distribution. Furthermore, we will present the conditions used to specifically determine CYB5D2 expression in primary cervical and cervical cancer tissues using immunohistochemistry (IHC) and the patient cohort involved in assessing the CYB5D2 protein levels in primary cervical and cervical cancer tissues.

Alzheimer’s disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.

BACKGROUND: India is at the nascent stage of competency-based medical education. Faculties trained in medical education are the main driving force for change. The present study explores the perception of faculties about the current practices and problems in medical/dental/nursing undergraduate assessment, barriers to adoption of best practices, and solutions for addressing them. METHODOLOGY: A qualitative study was designed and data collected through an asynchronous online discussion forum. A group of 31 health professionals (FAIMER fellows selected on the basis of active participation in department of medical education of respective colleges) participated in the forum. An open-ended topic guide with prompts was designed. The forum was initiated by release of discussion topics (threads) at the start of the month and remained in forum throughout the month. Researchers moderated and recorded day-to-day events. All online forum data were coded line by line and analyzed using conventional content analysis. RESULTS: Four categories generated were: (1) Low utility of current skill assessment system due to low validity and reliability; (2) Barrier in adopting newer assessment tool due to the absence of felt need of faculties and students, mistaken beliefs, and limited resources; (3) Poor implementation of newer assessment tools such as formatives and objective structured clinical examination with no blueprinting; and (4) Solutions proposed were regular formative assessment, criterion-based examination, quality-assured faculty development programs, and administrative support. CONCLUSIONS: Barriers in adopting newer assessment tools are related to the faculty's perception and resource constraint. This can be addressed by quality-assured faculty development programs and effective implementation of competency-based education.

OBJECTIVE: We refer to the effectiveness (known as pragmatic or real world) and efficacy (known as explanatory or desired or ideal world) of interventions. However, these terms seem to be randomly chosen by investigators who design clinical trials and do not always reflect the true purpose of the study. A pragmatic-explanatory continuum indicator summary tool was thus developed with the aim of identifying the characteristics of clinical trials that distinguish between effectiveness and efficacy issues. We verified whether clinical trials used the criteria proposed by the indicator summary tool, and we categorized these clinical trials according to a new classification. METHOD: A systematic survey of randomized clinical trials was performed. We added a score ranging from 0 (more efficacious) to 10 (more effective) to each domain of the indicator summary tool and proposed the following classifications: high efficacy (

Emphysematous pyelonephritis (EPN) in renal allograft is rare but potentially lethal complication and requires aggressive medical and/or surgical therapy to achieve cure. We report a case of 60-year-old diabetic male with poor cardiac function on maintenance hemodialysis, who underwent delayed allograft nephrectomy for EPN in failed renal allograft. Blood culture grew Bacteroides. He was stable in the postoperative period but passed away on day 4 due to myocardial infarction likely secondary to poor baseline cardiac function. Delay in diagnosis and treatment could have contributed to this unfavorable outcome. There is a paucity of published literature regarding EPN in the transplant population, such that management decisions (percutaneous conservative versus urgent surgical) are challenging. Further studies are required to establish treatment guidelines.

BACKGROUND:Anderson-Fabry disease (AFD) is an X-linked recessive inborn error of glycosphingolipid metabolism caused by a deficiency of alpha-galactosidase A. Renal failure, heart and cerebrovascular involvement reduce survival. A Cochrane review provided little evidence on the use of enzyme replacement therapy (ERT). We now complement this review through a linear regression and a pooled analysis of proportions from cohort studies. OBJECTIVES:To evaluate the efficacy and safety of ERT for AFD. MATERIALS AND METHODS:For the systematic review, a literature search was performed, from inception to March 2016, using Medline, EMBASE and LILACS. Inclusion criteria were cohort studies, patients with AFD on ERT or natural history, and at least one patient-important outcome (all-cause mortality, renal, cardiovascular or cerebrovascular events, and adverse events) reported. The pooled proportion and the confidence interval (CI) are shown for each outcome. Simple linear regressions for composite endpoints were performed. RESULTS:77 cohort studies involving 15,305 participants proved eligible. The pooled proportions were as follows: a) for renal complications, agalsidase alfa 15.3% [95% CI 0.048, 0.303; I2 = 77.2%, p = 0.0005]; agalsidase beta 6% [95% CI 0.04, 0.07; I2 = not applicable]; and untreated patients 21.4% [95% CI 0.1522, 0.2835; I2 = 89.6%, p

PURPOSE: Systematic reviews are criticized for frequently offering inconsistent evidences and absence of straightforward recommendations. Their value seems to be depreciated when the conclusions are uncertain. To describe an alternative approach of evaluating case series studies in health care when there is absence of clinical trials. METHODS: We provide illustrations from recent experiences. Proportional meta-analysis was performed on surgical outcomes: (a) case series studies, (b) use of cryoablation or radiofrequency ablation, and (c) patients with small renal cell carcinoma. The statistically significant difference between both interventions studied was defined if their combined 95% confidential interval (CI) did not overlap. RESULTS: As demonstrated by the example, this analysis is an alternative approach to provide some evidence of the intervention´s effects under evaluation and plotting all available case series in the absence of clinical trials for the health field. CONCLUSIONS: Although we are leading to a low level of evidence to determine efficacy, effectiveness and safety of interventions this alternative approach can help surgeons, physicians and health professionals for a provisionally decision in health care along with their clinical expertise and the patient´s wishes and circumstances in the absence of high-quality primary studies. It´s not a replacement for the gold standard randomized clinical trial, but an alternative analysis for clinical research.

Fungi can cause serious cranial infections in immunocompromised and diabetic patients. Common pathogens mainly include Aspergillus and Mucor. These organisms cause tissue invasion and destruction of adjacent structures (e.g. orbit, ethmoid, sphenoid, maxillary & cavernous sinuses). Mortality and morbidity rate is high despite combined surgical, antifungal and antidiabetic treatment. We present our experience of six cases with such infection.

Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual’s quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. The three classes of drugs approved for treating BPH include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors. Individually, each class of drug has been studied and shown to improve symptom relief through a variety of different mechanisms. A more recent focus has been on the development of combinatorial therapies that combine classes of drugs in order to provide maximal benefit. The mTOPS and CombAT studies were the first of their kind to examine whether the combination of 5-ARIs and α-blockers was more effective than monotherapy alone. Both studies found similar results in that the combinatorial therapy was superior to monotherapy. Over the last decade other combinatorial therapies have been at the forefront of investigation. One in particular is the combination of tadalafil, a PDE-5 inhibitor, with finasteride, a 5-ARI. Studies have shown that the combination of tadalafil and finasteride is a safe, effective, and well tolerated treatment for BPH. Evidence suggests that this combination may be particularly effective in reducing treatment-related sexual adverse events associated with 5-ARI treatments. The following review will explore in detail the current evidence surrounding treatment of BPH LUTS using tadalafil and finasteride.

Purpose : Data of laparoscopic donor nephrectomy (LDN) with multiple renal arteries for donor and recipient outcomes were reviewed, with the aim of clarifying whether the laparoscopic approach is safe in the presence of multiple renal arteries. Materials and Methods : All donor nephrectomies performed at our institution from 2004 to 2008 were reviewed retrospectively. Results were compared between LDN kidneys with multiple arteries and those with a single renal artery. Results : Out of 171 donor nephrectomies, 21 (12%) were performed for kidneys with multiple renal arteries. All of the 150 (88%) donor nephrectomies in the single vessel group were performed laparoscopically. In the multiple artery group, 9 (43%) underwent an open procedure while 12 (57%) underwent a laparoscopic procedure. The warm ischemia time was longer in the multiple artery group than the single artery group, but the difference was not statistically significant (4.25±0.87 min vs. 4.12±0.95 min, respectively). Regarding transplant recipients, the vascular anastomosis time was similar in both groups (30±4.6 min vs. 29.5±3.7 min). The operative blood loss in the transplant recipients was significantly more in the multiple artery group compared to the single artery group (339±292 ml and 130.7±44.8 ml, respectively; P=0.03). The recipient renal function was similar for both the groups at postoperative day 7, 1 month, and at 1 year. Conclusion : The data support the fact that the laparoscopic approach to donor nephrectomy in the presence of multiple renal arteries can be performed safely with adequate laparoscopic experience.

Rohan Shahani, Kevin G Kwan, Anil KapoorDivision of Urology, Department of Surgery, St. Joseph’s Healthcare Hamilton and McMaster University, Hamilton, Ontario, CanadaAbstract: Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma.Keywords: metastatic renal cell carcinoma, everolimus, mTOR inhibitors, VEGF inhibitors

Background: Observational data and funnel plots are routinely used outside of pathology to understand trends and improve performance. Objective: Extract diagnostic rate (DR) information from free text surgical pathology reports with synoptic elements and assess whether inter-rater variation and clinical history completeness information useful for continuous quality improvement (CQI) can be obtained. Methods: All in-house prostate biopsies in a 6-year period at two large teaching hospitals were extracted and then diagnostically categorized using string matching, fuzzy string matching, and hierarchical pruning. DRs were then stratified by the submitting physicians and pathologists. Funnel plots were created to assess for diagnostic bias. Results: 3,854 prostate biopsies were found and all could be diagnostically classified. Two audits involving the review of 700 reports and a comparison of the synoptic elements with the free text interpretations suggest a categorization error rate of 40 cases and together assessed 3,690 biopsies. There was considerable inter-rater variability and a trend toward more World Health Organization/International Society of Urologic Pathology Grade 1 cancers in older pathologists. Normalized deviations plots, constructed using the median DR, and standard error can elucidate associated over- and under-calls for an individual pathologist in relation to their practice group. Clinical history completeness by submitting medical doctor varied significantly (100% to 22%). Conclusion: Free text data analyses have some limitations; however, they could be used for data-driven CQI in anatomical pathology, and could lead to the next generation in quality of care.

PTEN is a potent tumor-suppressor protein. Aggressive and metastatic prostate cancer (PC) is associated with a reduction or loss of PTEN expression. PTEN reduction often occurs without gene mutations, and its downregulation is not fully understood. Herein, we show that PTEN is incorporated in the cargo of exosomes derived from cancer cells. PTEN is not detected in exosomes derived from normal, noncancerous cells. We found that PTEN can be transferred to other cells through exosomes. In cells that have a reduction or complete loss of PTEN expression, the transferred PTEN is competent to confer tumor-suppression activity to acceptor cells. In PC patients, we show that PTEN is incorporated in the cargo of exosomes that circulate in their blood. Interestingly, normal subjects have no PTEN expression in their blood exosomes. Further, we found that the prostate-specific antigen (PSA) is incorporated in PC patients' and normal subjects' blood exosomes. These data suggest that exosomal PTEN can compensate for PTEN loss in PTEN deficient cells, and may have diagnostic value for prostate cancer.