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Abstract Epigenetic modulation is well established in hematologic malignancies but to a lesser degree in solid tumors. Here we report the results of a phase Ib/II study of guadecitabine and durvalumab in advanced clear cell renal cell carcinoma (ccRCC; NCT03308396). Patients received guadecitabine (starting at 60 mg/m2 subcutaneously on days 1-5 with de-escalation to 45 mg/m2 in case of dose limiting toxicity) with durvalumab (1500 mg intravenously on day 8). The study enrolled 57 patients, 6 in phase Ib with safety being the primary objective and 51in phase II, comprising 2 cohorts: 36 patients in Cohort 1 were treatment naive to checkpoint inhibitors (CPI) with 0-1 prior therapies and 15 patients in Cohort 2 were treated with up to two prior systemic therapies including one CPI. The combination of guadecitabine 45 mg/m2 with durvalumab 1500 mg was deemed safe. The primary objective of overall response rate (ORR) in cohort 1 was 22%. Sixteen patients (44%) experienced stable disease (SD). Secondary objectives included overall survival (OS), duration of response, progression-free survival (PFS), clinical benefit rate, and safety as well as ORR for Cohort 2. Median PFS for cohort 1 and cohort 2 were 14.26 and 3.91 months respectively. Median OS was not reached. In cohort 2, one patient achieved a partial response and 60% achieved SD. Asymptomatic neutropenia was the most common adverse event. Even though the trial did not meet the primary objective in cohort 1, the tolerability and PFS signal in CPI naive patients are worth further investigation.

Stereotactic ablative radiotherapy (SABR) has challenged the conventional wisdom surrounding the radioresistance of renal cell carcinoma (RCC). In the past decade, there has been a significant accumulation of clinical data to support the safety and efficacy of SABR in RCC. Herein, we review the use of SABR across the spectrum of RCC. We performed an online search of the Pubmed database from January 1990 through April 2023. Studies of SABR/stereotactic radiosurgery targeting primary, extracranial, and intracranial metastatic RCC were included. For SABR in non-metastatic RCC, this includes its use in small renal masses, larger renal masses, and inferior vena cava tumor thrombi. In the metastatic setting, SABR can be used at diagnosis, for oligometastatic and oligoprogressive disease, and for symptomatic reasons. Notably, SABR can be used for both the primary renal tumor and metastasis-directed therapy. Management of RCC is evolving rapidly, and the role that SABR will have in this landscape is being assessed in a number of ongoing prospective clinical trials. The objective of this narrative review is to summarize the evidence corroborating the use of SABR in RCC.

Abstract Background Immuno‐oncology therapy (IO) is associated with a variety of treatment‐related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune‐related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females. Aims Our aim was to determine if there was a difference in the rate of immunotherapy treatment change due to toxicity between males and females. Methods and Results The Oncology Research Information Exchange Network Avatar Database collected clinical data from 10 United States cancer centers. Of 1035 patients receiving IO, 447 were analyzed, excluding those who did not have documentation noting if a patient changed treatment (n = 573). Fifteen patients with unknown or gender‐specific cancer were excluded. All cancer types and stages were included. The primary endpoint was documented treatment change due to toxicity. Four hundred and forty‐seven patients (281 males and 166 females) received IO treatment. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course than males (median 3.7 vs. 5.1 months, respectively, p = .02). Fifty‐four patients changed treatment due to toxicity. There was no significant difference between females and males on chi‐square test (11.4% vs. 12.5%, respectively, p = 0.75) and multivariable logistic regression (OR 0.924, 95% CI 0.453–1.885, p = .827). Significantly more patients with chronic obstructive pulmonary disease (COPD) changed therapy due to toxicity (OR 2.491, 95% CI 1.025–6.054, p = .044). Conclusion Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity‐related treatment change was associated with COPD.

Abstract Kidney cancer is a common urologic malignancy with either laparoscopic (LPN) or robotic partial nephrectomy as therapeutic options of choice for localized tumors. However, renal resection and suturing are challenging steps of the procedure that can lead to complications such as prolonged warm ischemia, bleeding, and urinary fistulas. LPN with a diode laser is an efficient technique due to its cutting and/or coagulation attributes. Surprisingly, key laser features such as wavelength and power remain undefined. Using a large porcine model, we evaluated the laser range of wavelength and power in a clamp-free LPN and compared it to the established gold-standard LPN technique (i.e., cold-cutting and suturing). By analyzing surgery duration, bleeding, presence of urine leak, tissue damage related to the resected renal fragment and the remaining organ, hemoglobin levels, and renal function, we show that an optimized experimental diode laser clamp-free LPN (wavelength, 980 nm; power, 15 W) had shorter surgery time with less bleeding, and better postoperative renal function recovery when compared to the well-established technique. Together, our data indicate that partial nephrectomy with a diode laser clamp-free LPN technique is an improved alternative to the gold-standard technique. Therefore, translational clinical trials towards human patient applications are readily feasible.

Intraoperative tumor thrombus embolization is a potentially lethal complication during inferior vena cava (IVC) thrombectomy for renal cell carcinoma (RCC). Intraoperative embolization is uncommonly encountered because IVC thrombectomy surgical technique is focused on avoiding this complication. Nonetheless, early recognition of embolization is essential so that emergent management can be instituted. When available, cardiopulmonary bypass (CPB) and embolectomy should be considered the gold standard for the management of intraoperative embolization. Several novel endovascular techniques are also available for selective use. We present the case of a 71-year-old female with a right renal mass and level II (retrohepatic) IVC tumor thrombus. During cytoreductive nephrectomy and IVC thrombectomy, tumor embolization was diagnosed during a period of hypotension based on transesophageal echocardiographic finding of new thrombus within the right atrium. This prompted sternotomy, CPB, and pulmonary artery embolectomy. The patient survived this embolization event and has a complete response to systemic therapy 9 months postoperatively. This case serves as the framework for a discussion on management considerations surrounding intraoperative embolization during IVC thrombectomy.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians’ understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.

Background: Prostate needle biopsy (PNB) remains the referent standard for diagnosing prostate cancer. Contemporary data highlight an increase in PNB-related infections particularly when performed transrectally. Non-infectious complications, however, may similarly contribute to biopsy-related morbidity. We review the incidence and predictors of non-infectious complications following transrectal PNB in a large statewide quality registry. Methods: Transrectal ultrasound-guided prostate needle biopsies performed between 2015 and 2018 were retrospectively reviewed. The incidence and distribution of non-infectious complications were annotated. Clinical, demographic, and biopsy variables of interest were evaluated by logistic regression for potential association with specific types of non-infectious complications. Results: Of 8,102 biopsies, 277 (3.4%) biopsies had reported post-procedure complications including 199 (2.5%) non-infectious and 78 (0.9%) infectious. Among the non-infectious complications, the most common events included urinary or rectal bleeding (74; 0.9%), urinary retention (70, 0.9%), vasovagal syncope (13, 0.2%), and severe post-operative pain (10, 0.1%). Approximately 56% of these non-infectious complications required an Emergency Department visit (111/199) and 27% (54/199) hospital admission for monitoring. Increasing transrectal ultrasound prostate volume was associated with post-procedure urinary retention (Odds ratio (OR) 1.07, 1.02–1.11, p = 0.002). No specific variables noted association with post-biopsy bleeding. Conclusion: Non-infectious complications occurred 2.5 times more often than infectious complications following transrectal ultrasound prostate needle biopsies. Larger prostate size was associated with a greater risk of post-procedure urinary retention. These data originating from experience from over 100 urologists across different health systems provide an important framework in counseling patients regarding expectations following transrectal prostate biopsy.

Purpose: Approximately 7% of patients with newly diagnosed prostate cancer (PCa) in the US will have have metastatic disease. The dogma that there is no role for surgery in this population has been questioned recently. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. Materials and methods: This is a multicenter phase 1 trial. The major inclusion criterion was biopsy proven N1M0 or NxM1a/b PCa. Primary end point was the Clavien-Dindo-based major complication rate. Secondary outcomes were biochemical progression and overall survival. RNA-seq correlative study was conducted in nine select cases as a pilot study. Results: Final accrual was 32 patients of which 25 and 7 were cNxM1 and cN1M0, respectively. With the median follow-up of 46 months (interquartile range 31.7 - 52.7 months), 25 out of the 32 patients (75%) were alive at the time of last contact. There were three disparate groups based on the oncologic outcome: favorable, intermediate, and poor. In seven men with favorable response, androgen deprivation therapy was switched to intermittent approach and five remain free of any evidence of disease after more than two years off all systemic therapy with the normalization of serum testosterone. Of these five patients, three had M1 disease. Long-term use of one pad or less per day was 80%. RNA-seq analysis revealed an enriched downregulation of tumor necrosis factor (TNF)-α signature in the favorable group. Conclusion: Overall long-term oncologic outcome of cytoreductive radical prostatectomy was significantly higher than historical results. Importantly, the combination of surgery with systemic therapy may result in a long durable response in a minority of men who present with metastatic PCa.

Abstract Background To investigate the effects of the U.S. Preventive Services Task Force’s (USPSTF) 2012 recommendation against prostate-specific antigen (PSA)-based screening for prostate cancer on survival disparities based on insurance status. Prior to the USPSTF’s 2012 screening recommendation, previous studies found that insured patients with prostate cancer had better outcomes than uninsured patients. Methods Using the SEER 18 database, we examined prostate cancer-specific survival (PCSS) based on diagnostic time period and insurance status. Patients were designated as belonging to the pre-USPSTF era if diagnosed in 2010–2012 or post-USPSTF era if diagnosed in 2014–2016. PCSS was measured with the Kaplan–Meier method, while disparities were measured with the Cox proportional hazards model. Results During the pre-USPSTF era, uninsured patients experienced worse PCSS compared to insured patients (adjusted HR 1.256, 95% CI 1.037–1.520, p = 0.020). This survival disparity was no longer observed during the post-USPSTF era as a result of decreased PCSS among insured patients combined with unchanged PCSS among uninsured patients (adjusted HR 0.946, 95% CI 0.642–1.394, p = 0.780). Conclusions Although the underlying reasons are not clear, the USPSTF’s 2012 PSA screening recommendation may have hindered insured patients from being regularly screened for prostate cancer and selectively led to worse outcomes for insured patients without affecting the survival of uninsured patients.

Modern advances in genomic and molecular technologies have sparked substantial research on the human intestinal microbiome over the past decade. A deeper understanding of the microbiome has illuminated that dysbiosis, or a disruption in the microbiome, is associated with inflammatory disease states and carcinogenesis. Novel therapies that target the microbiome and restore healthy flora may have value in dampening the immunopathologic state induced by dysbiosis. A narrative review of the literature on the use of microbiota-centered interventions (MCIs) was conducted. Several randomized clinical trials show that MCIs can augment response to immune checkpoint inhibitor (ICI) therapy in patients with metastatic cancer. Clinical trials have also demonstrated that modulation of the intestinal microbiome can enhance recovery and reduce infectious complications in the surgical management of colorectal adenocarcinoma. Overall, these major discoveries suggest future clinical applications of MCIs for a wide range of immune-mediated conditions. These results may also translate to improved patient outcomes in systemic immunotherapy for urothelial carcinoma as well as in patients recovering from radical cystectomy (RC), which is complicated by high infection rates. Further research is needed to evaluate the optimal bacterial composition of microbiota-centered therapies and the specific cellular changes that lead to improved tumor antigen recognition after microbiota-centered therapies.

Abstract Since 2004, multiple blockbuster drugs have been approved for men with metastatic prostate cancer. Nevertheless, it has been reported that no improvement in survival was observed between 2004 and 2009. Herein, we have analyzed the SEER database to assess the survival outcome of metastatic prostate cancer patients since 2000. The results demonstrated that there was an improvement in both overall and prostate cancer‐specific survival for 4 months among men diagnosed with metastatic prostate cancer from 2010 to 2016 when compared to those in the pre‐2010 period. Interestingly, this survival benefit was limited to patients with bone and visceral metastasis (M1b and M1c stages). Collectively, our observation suggests that despite the new treatment agents such as second‐line antiandrogen therapies introduced in the modern era, the improvement in survival of metastatic prostate cancer patients has been surprisingly small.

While the gold-standard for management of localized renal cell carcinoma (RCC) is partial nephrectomy, recent ablative strategies are emerging as alternatives with comparable rates of complications and oncologic outcomes. Thermal ablation, in the form of radiofrequency ablation and cryoablation, is being increasingly accepted by professional societies, and is particularly recommended in patients with a significant comorbidity burden, renal impairment, old age, or in those unwilling to undergo surgery. Maturation of long-term oncologic outcomes has further allowed increased confidence in these management strategies. New and exciting ablation technologies such as microwave ablation, stereotactic body radiotherapy, and irreversible electroporation are emerging. In this article, we review the existing management options for localized RCC, with specific focus on the oncologic outcomes associated with the various ablation modalities.

Background: Recent studies suggest an association between prostate cancer and inflammatory bowel disease (IBD). Our objectives were to investigate clinical and financial impacts of IBD on radical prostatectomy (RP) and to determine the impact of surgical approach on our findings. Methods: The Premier Hospital Database was queried for patients who underwent RP from 2003 to 2017. Multivariable logistic regression models were used to determine the independent impact of IBD on complications and readmission rates. We determined 90-day readmissions and examined 90-day hospital costs adjusted to 2019 US dollars with multivariable quantile regression models. Results: Our study population included 262,189 men with prostate cancer, including 3,408 (1.3%) with IBD. There were higher odds for any complication for IBD patients compared with non-IBD controls for RP (15.64% vs. 10.66%). Patients with IBD had overall complication rates of 14.1% (P

Background: We aimed to illustrate national trends of post-radical prostatectomy (RP) radiotherapy (RT) and compare outcomes and toxicities in patients receiving eRT versus observation with or without late radiotherapy (lRT). Methods: Utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2001 to 2011, we identified 7557 patients with high-risk pathologic features after RP (≥pT3N0 and/or positive surgical margins). Our study cohort consisted of patients receiving RT within 6 months of surgery (eRT), those receiving RT after 6 months (lRT), and those never receiving RT (observation). Another subcohort, delayed RT (dRT), encompassed both lRT and observation. Trends of post-RP RT were compared using the Cochran–Armitage trend test. Cox regression models identified factors predictive of worse survival outcomes. Kaplan–Meier analyses compared the eRT and the dRT groups. Results: Among those with pathologically confirmed high-risk prostate cancer (PCa) after RP, 12.7% (n = 959), 13.2% (n = 1710), and 74.1% (n = 4888) underwent eRT, lRT, and observation without RT, respectively. Of these strategies, the proportion of men on observation without RT increased significantly over time (p = 0.004). The multivariable Cox regression model demonstrated similar outcomes between the eRT and the dRT groups. At a median follow-up of 5.9 years, five-year overall and cancer-specific survival outcomes were more favorable in the dRT group, when compared to the eRT group. Conclusions: A blanket adoption of the eRT in high-risk PCa based on clinical trials with limited follow-up may result in overtreatment of a significant number of men and expose them to unnecessary radiation toxicity.

Treatment of metastatic renal cell carcinoma (mRCC) has evolved with the development of a variety of systemic agents; however, these therapies alone rarely lead to a complete response. Complete consolidative surgery with surgical metastasectomy has been associated with improved survival outcomes in well-selected patients in previous reports. No randomized control trial exists to determine the effectiveness of metastasectomy. Therefore, reviewing observational studies is important to best determine which patients are most appropriate for metastasectomy for mRCC and if such treatment continues to be effective with the development of new systemic therapies such as immunotherapy. In this narrative review, we discuss the indications for metastasectomies, outcomes, factors associated with improved survival, and special considerations such as location of metastasis, number of metastases, synchronous metastases, and use of systemic therapy. Additionally, alternative treatment options and trials involving metastasectomy will be reviewed.

Cardiac metastases from renal cell carcinoma (RCC) are very rare. We describe the case of a woman with RCC with cardiac metastases involving the entire right atrium, penetrating through the myocardium, with extension into the tricuspid valve and right ventricle. This report highlights the unique challenge of the diagnosis and treatment of cardiac metastases in RCC.

Renal cell carcinoma (RCC) metastases to the testicle are an extremely rare clinical entity. Here, we describe the case of a man with metastatic RCC who developed a new testicular mass. Pathologic analysis after surgical removal of this testicle confirmed the diagnosis of metastatic RCC. This report highlights the unique diagnostic and therapeutic challenges associated with such a disease process.

Renal angiomyolipomas (AMLs) are a subset of perivascular epithelioid cell neoplasms (PEComas) that are associated with tuberous sclerosis complex (TSC). Epithelioid angiomyolipomas (EAMLs) are a rare variant of AML with more aggressive propensities. EAMLs with malignant potential can be difficult to distinguish from relatively benign AMLs and other renal tumors. Although there are no established criteria for predicting EAML malignancy, there are proposed histologic parameters that are associated with higher tumor risk. EAML can be treated with surgical resection as well as mTOR inhibitors. Here, we present a unique case of a patient with a 36-cm renal EAML metastatic to the lungs that was treated with complete surgical resection of the primary lesion and mTOR inhibition.

We report on an enhancing, heterogenous renal pelvis mass growing over 2 years which was found to be a benign hibernoma with inflammatory and lipomatous features originating from the renal hilum. To our knowledge, this is the first case reported on a hibernoma compressing on the renal pelvis and second case of a hibernoma with the inflammatory variant.

Background: Prostate cancer (PCa) phenotypes vary from indolent to aggressive. Molecular subtyping may be useful in predicting aggressive cancers and directing therapy. One such subtype involving deletions of chromodomain helicase DNA binding protein 1 ( CHD1 ), a tumor suppressor gene, are found in 10–26% of PCa tumors. In this study, we evaluate the functional cellular effects that follow CHD1 deletion. Methods: CHD1 was knocked out (KO) in the non-tumorigenic, human papillomavirus 16 (HPV16)-immortalized prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. In vitro assays such as T7 endonuclease assay, western blot, and sequencing were undertaken to characterize the CHD1 KO clones. Morphologic and functional assays for cell adhesion and viability were performed. To study expression of extracellular matrix (ECM) and adhesion molecules, a real-time (RT) profiler assay was performed using RWPE-1 parental, non-target cells (NT2) and CHD1 KO cells. Result: Compared to parental RWPE-1 and non-target cells (NT2), the CHD1 KO cells had a smaller, rounder morphology and were less adherent under routine culture conditions. Compared to parental cells, CHD1 KO cells showed a reduction in ECM and adhesion molecules as well as a greater proportion of viable suspension cells when cultured on standard tissue culture plates and on plates coated with laminin, fibronectin or collagen I. CHD1 KO cells showed a decrease in the expression of secreted protein acidic and rich in cysteine (SPARC), matrix metalloproteinase 2 (MMP2), integrin subunit alpha 2 (ITGA2), integrin subunit alpha 5 (ITGA5), integrin subunit alpha 6 (ITGA6), fibronectin (FN1), laminin subunit beta-3 precursor (LAMB3), collagen, tenascin and vitronectin as compared to parental and NT2 cells. Conclusion: These data suggest that in erythroblast transformation specific (ETS) fusion-negative, phosphatase and tensin homolog ( PTEN ) wildtype PCa, deletion of CHD1 alters cell-cell and cell-matrix adhesion dynamics, suggesting an important role for CHD1 in the development and progression of PCa.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Background: Preclinical and retrospective data suggest that cytoreductive radical prostatectomy may benefit a subset of men who present with metastatic prostate cancer (mPCa). Herein, we report the results of the first planned Phase 1 study on cytoreductive surgery. Methods: From four institutions, 36 patients consented to the study. However, four did not complete surgery because of rapid disease progression (n = 3) and another because of an intraoperatively discovered pericolonic abscess. Men with newly diagnosed clinical mPCa to lymph nodes or bones were eligible. The primary endpoint was the rate of major perioperative complications (Clavien-Dindo Grade 3 or higher) occurring within 90 days of surgery. Results: The mean age at surgery was 64.0 years. The 90-day overall complication rate was 31.2% (n = 10), of which two (6.25%) were considered major complications: one acute tubular necrosis requiring temporary dialysis and one death. In men with more than 6 months of follow-up, 67.9% had prostate specific antigen nadir ≤0.2 ng/mL, while one patient experienced a rapid rise in prostate specific antigen and another a widely disseminated disease that resulted in death 5 months after surgery. Altogether, these results demonstrate that cytoreductive radical prostatectomy is safe and surgically feasible in selected patients who present with mPCa . Yet, there may be a small subset of patients in whom surgery may cause a significant harm. Conclusion: Therefore, cytoreductive surgery in men with mPCa should be limited to clinical trials until robust data are available. Keywords: Cytoreduction, Clinical trial, Metastasis, Prostate cancer

Immune checkpoint blockade leads to unprecedented responses in many cancers. Although currently available agents mostly target the PD-1 and CTLA-4 pathways, agents targeting the immune checkpoint protein LAG-3 are under active clinical development, and early clinical data show that LAG-3 expression is a biomarker of response to LAG-3 blockade. To determine which cancers may benefit most from LAG-3 blockade, we performed a pan-cancer analysis of The Cancer Genome Atlas dataset to identify genomic and immunologic correlates of LAG-3 expression. High mutation burden, and expression of exogenous virus (EBV, HPV) or endogenous retrovirus (ERV3-2), were associated with overexpression of LAG-3 in multiple cancers. Although CD8+ T-cell marker (CD8A) and LAG-3 were strongly co-expressed with each other and with PD-L1 in most cancers, there were three notable exceptions: HPV+ head-neck squamous cell cancer, renal cell cancer, and glioblastoma. These results may have important implications for guiding development clinical trials of LAG-3 blockade.

Computational image analysis is one means for evaluating digitized histopathology specimens that can increase the reproducibility and reliability with which cancer diagnoses are rendered while simultaneously providing insight as to the underlying mechanisms of disease onset and progression. A major challenge that is confronted when analyzing samples that have been prepared at disparate laboratories and institutions is that the algorithms used to assess the digitized specimens often exhibit heterogeneous staining characteristics because of slight differences in incubation times and the protocols used to prepare the samples. Unfortunately, such variations can render a prediction model learned from one batch of specimens ineffective for characterizing an ensemble originating from another site. In this work, we propose to adopt unsupervised domain adaptation to effectively transfer the discriminative knowledge obtained from any given source domain to the target domain without requiring any additional labeling or annotation of images at the target site. In this paper, our team investigates the use of two approaches for performing the adaptation: (1) color normalization and (2) adversarial training. The adversarial training strategy is implemented through the use of convolutional neural networks to find an invariant feature space and Siamese architecture within the target domain to add a regularization that is appropriate for the entire set of whole-slide images. The adversarial adaptation results in significant classification improvement compared with the baseline models under a wide range of experimental settings.

Although the gold standard treatment for localized renal cell carcinoma (RCC) is radical nephrectomy (RN) or partial nephrectomy (PN), recurrence rates remain high at 7%, 26%, and 39% for T1, T2, and T3 staged disease, respectively [...]

The past decade has seen a rapid proliferation in the number and types of systemic therapies available for renal cell carcinoma. However, surgery remains an integral component of the therapeutic armamentarium for advanced and metastatic kidney cancer. Cytoreductive surgery followed by adjuvant cytokine-based immunotherapy (predominantly high-dose interleukin 2) has largely given way to systemic-targeted therapies. Metastasectomy also has a role in carefully selected patients. Additionally, neoadjuvant systemic therapy may increase the feasibility of resecting the primary tumor, which may be beneficial for patients with locally advanced or metastatic disease. Several prospective trials examining the role of adjuvant therapy are underway. Lastly, the first immune checkpoint inhibitor was approved for metastatic renal cell carcinoma (mRCC) in 2015, providing a new treatment mechanism and new opportunities for combining systemic therapy with surgery. This review discusses current and historical literature regarding the surgical management of patients with advanced and mRCC and explores approaches for optimizing patient selection.

Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dubé (BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer.