Publications by authors named "Jonathan A Coleman"

159 Publications

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

Urol Oncol 2021 Sep 24. Epub 2021 Sep 24.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC.

Materials And Methods: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size).

Results: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011).

Conclusion: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2021.08.018DOI Listing
September 2021

Robotic colectomy and repair of colovesical fistula due to diverticulitis - A Video Vignette.

Colorectal Dis 2021 Sep 7. Epub 2021 Sep 7.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/codi.15903DOI Listing
September 2021

Focal therapy for primary and salvage prostate cancer treatment: a narrative review.

Transl Androl Urol 2021 Jul;10(7):3144-3154

Division of Urology, Department of Surgery, University of Missouri, Columbia, MO, USA.

Despite innovations in surgical technology and advancements in radiation therapy, radical treatments for clinically localized prostate cancer are associated with significant patient morbidity, including both urinary and sexual dysfunction. This has created a vital need for therapies and management strategies that provide an acceptable degree of oncologic efficacy while mitigating these undesirable side effects. Successful developments in screening approaches and advances in prostate imaging have allowed clinicians to identify, localize, and more precisely target early cancers. This has afforded urologists with an important opportunity to develop and employ focal ablation techniques that selectively destroy tumors while preserving the remainder of the gland, thus avoiding detrimental treatment effects to surrounding sensitive structures. A lack of high-level evidence supporting such an approach had previously hindered widespread adoption of focal treatments, but there are now numerous published clinical trials which have sought to establish benchmarks for safety and efficacy. As the clinical evidence supporting a potential role in prostate cancer treatment begins to accumulate, there has been a growing acceptance of focal therapy in the urologic oncology community. In this narrative review article, we describe the techniques, advantages, and side effect profiles of the most commonly utilized focal ablative techniques and analyze published clinical trial data supporting their evolving role in the prostate cancer treatment paradigm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tau-20-1212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350247PMC
July 2021

The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter.

Nat Commun 2021 08 20;12(1):5063. Epub 2021 Aug 20.

Laboratory for Membrane Protein Dynamics. Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-25363-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379219PMC
August 2021

Functional and Oncological Outcomes of Renal Surgery for Hilar Tumors: Informing the Decisions in Risk-Adapted Management.

Urology 2021 Jul 29. Epub 2021 Jul 29.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: To describe the safety and efficacy of partial nephrectomy (PN) in comparison to radical nephrectomy (RN) for surgically managed renal hilar tumors.

Materials And Methods: We retrospectively reviewed institutional records of patients with a small (<5 cm) solitary renal (hilar or non-hilar) mass who underwent PN or RN between 2008 and 2018. Hilar tumors were defined as those at medial position, abutting the renal vessels. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method.

Results: Of 1,951 eligible patients, 399 had hilar tumors (292 scheduled for PN, 107 RN) and 1,552 had non-hilar tumors (scheduled for PN). We found no significant differences in survival measures between hilar and non-hilar tumors in patients selected for PN. Patients scheduled for PN for hilar tumors had higher rates of ≥grade II postoperative surgical complications compared to patients scheduled to receive PN for non-hilar tumors (13% vs 8.6%; log-rank P = .018) and non-statistically significantly elevated rates of ≥grade II complications compared to patients scheduled for RN for hilar tumors (13% vs 6.5%; difference 6%, 95% CI 0.4%, 13%; log-rank P = .07).

Conclusion: PN for hilar and non-hilar renal masses (<5cm) experience comparable oncologic outcomes though increased risk of complications for hilar masses. PN for hilar tumors was associated with better renal function and overall survival with non-statistically elevated risk of grade II or higher complications than RN. A renal tumor located at the hilum should not be a contra-indication for performing PN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2021.07.014DOI Listing
July 2021

Resource-efficient pooled sequencing expands translational impact in solid tumors.

Kidney Cancer J 2021 Jun 24;19(2):18-23. Epub 2021 Jun 24.

Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, USA.

Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.52733/KCJ18n2.a1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312736PMC
June 2021

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

Cancer 2021 Nov 19;127(21):3946-3956. Epub 2021 Jul 19.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes.

Methods: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition.

Results: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001).

Conclusions: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516697PMC
November 2021

Combined OX40 Agonist and PD-1 Inhibitor Immunotherapy Improves the Efficacy of Vascular Targeted Photodynamic Therapy in a Urothelial Tumor Model.

Molecules 2021 Jun 19;26(12). Epub 2021 Jun 19.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Purpose: Vascular targeted photodynamic therapy (VTP) is a nonsurgical tumor ablation approach used to treat early-stage prostate cancer and may also be effective for upper tract urothelial cancer (UTUC) based on preclinical data. Toward increasing response rates to VTP, we evaluated its efficacy in combination with concurrent PD-1 inhibitor/OX40 agonist immunotherapy in a urothelial tumor-bearing model.

Experimental Design: In mice allografted with MB-49 UTUC cells, we compared the effects of combined VTP with PD-1 inhibitor/OX40 agonist with those of the component treatments on tumor growth, survival, lung metastasis, and antitumor immune responses.

Results: The combination of VTP with both PD-1 inhibitor and OX40 agonist inhibited tumor growth and prolonged survival to a greater degree than VTP with either immunotherapeutic individually. These effects result from increased tumor infiltration and intratumoral proliferation of cytotoxic and helper T cells, depletion of Treg cells, and suppression of myeloid-derived suppressor cells.

Conclusions: Our findings suggest that VTP synergizes with PD-1 blockade and OX40 agonist to promote strong antitumor immune responses, yielding therapeutic efficacy in an animal model of urothelial cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26123744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234268PMC
June 2021

The association between modifiable perioperative parameters and renal function after nephrectomy.

BJU Int 2021 Jun 30. Epub 2021 Jun 30.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Objective: To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy.

Patients And Methods: We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy.

Results: Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance.

Conclusions: Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.15531DOI Listing
June 2021

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Cancer Cell 2021 Jun;39(6):793-809.e8

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccell.2021.05.008DOI Listing
June 2021

Extracellular loops of the serotonin transporter act as a selectivity filter for drug binding.

J Biol Chem 2021 07 9;297(1):100863. Epub 2021 Jun 9.

Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Austria.

The serotonin transporter (SERT) shapes serotonergic neurotransmission by retrieving its eponymous substrate from the synaptic cleft. Ligands that discriminate between SERT and its close relative, the dopamine transporter DAT, differ in their association rate constant rather than their dissociation rate. The structural basis for this phenomenon is not known. Here we examined the hypothesis that the extracellular loops 2 (EL2) and 4 (EL4) limit access to the ligand-binding site of SERT. We employed an antibody directed against EL4 (residues 388-400) and the antibody fragments 8B6 scFv (directed against EL2 and EL4) and 15B8 Fab (directed against EL2) and analyzed their effects on the transport cycle of and inhibitor binding to SERT. Electrophysiological recordings showed that the EL4 antibody and 8B6 scFv impeded the initial substrate-induced transition from the outward to the inward-facing conformation but not the forward cycling mode of SERT. In contrast, binding of radiolabeled inhibitors to SERT was enhanced by either EL4- or EL2-directed antibodies. We confirmed this observation by determining the association and dissociation rate of the DAT-selective inhibitor methylphenidate via electrophysiological recordings; occupancy of EL2 with 15B8 Fab enhanced the affinity of SERT for methylphenidate by accelerating its binding. Based on these observations, we conclude that (i) EL4 undergoes a major movement during the transition from the outward to the inward-facing state, and (ii) EL2 and EL4 limit access of inhibitors to the binding of SERT, thus acting as a selectivity filter. This insight has repercussions for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253976PMC
July 2021

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

World J Urol 2021 Sep 29;39(9):3359-3365. Epub 2021 Mar 29.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, USA.

Purpose: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center.

Methods: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS).

Results: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001).

Conclusion: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00345-021-03650-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478968PMC
September 2021

Neoadjuvant vascular-targeted photodynamic therapy improves survival and reduces recurrence and progression in a mouse model of urothelial cancer.

Sci Rep 2021 Mar 1;11(1):4842. Epub 2021 Mar 1.

Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA.

Locally advanced urothelial cancer has high recurrence and progression rates following surgical treatment. This highlights the need to develop neoadjuvant strategies that are both effective and well-tolerated. We hypothesized that neoadjuvant sub-ablative vascular-targeted photodynamic therapy (sbVTP), through its immunotherapeutic mechanism, would improve survival and reduce recurrence and progression in a murine model of urothelial cancer. After urothelial tumor implantation and 17 days before surgical resection, mice received neoadjuvant sbVTP (WST11; Tookad Soluble, Steba Biotech, France). Local and systemic response and survival served as measures of therapeutic efficacy, while immunohistochemistry and flow cytometry elucidated the immunotherapeutic mechanism. Data analysis included two-sided Kaplan-Meier, Mann-Whitney, and Fischer exact tests. Tumor volume was significantly smaller in sbVTP-treated animals than in controls (135 mm vs. 1222 mm, P < 0.0001) on the day of surgery. Systemic progression was significantly lower in sbVTP-treated animals (l7% vs. 30%, P < 0.01). Both median progression-free survival and overall survival were significantly greater among animals that received sbVTP and surgery than among animals that received surgery alone (P < 0.05). Neoadjuvant-treated animals also demonstrated significantly lower local recurrence. Neoadjuvant sbVTP was associated with increased early antigen-presenting cells, and subsequent improvements in long-term memory and increases in effector and active T-cells in the spleen, lungs, and blood. In summary, neoadjuvant sbVTP delayed local and systemic progression, prolonged progression-free and overall survival, and reduced local recurrence, thereby demonstrating therapeutic efficacy through an immune-mediated response. These findings strongly support its evaluation in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-84184-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921650PMC
March 2021

Defining the index lesion for potential salvage partial or hemi-gland ablation after radiation therapy for localized prostate cancer.

Urol Oncol 2021 08 12;39(8):495.e17-495.e24. Epub 2021 Feb 12.

Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

Background: Salvage partial gland ablation (sPGA) has been proposed to treat some localized radiorecurrent prostate cancer. The role of prostate biopsy and magnetic resonance imaging (MRI) characteristics to identify patients eligible for sPGA is unknown.

Objective: To evaluate the ability of MRI and prostate biopsy characteristics to identify an index lesion suitable for sPGA and validate this selection using detailed tumor maps created from whole-mount slides from salvage radical prostatectomy (sRP) specimens.

Design, Setting, And Participants: Men who underwent sRP for recurrent prostate cancer following primary radiotherapy with external beam radiotherapy (EBRT) and/or brachytherapy between 2000 and 2014 at a single high-volume cancer center were eligible. Those with tumor maps, MRI and biopsy data were included in analysis.

Outcome Measurements And Statistical Analysis: Primary outcome was the ability of clinicopathologic and imaging criteria to identify patients who may be eligible for sPGA based on detailed tumor map from whole-mount sRP slides.

Results And Limitations: Of 216 men who underwent sRP following whole gland radiotherapy, tumor maps, MRI, and biopsy data were available for 77. Of these, 15 (19%) were determined to be eligible for sPGA based on biopsy-proven unilateral disease in contiguous sextant segments, a dominant lesion on MRI concordant with biopsy location or no focal region of interest, and no imaging evidence of extraprostatic disease. Review of tumor maps identified 6 additional men who would have met criteria for sPGA, resulting in sensitivity of 71% (95% C.I. 48%-89%) and specificity of 100% (lower bound of 95% C.I. 94%). None of the 15 men who met the criteria for sPGA on clinical data were identified incorrectly on tumor maps to require full gland surgery (upper bound of 95% C.I. 22%). Median tumor volume of the index lesion was 0.4 cc and recurrent cancer was noted in the apex, mid-gland, and base in 81%, 100%, and 29% of men.

Conclusions: In men with recurrent prostate cancer after radiotherapy, biopsy findings and MRI can be used to select index lesions potentially amenable for sPGA and can guide patient evaluation for inclusion in clinical trials of sPGA following radiation failure. Larger, prospective studies are required to evaluate both the role of MRI and clinical criteria in guiding focal salvage therapy and the effectiveness of this modality for radiorecurrent prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2021.01.011DOI Listing
August 2021

Photoselective Vaporization of the Prostate in the Management of Lower Urinary Tract Symptoms in Prostate Cancer Patients on Active Surveillance.

Urology 2021 Feb 2. Epub 2021 Feb 2.

Urology Service, Department of Surgery; Memorial Sloan Kettering Cancer Center, NY.

Objective: To demonstrate the safety and efficacy of photoselective vaporization of the prostate in alleviating refractory lower urinary tract symptoms in prostate cancer patients who are managed with active surveillance and to explore the association of this procedure with prostate specific antigen (PSA) levels and cancer progression rates.

Methods: Between 2008-2018, active surveillance patients who had refractory symptoms and needed surgery were studied. Perioperative functional variables were collected and analyzed. Disease progression was defined as an upgrade or upstage on surveillance biopsies or multiparametric prostate magnetic resonance imaging. Mean postop scores were estimated using locally-weighted methods. The risk of progression was reported using Kaplan-Meier's method.

Results: Seventy-one patients were included in the study. The median age was 68 years and the median surveillance time before surgery was 4 years. At 12 months, there were substantial improvements in the mean International Prostate Symptom Score (18-5.9), maximum flow rate (6.8-14 mL/s), postvoid residual (240-73mL), PSA (8.1-5.2 ng/mL), and prostate volume (85-57mL). At 30-days, only 2 patients with grade-III complications. Late consequences included tissue regrowth in 4 and urethral stricture (requiring a single dilation) in 3 patients. PSA levels decreased by 36% at 12 months postoperatively. With a median follow-up of 3.7 years, 7 men progressed and received radical treatment. At 3 years, the probability of remaining on surveillance was 93% (95% CI 87%- 100%).

Conclusion: Photoselective vaporization of the prostate offers substantial relief of symptoms in active surveillance patients with refractory symptoms, without adverse effects on disease progression rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2021.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326299PMC
February 2021

Inguinal hernia of the distal ureter causing hydronephrosis: A rare case.

Urol Case Rep 2021 Mar 28;35:101549. Epub 2020 Dec 28.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, USA.

Ureteral involvement in inguinal hernias is a rare occurrence. A 63-year-old man presented for surveillance of renal cell carcinoma with new onset mild intermittent flank pain. CT scan revealed new left hydroureteronephrosis to the level of the inguinal canal with dilated segments of ureter within an inguinal hernia. The patient underwent robot-assisted laparoscopic left ureterolysis and hernia repair. Ureter-containing inguinal hernias represent an uncommon but important source of obstructive uropathy. When encountered, robotic hernia repair provides a safe and effective treatment option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eucr.2020.101549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787945PMC
March 2021

Summary from the Kidney Cancer Association's Inaugural Think Thank: Coalition for a Cure.

Clin Genitourin Cancer 2021 04 14;19(2):167-175. Epub 2020 Nov 14.

Urologic Oncology Branch, Center for Cancer Research, Mayo Clinic, Rochester, MN.

Close to 74,000 cases of renal cell carcinoma (RCC) are diagnosed each year in the United States. The past 2 decades have shown great developments in surgical techniques, targeted therapy and immunotherapy agents, and longer complete response rates. However, without a global cure, there is still room for further advancement in improving patient care in this space. To address some of the gaps restricting this progress, the Kidney Cancer Association brought together a group of 27 specialists across the areas of clinical care, research, industry, and advocacy at the inaugural "Think Tank: Coalition for a Cure" session. Topics addressed included screening, imaging, rarer RCC subtypes, combination drug therapy options, and patient response. This commentary summarizes the discussion of these topics and their respective clinical challenges, along with a proposal of projects for collaboration in overcoming those needs and making a greater impact on care for patients with RCC moving forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2020.10.005DOI Listing
April 2021

Developments in Vascular-Targeted Photodynamic Therapy for Urologic Malignancies.

Molecules 2020 Nov 19;25(22). Epub 2020 Nov 19.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

With improved understanding of cancer biology and technical advancements in non-invasive management of urological malignancies, there is renewed interest in photodynamic therapy (PDT) as a means of focal cancer treatment. The application of PDT has also broadened as a result of development of better-tolerated and more effective photosensitizers. Vascular-targeted PDT (VTP) using padeliporfin, which is a water-soluble chlorophyll derivative, allows for tumor-specific cytotoxicity and has demonstrated efficacy in the management of urologic malignancies. Herein, we describe the evolution of photodynamic therapy in urologic oncology and the role of VTP in emerging treatment paradigms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25225417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699359PMC
November 2020

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management.

Eur Urol 2021 04 10;79(4):468-477. Epub 2020 Oct 10.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.

Objective: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.

Design, Setting, And Participants: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.

Outcome Measurements And Statistical Analysis: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.

Results And Limitations: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).

Conclusions: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.

Patient Summary: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327325PMC
April 2021

Preoperative nomogram predicting 12-year probability of metastatic renal cancer - evaluation in a contemporary cohort.

Urol Oncol 2020 11 6;38(11):853.e1-853.e7. Epub 2020 Sep 6.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objectives: Preoperative models, based on patient and tumor characteristics, predict risk for adverse outcomes after nephrectomy. Changes in renal tumor characteristics over the last decades, warrant further evaluation using contemporary cohorts. We aimed to validate a previously published preoperative nomogram predicting 12-year metastasis-free probability after nephrectomy for localized renal tumors in a contemporary cohort.

Patients And Methods: After obtaining institutional review board approval, data of 1,760 patients who underwent nephrectomy for a localized renal mass between 2005 and 2011 were reviewed. Preoperative images were evaluated for the presence of tumor necrosis, lymphadenopathy, and tumor size. The study outcome was metastatic-free probability. Model discrimination was assessed with Gönen and Heller's concordance probability estimate, and calibration was evaluated.

Results: The cohort included 1,102 male and 658 female patients with a median age of 60 years. Most patients presented incidentally (84%). On imaging, 3% had evidence of lymphadenopathy, 55% had necrosis and median tumor diameter was 3.7 cm (interquartile range [IQR]: 2.5, 5.5). Median follow-up in non-metastatic patients was 7.7 years (IQR: 5.3, 9.7). Estimated 12-year metastatic-free probability was 88% (86%-90%). The model showed strong discrimination (concordance probability estimate [CPE]: 0.77), and fair calibration. The time-dependent receiver operating characteristic (ROC) curves showed strong discrimination at all-time points and the area under the curve (AUC) for year 12 was 0.83 (95% Confidence Interval: 0.78-0.89).

Conclusions: We validated the preoperative nomogram of 12-year metastasis-free probability in a contemporary cohort despite different tumor characteristics. Future studies should evaluate the role of preoperative risk stratification in patient selection for neoadjuvant treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2020.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607679PMC
November 2020

Impact of intraoperative opioid and adjunct analgesic use on renal cell carcinoma recurrence: role for onco-anaesthesia.

Br J Anaesth 2020 11 21;125(5):e402-e404. Epub 2020 Jul 21.

Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA; Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2020.06.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844372PMC
November 2020

Chemical and structural investigation of the paroxetine-human serotonin transporter complex.

Elife 2020 07 3;9. Epub 2020 Jul 3.

Vollum Institute, Oregon Health & Science University, Portland, United States.

Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of ∆N72/∆C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.56427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470834PMC
July 2020

An evaluation of the role of tumor load in cytoreductive nephrectomy.

Can Urol Assoc J 2020 Dec;14(12):E625-E630

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

Introduction: New radiological tools can accurately provide preoperative three-dimensional spatial assessment of metastatic renal cell carcinoma (RCC). We aimed to determine whether the distribution, volume, shape, and fraction of RCC resected in a cytoreductive nephrectomy associates with survival.

Methods: We retrospectively reviewed 560 patients undergoing cytoreductive nephrectomy, performing a comprehensive volumetric analysis in eligible patients of all detectable primary and metastatic RCC prior to surgery. We used Cox regression analysis to determine the association between the volume, shape, fraction resected, and distribution of RCC and overall survival (OS).

Results: There were 62 patients eligible for volumetric analysis, with similar baseline characteristics to the entire cohort, and median survivor followup was 34 months. Larger primary tumors were less spherical, but not associated with different metastatic patterns. Increased primary tumor volume and tumor size, but not the fraction of tumor resected, were associated with inferior survival. The rank of tumors based on unidimensional size did not completely correspond to the rank by primary tumor volume, however, both measurements yielded similar concordance for predicted OS. Larger tumor volume was not associated with a longer postoperative time off treatment.

Conclusions: Primary tumor volume was significant for predicting OS, while the fraction of disease resected did not appear to impact patient outcomes. Although rich in detail, our study is potentially limited by selection bias. Future temporal studies may help elucidate whether the primary tumor shape is associated with tumor growth kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5489/cuaj.6350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704090PMC
December 2020

Routine Postoperative Hemoglobin Assessment Poorly PredictsTransfusion Requirement among Patients Undergoing Minimally Invasive Radical Prostatectomy.

Urol Pract 2020 Jul;7(4):299-304

Urology Service, Department of Surgery (GTC, NB, DB, LWD, PTS, JAE, BE, JAC, TFD, KAT, VPL), and Department of Epidemiology and Biostatistics (AT, DDS), Memorial Sloan Kettering Cancer Center, New York, New York.

Introduction: An advantage of minimally invasive radical prostatectomy over open surgery is decreased blood loss. At our institution hemoglobin is routinely checked 4 and 14 hours postoperatively. We assessed the relevance of this practice in a contemporary cohort undergoing minimally invasive radical prostatectomy.

Methods: We retrospectively reviewed data from patients undergoing laparoscopic or robotic radical prostatectomy at our institution between January 2010 and September 2018. We identified 3,631 patients with preoperative and postoperative hemoglobin values, and assessed the role of routine hemoglobin assessment in determining need for transfusion within 30 days. Medicare reimbursement rates for 2019 were used for cost analysis.

Results: Of 3,631 patients in our cohort 44 (1.2%) required transfusion. At 4 hours following surgery the median hemoglobin decrease was 8.0% (IQR 4.8 to 11.4) for patients who did not receive transfusion and 12.5% (9.5 to 19.2) for those who received transfusion. At 14 hours the median decrease was 14.2% (IQR 10.0 to 18.4) vs 33.1% (22.6 to 38.6). Routine hemoglobin assessment had no role in the decision to transfuse in 18 patients (41%). No patient was transfused based on 4-hour values alone. Omitting 1 hemoglobin assessment could have resulted in institutional savings of $37,000 during this period.

Conclusions: As transfusion following minimally invasive radical prostatectomy is rare, scheduled postoperative hemoglobin assessments in the absence of symptoms are unnecessary to recognize bleeding events. The largest hemoglobin difference between men who did vs did not receive transfusion was seen at 14 hours postoperatively. Thus, this single hemoglobin evaluation is sufficient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/UPJ.0000000000000108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301724PMC
July 2020

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Nat Commun 2020 04 24;11(1):1975. Epub 2020 Apr 24.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15885-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181640PMC
April 2020

Importance of long-term follow-up after endoscopic management for upper tract urothelial carcinoma and factors leading to surgical management.

Int Urol Nephrol 2020 Aug 11;52(8):1465-1469. Epub 2020 Mar 11.

Division of Urology, Department of Surgery, University of Missouri, Columbia, MO, USA.

Purpose: Patients undergoing endoscopic management for upper tract urothelial carcinoma often progress to definitive therapy with radical nephroureterectomy. This study examined the rate of progression as well as risk factors for transitions in treatment over time.

Methods: Retrospective review at two institutions identified patients undergoing endoscopic management for upper tract urothelial carcinoma. Patients were assessed for progression to radical nephroureterectomy. Baseline characteristics were compared using Chi square analysis. Kaplan-Meier method analyzed the probability of patients not progressing to radical nephroureterectomy. Cox proportional hazards identified factors associated with progression to radical nephroureterectomy.

Results: Eighty-one patients had endoscopic management alone and 89 progressed to radical nephroureterectomy. The two groups had similar age, histories of bladder cancer, and Charlson comorbidity index. Positive urinary cytology, ureteroscopic visualization, and biopsy grade were higher in those progressing to RNU (p < 0.001). Hazard modeling demonstrated higher rates of progression to radical nephroureterectomy with positive biopsy (HR 11.8, 95% CI 2.4-59.5, p = 0.003) or visible lesion on ureteroscopy (HR 8.4, 95% CI 3.0-23.9, p < 0.001). Patients with a higher Charlson comorbidity index were less likely to have radical nephroureterectomy. On Kaplan-Meier modeling, the probability of not undergoing radical nephroureterectomy at 2 years and 5 years was 50% and 20%, respectively.

Conclusions: Patients who progress to radical nephroureterectomy after endoscopic management have fewer comorbid conditions and changes in disease status including visible lesions on ureteroscopy and positive biopsies. The high rate of progression to radical nephroureterectomy reinforces the need for long-term follow-up of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11255-020-02439-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572076PMC
August 2020

Patient-Derived Xenograft Models in Urological Malignancies: Urothelial Cell Carcinoma and Renal Cell Carcinoma.

Cancers (Basel) 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

The engraftment of human tumor tissues into immunodeficient host mice to generate patient-derived xenograft (PDX) models has become increasingly utilized for many types of cancers. By capturing the unique genomic and molecular properties of the parental tumor, PDX models enable analysis of patient-specific clinical responses. PDX models are an important platform to address the contribution of inter-tumoral heterogeneity to therapeutic sensitivity, tumor evolution, and the mechanisms of treatment resistance. With the increasingly important role played by targeted therapies in urological malignancies, the establishment of representative PDX models can contribute to improved facilitation and adoption of precision medicine. In this review of the evolving role of the PDX in urothelial cancer and kidney cancer, we discuss the essential elements of successful graft development, effective translational application, and future directions for clinical models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072311PMC
February 2020

Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline.

J Clin Oncol 2020 06 15;38(17):1963-1996. Epub 2020 Jan 15.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Provide evidence- and expert-based recommendations for optimal use of imaging in advanced prostate cancer. Due to increases in research and utilization of novel imaging for advanced prostate cancer, this guideline is intended to outline techniques available and provide recommendations on appropriate use of imaging for specified patient subgroups.

Methods: An Expert Panel was convened with members from ASCO and the Society of Abdominal Radiology, American College of Radiology, Society of Nuclear Medicine and Molecular Imaging, American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology to conduct a systematic review of the literature and develop an evidence-based guideline on the optimal use of imaging for advanced prostate cancer. Representative index cases of various prostate cancer disease states are presented, including suspected high-risk disease, newly diagnosed treatment-naïve metastatic disease, suspected recurrent disease after local treatment, and progressive disease while undergoing systemic treatment. A systematic review of the literature from 2013 to August 2018 identified fully published English-language systematic reviews with or without meta-analyses, reports of rigorously conducted phase III randomized controlled trials that compared ≥ 2 imaging modalities, and noncomparative studies that reported on the efficacy of a single imaging modality.

Results: A total of 35 studies met inclusion criteria and form the evidence base, including 17 systematic reviews with or without meta-analysis and 18 primary research articles.

Recommendations: One or more of these imaging modalities should be used for patients with advanced prostate cancer: conventional imaging (defined as computed tomography [CT], bone scan, and/or prostate magnetic resonance imaging [MRI]) and/or next-generation imaging (NGI), positron emission tomography [PET], PET/CT, PET/MRI, or whole-body MRI) according to the clinical scenario.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.02757DOI Listing
June 2020

Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An Emerging Entity with Variable Clinical Course.

Eur Urol Focus 2021 Mar 6;7(2):381-389. Epub 2019 Dec 6.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with clear-cell features. Owing to its unique morphological and molecular features it has recently been proposed as a separate entity. Initial series suggested an indolent, early-stage phenotype. Here we expand our clinical cohort and describe a more detailed genomic analysis looking for potential drivers of aggressiveness.

Design, Setting, And Participants: We identified five new cases in our institutional sequencing cohort, four of whom were found to have high-stage disease (American Joint Committee on Cancer stage III/IV). Twelve previously reported cases were pooled for comparison purposes (Sato, The Cancer Genome Atlas, TRACERx Renal).

Outcome Measures And Statistical Analysis: We used our previously validated pipeline to analyze somatic mutations and copy number alterations (CNAs) in seven tumor samples with available data and estimated the number of cancer cells bearing each somatic mutation. The oncogenic potential of mutations was assessed using OncoKB and two other algorithms. Mann-Whitney U tests were used to evaluate differences in genomic markers between stage groups.

Results And Limitations: All tumors showed biallelic inactivation of the TCEB1 gene according to a combination of somatic mutation and CNA analyses. Mutations were always found in residues involved in hydrophobic interactions with VHL. We found that high-stage tumors had additional oncogenic mutations (median 1, interquartile range [IQR] 1-1 vs 2, IQR 2-2; median difference 1, 95% confidence interval [CI] 1-1; p= 0.002) and showed whole-genome doubling events. They also seemed to have a higher burden of somatic CNAs (median fraction CNA genome 0.10, IQR 0.10-0.15 vs 0.63, IQR 0.58-0.68), however, this finding did not reach statistical significance (median difference 0.49, 95% CI 0.33-0.63; p=0.052).

Conclusions: TCEB1-mutant RCC can show variable behavior ranging from very indolent to aggressive. Specific molecular events leading to high genomic instability seem to be associated with aggressiveness. This study expands the clinical spectrum of TCEB1-mutant RCC.

Patient Summary: We present four cases of aggressive TCEB1-mutant renal cell carcinoma, a rare type of kidney cancer. In-depth analysis of the genomes of these tumors revealed certain abnormalities that might explain this aggressive behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euf.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274909PMC
March 2021

Cancer Susceptibility Mutations in Patients With Urothelial Malignancies.

J Clin Oncol 2020 02 3;38(5):406-414. Epub 2019 Dec 3.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors.

Patients And Methods: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database.

Results: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were (n = 9; 1.5%), (n = 8; 1.4%), (n = 8; 1.4%), (n = 6; 1.0%), (n = 4; 0.7%), and and (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% 6% in those without variants; = .01). and were significantly associated with an increased risk for UC (odds ratio, 3.7 [ = .004] and 4.6 [ = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants.

Conclusion: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351337PMC
February 2020
-->