Publications by authors named "Michael R Harrison"

149 Publications

Active surveillance of metastatic renal cell carcinoma: Results from a prospective observational study (MaRCC).

Cancer 2021 Mar 25. Epub 2021 Mar 25.

Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.

Background: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature.

Methods: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival.

Results: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST.

Conclusions: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.
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http://dx.doi.org/10.1002/cncr.33494DOI Listing
March 2021

The Lymphatic System in Zebrafish Heart Development, Regeneration and Disease Modeling.

J Cardiovasc Dev Dis 2021 Feb 19;8(2). Epub 2021 Feb 19.

Cardiovascular Research Institute, Weill Cornell Medical College, New York, NY 10021, USA.

Heart disease remains the single largest cause of death in developed countries, and novel therapeutic interventions are desperately needed to alleviate this growing burden. The cardiac lymphatic system is the long-overlooked counterpart of the coronary blood vasculature, but its important roles in homeostasis and disease are becoming increasingly apparent. Recently, the cardiac lymphatic vasculature in zebrafish has been described and its role in supporting the potent regenerative response of zebrafish heart tissue investigated. In this review, we discuss these findings in the wider context of lymphatic development, evolution and the promise of this system to open new therapeutic avenues to treat myocardial infarction and other cardiopathologies.
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http://dx.doi.org/10.3390/jcdd8020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922492PMC
February 2021

mutations are associated with favorable outcomes to immune checkpoint inhibitors across multiple cancer types.

J Immunother Cancer 2021 Mar;9(3)

Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina, USA

Background: Low-density lipoprotein receptor-related protein 1b (encoded by ) is a putative tumor suppressor, and preliminary evidence suggests mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).

Methods: We conducted a multicenter, retrospective pan-cancer analysis of patients with alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP) alterations compared with variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by status.

Results: We identified 101 patients (44 Duke, 35 JHU, 22 UM) with alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).

Conclusions: This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.
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http://dx.doi.org/10.1136/jitc-2020-001792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929846PMC
March 2021

Combination antiangiogenic tyrosine kinase inhibition and anti-PD1 immunotherapy in metastatic renal cell carcinoma: A retrospective analysis of safety, tolerance, and clinical outcomes.

Cancer Med 2021 Apr 1;10(7):2341-2349. Epub 2021 Mar 1.

Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches.

Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1.

Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event.

Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.
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http://dx.doi.org/10.1002/cam4.3812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982609PMC
April 2021

Body composition, physical function and quality of life in healthy men and across different stages of prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jan 25. Epub 2021 Jan 25.

Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Androgen deprivation therapy (ADT) for prostate cancer (PC) has detrimental effects on physical function and quality of life (QoL), but the addition of androgen receptor signalling inhibitors (ARSI) on these outcomes is unclear.

Purpose: To compare body composition, physical function, and QoL across progressive stages of PC and non-cancer controls (CON).

Methods: In men with hormone sensitive PC (HSPC, n = 43) or metastatic castration-resistant PC (mCRPC, n = 22) or CON (n = 37), relative and absolute lean and fat mass, physical function (6 m walk, chair stands, timed up and go [TUG], stair climb), and QoL were determined.

Results: Relative body composition differed amongst all groups, along with ~39% greater absolute fat mass in mCRPC vs. CON. TUG and chair stands were ~71% and ~33% slower in mCRPC compared to both CON and HSPC, whereas stair climb was ~29% and 6 m walk was ~18% slower in mCRPC vs. CON. Relative body composition was correlated with physical function (r = 0.259-0.385). Clinically relevant differences for mCRPC were observed for overall QoL and several subscales vs. CON, although body composition and physical function did not influence QoL.

Conclusions: PC progression is associated with deteriorations in body composition and physical function. As ADT length was similar between groups, ARSI use for mCRPC likely contributed in part to these changes. Given the difficulties of improving lean mass during ADT, interventions that reduce adiposity may lessen the side effects of hormone therapy.
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http://dx.doi.org/10.1038/s41391-020-00317-wDOI Listing
January 2021

Metastatic Urothelial Carcinoma from Transplanted Kidney with Complete Response to an Immune Checkpoint Inhibitor.

Case Rep Urol 2020 23;2020:8881841. Epub 2020 Dec 23.

Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.

Background: Donor-derived malignancy is a rare complication in patients who undergo organ transplant. Approaches to treatment have largely been individualized based on clinical circumstances given the lack of evidence-based guidelines, with therapeutic options ranging from discontinuation of immunosuppression and transplantectomy to the addition of chemotherapy or radiotherapy. . Herein, we describe a 60-year-old woman with metastatic donor-derived upper tract urothelial carcinoma (UTUC) discovered nine years postrenal transplant. Molecular diagnostic studies using polymerase chain reaction amplification of short tandem repeat alleles and HLA tissue typing proved that the urothelial carcinoma originated from donor tissue. She achieved sustained complete remission with transplant nephroureterectomy, retroperitoneal lymphadenectomy, immunosuppression withdrawal, and immunotherapy with pembrolizumab. Routine radiologic surveillance has demonstrated 15-month progression-free survival to date off pembrolizumab, and she is now under consideration for retransplantation.

Conclusions: Immunotherapy using checkpoint inhibitors can serve as a novel treatment option for patients in the clinical predicament of having a solid organ transplant and simultaneous metastatic malignancy. In this report, we also discuss the oncogenic potential of BK virus, the use of checkpoint inhibitors in urothelial carcinoma, and the feasibility of retransplant for this patient population.
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http://dx.doi.org/10.1155/2020/8881841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773455PMC
December 2020

Combination of Radiation Therapy and Short-Term Androgen Blockade With Abiraterone Acetate Plus Prednisone for Men With High- and Intermediate-Risk Localized Prostate Cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 28;109(5):1271-1278. Epub 2020 Nov 28.

Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina; Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina; Department of Surgery, Division of Urology, Duke University, Durham, North Carolina; Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.

Purpose: Long-term androgen-deprivation therapy (ADT) is the standard of care in combination with radiation therapy (RT) in high-risk prostate cancer (PC), despite substantial toxicity from the resulting hypogonadism. We hypothesized that a combination of more potent but shorter-term androgen inhibition in men with intermediate- or high-risk localized PC would synergize with definitive RT to provide short-term testosterone recovery and improve disease control.

Methods And Materials: This prospective phase 2 single-arm trial enrolled men with low-volume unfavorable intermediate or high-risk localized PC. Treatment included 6 months of ADT concurrent with abiraterone acetate plus prednisone (AAP) once daily and RT to prostate and seminal vesicles. The primary endpoint was the proportion of men with an undetectable prostate-specific antigen (PSA) at 12-months; secondary objectives included biochemical progression-free survival (PFS), testosterone recovery, toxicity, and sexual and hormonal quality of life.

Results: We enrolled 37 men between January 2014 and August 2016, 45% of whom were high risk. All patients had T1-2 disease and PSA < 20 ng/mL. Median follow-up is 37 months (95% confidence interval [CI], 35.7-39.1). Treatment noted 32% grade 3 toxicities related to AAP, predominantly hypertension, with no toxicities ≥G4. The rate of undetectable PSA at 12 months was 55% (95% CI, 36%-72%). With 46 months of median follow-up, 2 of 37 patients developed PSA progression (36-month PFS = 96%; 95% CI, 76%-99%), and 81% of patients recovered testosterone with a median time to recovery of 9.2 months. Hormonal or sexual function declined at 6 months with subsequent improvement by 24 months.

Conclusions: The combination of RT and 6 months of ADT and AAP demonstrated acceptable toxicity and a high rate of testosterone recovery with restoration of quality of life and excellent disease control in men with low-volume, intermediate- or high-risk localized prostate cancer. Prospective comparative studies are justified.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.059DOI Listing
April 2021

Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer.

JCO Precis Oncol 2020 28;4. Epub 2020 Oct 28.

Department of Biostatistics and Bioinforamtics, Duke University, Durham, NC.

Purpose: Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy.

Patients And Methods: PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points.

Results: We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors.

Conclusion: Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7-positive disease still experience clinical benefits from taxane chemotherapy.
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http://dx.doi.org/10.1200/PO.20.00200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608579PMC
October 2020

Novel therapies are changing treatment paradigms in metastatic prostate cancer.

J Hematol Oncol 2020 10 28;13(1):144. Epub 2020 Oct 28.

Division of Medical Oncology, Department of Medicine, Duke University, DUMC 103861, Durham, NC, 27710, USA.

Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.
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http://dx.doi.org/10.1186/s13045-020-00978-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594418PMC
October 2020

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

Clin Cancer Res 2021 Jan 1;27(1):78-86. Epub 2020 Sep 1.

Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.

Patients And Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.

Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); = 74] versus sunitinib [14.2 months (9.3-22.9); = 65; HR, 0.45 (95% CI, 0.3-0.7; = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.

Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2063DOI Listing
January 2021

A randomized phase 2 trial of pembrolizumab versus pembrolizumab and acalabrutinib in patients with platinum-resistant metastatic urothelial cancer.

Cancer 2020 Oct 5;126(20):4485-4497. Epub 2020 Aug 5.

Duke Cancer Institute, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

Background: Inhibition of the programmed cell death protein 1 (PD-1) pathway has demonstrated clinical benefit in metastatic urothelial cancer (mUC); however, response rates of 15% to 26% highlight the need for more effective therapies. Bruton tyrosine kinase (BTK) inhibition may suppress myeloid-derived suppressor cells (MDSCs) and improve T-cell activation.

Methods: The Randomized Phase 2 Trial of Acalabrutinib and Pembrolizumab Immunotherapy Dual Checkpoint Inhibition in Platinum-Resistant Metastatic Urothelial Carcinoma (RAPID CHECK; also known as ACE-ST-005) was a randomized phase 2 trial evaluating the PD-1 inhibitor pembrolizumab with or without the BTK inhibitor acalabrutinib for patients with platinum-refractory mUC. The primary objectives were safety and objective response rates (ORRs) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Immune profiling was performed to analyze circulating monocytic MDSCs and T cells.

Results: Seventy-five patients were treated with pembrolizumab (n = 35) or pembrolizumab plus acalabrutinib (n = 40). The ORR was 26% with pembrolizumab (9% with a complete response [CR]) and 20% with pembrolizumab plus acalabrutinib (10% with a CR). The grade 3/4 adverse events (AEs) that occurred in ≥15% of the patients were anemia (20%) with pembrolizumab and fatigue (23%), increased alanine aminotransferase (23%), urinary tract infections (18%), and anemia (18%) with pembrolizumab plus acalabrutinib. One patient treated with pembrolizumab plus acalabrutinib had high MDSCs at the baseline, which significantly decreased at week 7. Overall, MDSCs were not correlated with a clinical response, but some subsets of CD8+ T cells did increase during the combination treatment.

Conclusions: Both treatments were generally well tolerated, although serious AE rates were higher with the combination. Acalabrutinib plus pembrolizumab did not improve the ORR, PFS, or OS in comparison with pembrolizumab alone in mUC. Baseline and on-treatment peripheral monocytic MDSCs were not different in the treatment cohorts. Proliferating CD8+ T-cell subsets increased during treatment, particularly in the combination cohort. Ongoing studies are correlating these peripheral immunome findings with tissue-based immune cell infiltration.
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http://dx.doi.org/10.1002/cncr.33067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590121PMC
October 2020

PD-L1 Assay Concordance in Metastatic Renal Cell Carcinoma and Metastatic Urothelial Carcinoma.

Clin Genitourin Cancer 2020 Dec 10;18(6):509-513. Epub 2020 Apr 10.

Department of Medicine, School of Medicine, Duke University, Durham, NC; Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC. Electronic address:

Background: Immune checkpoint inhibitors are now standard of care for many patients with metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC). Given real-world limitations in programmed death-ligand 1 (PD-L1) testing, concordance studies between PD-L1 assays are needed. We undertook comparisons of Dako 28-8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC.

Patients And Methods: Thirty-two patients with mRCC and 18 patients with mUC who had received immune checkpoint inhibitor therapy were identified. Formalin-fixed paraffin-embedded tumor samples for patients with mRCC were evaluated with Dako 28-8 and Ventana SP142 PD-L1 immunohistochemistry assays. For patients with mUC, formalin-fixed paraffin-embedded tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 immunohistochemistry assays.

Results: The majority (29/32; 91%) of mRCC cases were concordant between assays. The majority (17/18; 94%) of mUC cases were also concordant between assays.

Conclusions: There was strong concordance between PD-L1 assays chosen for comparison in both mRCC and mUC, with similar performance characteristics. One limitation is the small number of cases in this study; larger comparison studies are needed for this biomarker in mRCC and mUC.
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http://dx.doi.org/10.1016/j.clgc.2020.03.020DOI Listing
December 2020

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study.

J Immunother Cancer 2020 03;8(1)

Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.

Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.

Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).

Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.
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http://dx.doi.org/10.1136/jitc-2020-000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174076PMC
March 2020

Phase II Trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in Men with High-risk Prostate-specific Antigen Recurrent Prostate Cancer: The STREAM Trial.

Eur Urol Oncol 2020 Feb 13. Epub 2020 Feb 13.

Department of Medicine, Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA; Department of Surgery, Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA; Department of Pharmacology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA; Department of Cancer Biology, Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA. Electronic address:

Background: Salvage external beam radiotherapy (RT) with androgen deprivation therapy (ADT) improves survival over RT in men with prostate cancer (PC) and rising prostate-specific antigen (PSA) levels after radical prostatectomy (RP).

Objective: To investigate the safety and efficacy of enzalutamide concurrent with salvage RT and ADT.

Design, Setting, And Participants: This was a three-center prospective phase 2 single-arm trial (NCT02057939) of men with Gleason 7-10 PC and PSA recurrence within 4 yr of RP ranging from 0.2 to 4.0 ng/dl, no prior hormonal therapy, and no radiographic evidence of metastases. We enrolled 38 men; 37 completed therapy and were evaluable with testosterone recovery at 2 yr.

Intervention: Six months of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed.

Outcome Measurements And Statistical Analysis: The primary endpoint was improved 2-yr progression-free survival (PFS) over historical controls. Secondary objectives included 3-yr PFS, safety, and patient-reported quality of life (QOL).

Results And Limitations: The primary endpoint of 2-yr PFS was 65% (95% confidence interval [CI]: 47, 78) versus 51% (95% CI: 33, 67) in a trial of men with similar eligibility treated with salvage RT and adjuvant docetaxel. The 3-yr PFS was 53%. Eleven (29%) men experienced G3 toxicities, and there were no G4-5 or unexpected toxicities. QOL data suggest modest worsening of bowel, bladder, and hormonal symptoms at 3 mo, with recovery by 24 mo in most men.

Conclusions: Salvage RT with enzalutamide and ADT following RP for men with PSA recurrent high-risk PC is safe and demonstrates encouraging efficacy, warranting prospective controlled phase 3 trials of ADT with or without potent androgen receptor inhibition in this curative-intent setting.

Patient Summary: Addition of 6 mo of oral daily enzalutamide to standard salvage radiation and hormone therapy is safe and may improve prostate cancer remission rates at 2 and 3 yr.
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http://dx.doi.org/10.1016/j.euo.2020.01.005DOI Listing
February 2020

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.

J Natl Compr Canc Netw 2019 11;17(11):1278-1285

National Comprehensive Cancer Network.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.
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http://dx.doi.org/10.6004/jnccn.2019.0054DOI Listing
November 2019

Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.

Prostate 2019 11 9;79(15):1752-1761. Epub 2019 Sep 9.

Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.

Background: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy.

Methods: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses.

Results: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2).

Conclusions: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.
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http://dx.doi.org/10.1002/pros.23899DOI Listing
November 2019

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.

Lancet Oncol 2019 10 16;20(10):1370-1385. Epub 2019 Aug 16.

Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Background: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.

Methods: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.

Findings: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.

Interpretation: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.

Funding: Bristol-Myers Squibb and ONO Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(19)30413-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497870PMC
October 2019

Presidential Forum.

Ann Surg 2019 10;270(4):573-584

Stanford University, Stanford, California.

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http://dx.doi.org/10.1097/SLA.0000000000003421DOI Listing
October 2019

An experimental study on magnetic esophageal compression anastomosis in piglets.

J Pediatr Surg 2020 Mar 11;55(3):425-432. Epub 2019 May 11.

Division of Pediatric Surgery, University of California San Francisco, San Francisco, CA, United States.

Introduction: Fashioning a patent, watertight anastomosis in patients with esophageal atresia is a challenging task in pediatric surgery, particularly when performed under tension. A reproducible suture-less alternative would decrease operative time. We evaluated magnetic esophageal compression anastomoses in a novel bypass-loop swine model.

Methods: Eight-week-old piglets underwent thoracotomy to mobilize the esophagus at the carina to create a U-shaped loop. Custom-made 8 mm diameter Neodymium Magnets were inserted into the esophagus proximal and distal to the loop, then mated side-to-side at the future anastomosis site. Pigs were observed for 8 (n = 4), 10 (n = 6), and 12 (n = 2) days and then sacrificed. The magnetic compression anastomosis was evaluated macroscopically, by radiography, burst pressure testing, and histology.

Results: All 12 pigs survived until the endpoint. Separation of the magnets occurred at a median of 9 days. Contrast esophagrams showed patency and no leak. All anastomoses withstood pressures well over 13 kPa without leak. Histopathology showed epithelialized circular scar tissue.

Conclusion: Magnetic compression anastomoses of the esophagus using our specially-designed magnets are formed between the 8th and 10th postoperative day, are patent and mechanically resistant to supraphysiologic intraluminal pressures. These data lay the basis for a potential clinical application in patients born with esophageal atresia.

Level Of Evidence: Not applicable (experimental animal study).
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http://dx.doi.org/10.1016/j.jpedsurg.2019.04.029DOI Listing
March 2020

Endoscopic Magnetic Compression Anastomosis For Small Bowel Bypass in a High Operative Risk Setting.

Surg Laparosc Endosc Percutan Tech 2019 Oct;29(5):e84-e87

Departments of Surgery.

The endoscopic enteroenteral bypass could revolutionize the treatment of small bowel obstruction (SBO) in inoperable patients. We describe the technique of endoscopic delivery of a magnetic compression anastomosis device and the creation of an enteroenteral anastomosis in a patient with recurrent acute on chronic SBOs and prohibitively high operative risk. In this novel procedure, a magnetic compression anastomosis device is delivered on either side of the obstruction using a hybrid endoscopic/fluorographic technique, effectively bypassing the obstruction and relieving symptoms. The anastomosis was endoscopically evaluated at regular intervals postprocedure. By 7 days, healthy villi were visible through the mated magnetic rings. By 10 days, the anastomosis was widely patent. The rings passed through the ileostomy and were evacuated, and the patient's symptoms completely resolved. The anastomosis remained widely patent at 1 year. In summary, this case demonstrates the benefit of magnetic compression anastomosis in a patient with SBO and high operative risk.
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http://dx.doi.org/10.1097/SLE.0000000000000669DOI Listing
October 2019

Biomaterials in fetal surgery.

Biomater Sci 2019 Aug 17;7(8):3092-3109. Epub 2019 May 17.

Department of Bioengineering, University of California, Berkeley, CA, USA. and Department of Materials Science and Engineering, University of California, Berkeley, CA, USA and Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

Fetal surgery and fetal therapy involve surgical interventions on the fetus in utero to correct or ameliorate congenital abnormalities and give a developing fetus the best chance at a healthy life. Historical use of biomaterials in fetal surgery has been limited, and most biomaterials used in fetal surgeries today were originally developed for adult or pediatric patients. However, as the field of fetal surgery moves from open surgeries to minimally invasive procedures, many opportunities exist for innovative biomaterials engineers to create materials designed specifically for the unique challenges and opportunities of maternal-fetal surgery. Here, we review biomaterials currently used in clinical fetal surgery as well as promising biomaterials in development for eventual clinical translation. We also highlight unmet challenges in fetal surgery that could particularly benefit from novel biomaterials, including fetal membrane sealing and minimally invasive myelomeningocele defect repair. Finally, we conclude with a discussion of the underdeveloped fetal immune system and opportunities for exploitation with novel immunomodulating biomaterials.
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http://dx.doi.org/10.1039/c9bm00177hDOI Listing
August 2019

Retrospective analysis of the efficacy and safety of neoadjuvant gemcitabine and cisplatin in muscle-invasive bladder cancer.

J Oncol Pharm Pract 2020 Mar 12;26(2):330-337. Epub 2019 May 12.

Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Background: Neoadjuvant cisplatin-based combination chemotherapy for muscle-invasive bladder cancer (MIBC) improves overall and disease-free survival. However, there is much debate over the optimal neoadjuvant regimen. Gemcitabine plus cisplatin (GC) has been the neoadjuvant regimen of choice for many institutions for patients with MIBC based on data extrapolated from the metastatic setting. Based on recent data, many institutions are transitioning to variations of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as the neoadjuvant regimen of choice.

Objective: To assess the effectiveness and safety of neoadjuvant chemotherapy with gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer prior to cystectomy.

Methods: This is a single-center, retrospective, cohort study at Duke University Hospital (DUH). Patients included had MIBC and received gemcitabine plus cisplatin chemotherapy prior to a cystectomy. The primary endpoint was to assess the pathologic complete response (pCR) rate in MIBC after treatment with gemcitabine and cisplatin. Patients were split into two groups, those who received their chemotherapy at DUH, and those who received their chemotherapy at an outside facility.

Results: Overall pCR rate for all patients (n = 36) was 14%. The pCR rates for patients in the Duke Chemotherapy Group (n = 17) and in the Community Chemotherapy Group (n = 19) were 24% and 5%, respectively. GC was overall well tolerated in most patients with few adverse events ≥ grade 3.

Conclusions: This retrospective study demonstrates a consistent pCR rate (24% in Duke Chemotherapy Group) for neoadjuvant GC in MIBC compared with other literature. The overall pCR rate for all patients was 14%.
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http://dx.doi.org/10.1177/1078155219845434DOI Listing
March 2020

Beyond Magnamosis: A Method to Test Sutureless Esophageal Anastomotic Devices in Living Swine by Creating an Esophageal Bypass Loop for Natural Oral Nutrition.

J Laparoendosc Adv Surg Tech A 2019 Jun 18;29(6):852-855. Epub 2019 Mar 18.

1 Department of Paediatric Surgery, and Universitätsmedizin Mainz der Johannes-Gutenberg-Universität, Mainz, Germany.

Thoracoscopic esophageal atresia repair has become increasingly popular, but is still limited to a few expert centers and has some challenges and shortcomings. One of them has a longer operation time compared with conventional thoracotomy. Magnetic compression anastomosis may contribute toward shorter operation times by avoiding the time-consuming anastomotic suturing. We aimed to establish a method of testing sutureless anastomoses in parallel to having swine eating the natural way. We used four juvenile Pietrain swine-aged 8 weeks, weighing 15 kg-to establish a living animal model after preceding cadaver tests. Esophagi were fully mobilized through right-sided thoracotomy to gain sufficient length to create an esophageal loop that served as a bypass for food after magnet deployment. Six hours later, patency of the bypass esophageal loop was assessed by passing an orogastric tube and by allowing swine to drink methylene blue-stained water. We also tested the device stability using the classical burst pressure test. The esophageal lumen was patent for feeding tube. Swine were able to drink and methylene blue colored fluid reached the stomach. Clinical signs of obstruction such as regurgitation or coughing were absent. Magnets sustained burst pressures up to 200,000 Pascal until they became disrupted. At 6 hours after magnet placing, we already saw subtle esophageal mucosa erosions indicating the beginning of anastomotic formation. This animal model is useful to test different magnet designs for sutureless esophageal anastomosis or even future devices for tissue engineering.
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http://dx.doi.org/10.1089/lap.2018.0778DOI Listing
June 2019

Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma.

Clin Genitourin Cancer 2019 06 5;17(3):e513-e521. Epub 2019 Feb 5.

Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Durham, NC. Electronic address:

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.
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http://dx.doi.org/10.1016/j.clgc.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004481PMC
June 2019

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study.

Lancet Oncol 2019 04 28;20(4):581-590. Epub 2019 Feb 28.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.

Methods: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.

Findings: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.

Interpretation: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.

Funding: None.
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http://dx.doi.org/10.1016/S1470-2045(18)30907-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849381PMC
April 2019

Magnetic compression anastomosis (magnamosis) in a porcine esophagus: Proof of concept for potential application in esophageal atresia.

J Pediatr Surg 2019 Mar 29;54(3):429-433. Epub 2018 Sep 29.

Division of Pediatric Surgery, Akron Children's Hospital, Akron, OH.

Background: Magnetic compression anastomosis (magnamosis) is the process of forming a sutureless anastomosis of the gastrointestinal tract using two magnetic Harrison rings. It has been shown to be effective in stomach, small bowel and colon, but has not been implemented in the esophagus. A pure esophageal atresia porcine model was developed to test the concept.

Methods: Five pigs weighing between 35 and 65 kg were used. In all pigs, a percutaneous endoscopic gastrostomy (PEG) tube was placed, and a right thoracotomy was performed. Esophageal atresia was simulated by transecting the esophagus with a cutting stapler, and magnets were placed endoscopically to approximate the two ends of the esophagus. In the first pig, the tissue within the magnetic ring was excised endoscopically to achieve immediate patency. In the second pig, approximation of the blind esophageal ends was reinforced with 3-4 externally-placed sutures but immediate patency was not performed. In the last three pigs, both external suture reinforcement and immediate patency were performed. The pigs survived for 10-14 days and received nutrition through PEG tube. At necropsy, an esophagram was performed, the specimen was explanted and a leak test was performed.

Results: The first pig died in the early postoperative period from a leak owing to separation of the magnets. The second pig died from aspiration before the anastomosis formed. The last three pigs survived until the study endpoint. The third pig had a contained leak owing to the staple line being placed between the magnets; this was not clinically significant. The last two pigs had well-formed anastomoses. Burst tests showed no leak when injecting saline up to 30 mmHg.

Conclusion: Magnamosis is technically feasible for esophagoesophageal anastomoses. A survival model for pure esophageal atresia was developed and refined in pigs. Further work in this area may lead to clinical use in humans.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.09.014DOI Listing
March 2019

Dietary patterns and health-related quality of life in bladder cancer survivors.

Urol Oncol 2018 10 17;36(10):469.e21-469.e29. Epub 2018 Aug 17.

Division of Urology, Duke University Medical Center, Durham, NC. Electronic address:

Purpose: A nutritious diet has been associated with better health-related quality of life (HRQOL) in a variety of cancer survivors. However, little is known about dietary habits and its association with HRQOL in bladder cancer survivors. The objective of this cross-sectional study is to describe dietary intake patterns and its relationship to HRQOL in a large cohort of bladder cancer survivors.

Methods: Bladder cancer survivors within our institutional database were mailed surveys to assess dietary intake patterns utilizing the Diet History Questionnaire II and assessing HRQOL utilizing the Functional Assessment of Cancer Therapy-Bladder Cancer. Diet quality was assessed via Healthy Eating Index 2010 scores based on subjects' Diet History Questionnaire II results. Univariate and multivariate analyses of HRQOL based on diet quality were used to evaluate whether diet quality was associated with HRQOL.

Results: Four hundred and fifty-nine patients (48%) returned questionnaires. Mean age was 74 years, 81% were male and 28% underwent radical cystectomy. Diet quality and quantity in our cohort was similar to the general older U.S. population and did not differ significantly between those managed conservatively or long-term following cystectomy. Our cohort had low intake of whole grains and fat-soluble vitamins, particularly vitamin D. Diet quality was significantly associated with HRQOL in the univariate analysis but lost statistical significance in our multivariate analysis. Elixhauser Comorbidity Index was significantly associated with HRQOL in the multivariate analysis.

Conclusions: This study demonstrates a similar diet quality of bladder cancer survivors to the older general U.S. population that, on average, "needs improvement." Dietary intake is particularly lacking in whole grain and vitamin D intake. Future studies are warranted to determine the impact on long-term outcome, but bladder cancer survivors should be counseled on the importance and benefits of adherence to dietary guidelines, including its potential contribution toward better HRQOL.
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http://dx.doi.org/10.1016/j.urolonc.2018.06.001DOI Listing
October 2018

How we treat brain metastases in metastatic renal cell carcinoma.

Clin Adv Hematol Oncol 2018 Feb;16(2):110-114

Duke Cancer Institute and Duke University School of Medicine, Durham, North Carolina.

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February 2018

Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract: an evidence-based review of safety, efficacy, and place in therapy.

Core Evid 2018 24;13:1-12. Epub 2018 Jan 24.

Division of Urology.

Background: A systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data.

Methods: This review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta-analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data.

Results: We identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan-Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non-hematologic adverse events (AEs). Most prevalent grade 3-4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3-4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%.

Conclusion: VIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients.
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http://dx.doi.org/10.2147/CE.S118670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790085PMC
January 2018