Explore the vast range of titles available.

Purpose of ReviewDue to the rapidly changing field of kidney cancer therapeutics, addressing the state of the art systemic therapy regimens, and sequencing with cytoreductive nephrectomy are the primary focus of this review. We will also discuss the role of biomarkers and novel therapeutic targets in the management of renal cell carcinoma.Recent FindingsThe management of metastatic renal cell cancer has undergone a paradigm shift with immune checkpoint inhibitors being used in the frontline setting. Over the last 4 years, programmed cell death-1 (PD-1) inhibitors as well as programmed cell death ligand-1 inhibitors have become available in various combinations with cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors and tyrosine kinase inhibitors (TKIs). These drugs have improved outcomes in patients with renal cell cancer and more work is being done to refine these targets as well as discover newer ones.SummaryDespite the availability of several new treatment options, some questions that still need to be addressed in the management of kidney cancer include the sequencing of treatment options, treatment of patients who progress on immune checkpoint inhibitors, and role of biomarkers to ascertain the best treatment options to minimize costs and improve outcomes.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non–clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1 + /TMB hi /MSI hi ). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).MethodsPeripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses.ResultsIncreased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1.ConclusionsOur data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Renal angiomyolipoma (rAML) occurs rarely sporadically but is commonly encountered in patients with tuberous sclerosis complex and lymphangioleiomyomatosis. rAML is a rare entity, not seen regularly in daily practice; however, is commonly encountered and diagnosed by clinicians who approach and treat kidney masses. Basic knowledge of this entity is necessary to recognize that despite being benign, these tumors can rarely cause deadly complications such as hemorrhage or severe renal dysfunction or may have malignant components associated with them.

Objectives To evaluate and categorize the survival benefit of tricyclic antidepressants (TCAs) in lung cancer patients based on systematic computational drug repositioning data. Methods Data were retrospectively extracted from the medical records of non-small cell lung cancer (NSCLC) patients from the University of Cincinnati Cancer Medical Center database. Patients receiving antidepressants during their course of anti-cancer treatment were compared with those without antidepressants. Data were analyzed using Kaplan–Meier survival curves with the log-rank test, and overall survival (OS) was calculated from the date of diagnosis until last follow-up or death. Results The median OS at 2 and 5 years for patients on antidepressants was 20.3 months (54.7% and 42%) vs 44.3 months (47.6% and 43.2%), which was not significant. The median OS for patients receiving TCAs, selective serotonin reuptake inhibitors, and other antidepressants was 3.17 months, 31.33 months, and 18.50 months, respectively. Conclusion We found no significant survival benefit for TCA use in combination with anti-cancer agents in NSCLC patients.

The COVID‐19 pandemic changed health‐care operations around the world and has interrupted standard clinical practices as well as created clinical research challenges for cancer patients. Cancer patients are uniquely susceptible to COVID‐19 infection and have some of the worst outcomes. Importantly, cancer therapeutics could potentially render cancer patients more susceptible to demise from COVID‐19 yet the poor survival outcome of many cancer diagnoses outweighs this risk. In addition, the pandemic has resulted in risks to health‐care workers and research staff driving important change in clinical research operations and procedures. Remote telephone and video visits, remote monitoring, electronic capture of signatures and data, and limiting sample collections have allowed the leadership in our institution to ensure the safety of our staff and patients while continuing critical clinical research operations. Here we discuss some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office. The COVID‐19 pandemic has resulted in important changes in cancer clinical research operations and procedures. This commentary discusses some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office.

American Society of Hematology conducts an annual meeting, where investigators from around the globe presented ground-breaking research in the fields of malignant and non-malignant hematology. We provide a summary of non-malignant hematology abstracts from the 2020 meeting. Topics included range from those related to thrombosis, including thrombotic complications of COVID-19, bleeding and novel therapies such as gene therapies. Readers are encouraged to access meeting materials for a more detailed coverage of the event.

BackgroundImmune checkpoint inhibitors (ICIs) are now approved for several cancer types due to superior outcomes compared to chemotherapy. PD-1/PD-L1 and CTLA-4 inhibitors reactivate T-cell mediated anti-tumor immunity but may also lead to immune-related adverse events (irAEs). Growing evidence suggests the onset of irAEs could be correlated with the efficacy of ICIs.1. 2 In this study, we investigated patterns and incidence of irAEs and their relationship to overall survival (OS) and progression-free survival (PFS) in multiple cancer types.MethodsThe electronic medical record was queried at the University of Cincinnati Medical Center for the administration of ICIs for the identification of irAEs. Data on new irAEs diagnosed after administration of at least one dose of ICI was collected along with relevant demographic and clinicopathologic variables including treatment type, cancer type, staging information, and the administration of immune suppression following the identification of an IRAE either inpatient or outpatient. Univariant and multivariant analysis were conducted and survival analysis was determined according to log-rank testing.ResultsOf our 210 initial patients, the median age was 64 (range 22–93), 37% were female, 72% had ECOG 0-1, and 79% were white. Cancer types included melanoma 24%, non-small cell lung cancer (NSCLC) 34%, small cell lung cancer 2%, renal cancer 12%, urothelial cancer 11%, head and neck cancers 12%, and 16% other primaries while 19% remained on ICI at the time of data entry. The most common ICIs were pembrolizumab, nivolumab, followed by ipilimumab-nivolumab, ipilimumab, and durvalumab. The overall incidence of irAEs was 22.6%. Overall survival and progression-free survival was improved for those who suffered an IRAE (median OS 8.3 vs. 3.5 years, HR 0.56, p=0.0092; median PFS 5.0 vs 2.5 years, HR 0.57, p=0.0052) (figure 1 and 2 respectively). ICI treatment in NSCLC was associated with decreased overall IRAE events by univariant analysis (Odds Ratio 0.39, 95% CI 0.17 - 0.86). Our multivariate analysis showed ICI treatment in hepatocellular carcinoma to be significantly associated with irAEs, however, this was likely due to low enrollment (n=4) and was not significant by univariant analysis. The most common IRAE overall was diarrhea/colitis (figure 3).Abstract 252 Figure 1irAEs are associated with enhanced overall survivaloverall survival of patients who suffered at least one irAE demonstrated increased median survival of 8.3 years compared to 3.5 years from diagnosis for a mix of malignancies. The hazard ratio for this finding was 0.56, with a p-value of 0.0092 by Mantel-Cox log-rank testAbstract 252 Figure 2irAEs are associated with enhanced progression-freeSimilarly, progression-free survival of patients who suffered at least one irAE demonstrated increased median survival of 1.6 years compared to 0.51 years from initiation of treatment with a checkpoint inhibitor for a mix of malignancies. The hazard ratio for this finding was 0.51, with a p-value of 0.0018 by Mantel-Cox log-rank testAbstract 252 Figure 3irAE Types Observed by IncidenceIn our cohort, 47 patients suffered a total incidence of 71 irAEs the most common individual event of which was colitis of all grades (12/71). Rash and transaminitis occurred the second most frequently (9/71 respectively), and pneumonitis/thyroiditis was the third most frequent (8/71 respectively) which together represented 65% of all irAEs in this cohortConclusionsIn our data set, irAEs were associated with increased OS and PFS regardless of disease site. ICI treatment of NSCLC was associated with significantly fewer irAEs compared to other malignancies. Further research is needed to determine irAE type-specific incidence, the incidence of multiple irAEs in a single patient, and response to corticosteroid therapy.AcknowledgementsWe would like to thank the Department of Hematology/Oncology of the University of Cincinnati, the University of Cincinnati Cancer Center, and the Department of Internal Medicine of the University of Cincinnati for their support.Ethics ApprovalConsidered and Approved by the University IRB Approval #2019-0610.ReferencesWeber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 2017;35(7):785–792.Yamauchi I, Yasoda A, Matsumoto S, et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS ONE. 2019;14(5):e0216954.

BackgroundThe use of immune checkpoint inhibitors (ICI) has increased significantly in the past five years, along with the number of available drugs and regimens. ICIs have dramatically increased survival in cancer patients, however, there has been data to show that they have reduced efficacy in the presence of antibiotics.1 Antibiotic use prior and during ICI therapy was associated with worsening clinical outcomes in patients with renal cell carcinoma,2 melanoma,3 and non-small-cell-lung-cancer.4 Specifically, exposure within 60 days of initiation of ICIs in NSCLC seemed most detrimental, however, some studies have suggested that antibiotics disrupt intestinal microflora for up to six months.5 6 Therefore, we hypothesized that the duration of the antibiotic effect on ICI efficacy may be present for a longer duration.MethodsThe electronic medical record was queried at the University of Cincinnati Medical Center for the administration of ICIs and antibiotics. Data was collected on the use, type, and duration of antibiotics before ICI use after administration with relevant demographic and clinicopathologic variables including treatment type, cancer type, staging information, and clinical course including subsequent antibiotic use. Univariant (Fischer’s Exact) and multivariant analysis (multiple logistic regression) were conducted and survival analysis was determined according to log-rank testing.Results217 patients were examined. The median age was 64 (range 22-93), 38% were female, 73% had ECOG 0-1, and 77% were white. Cancer types included melanoma 24%, non-small cell lung cancer (NSCLC) 34%, small cell lung cancer 2%, renal cancer 11%, urothelial cancer 10%, head and neck cancers 11%, and 16% other primaries. 20% remained on ICI at the time of data entry. The most common ICIs were pembrolizumab, nivolumab, followed by ipilimumab-nivolumab, ipilimumab, and durvalumab. 81 patients of 218 received antibiotics within 6 months of receiving checkpoint inhibitors. Of antibiotics administered, the most common classes were cephalosporins (86%), fluoroquinolones (28%), and glycopeptides (23%) with substantial overlap. Overall survival and progression-free survival was improved for those who did not receive antibiotics prior to ICI therapy (median OS 6.5 vs. 2.3 years, HR 0.36, p<0.0001; median PFS 1.1 vs 0.5 years, HR 0.6, p=0.0027) (figure 1 and 2 respectively). Linear regression showed no significant association between antibiotic use prior to ICI use and age, sex, race, ICI type, or ECOG status.Abstract 774 Figure 1Antibiotics up to six months before ICI reduce OSFigure 1: Antibiotics Prior to Checkpoint Inhibitor Therapy Lead to Inferior Overall Survival: Analysis of patients treated with any type of antibiotic lead to worsened overall survival compared to those who did not receive antibiotics or who received a one time dose of cefazolin. Statistical analysis showed by both Log Rank and Wilcoxon testing p-values were <0.0001 with median survival 6.5y vs. 2.3y for those who received antibiotics prior to ICI treatment (HR 3.4, 95% CI 2.2 to 5.3).Abstract 774 Figure 2Antibiotics up to six months before ICI reduce PFSFigure 2: Antibiotics Prior to Checkpoint Inhibitor Therapy Lead to Inferior Progression-Free Survival: Analysis of patients treated with any type of antibiotic lead to worsened progression-free survival as well compared to those who did not receive antibiotics or who received a one time dose of cefazolin. Statistical analysis showed by both Log Rank and Wilcoxon testing p-values were 0.0027 and 0.0011 respectively. Median PFS from initiation of immunotherapy was 1.1y vs. 0.46y for those who received antibiotics prior to ICI treatment (HR 1.7, 95% CI 1.2 to 2.5).ConclusionsThis data adds to the growing body of knowledge that the use of antibiotics prior to ICI treatment leads to inferior overall and progression-free survival.AcknowledgementsWe would like to thank the Roman Jandarov, UC Cancer Center, the University of Cincinnati Division of Hematology and Oncology, Department of Internal Medicine of the University of Cincinnati, and the University of Cincinnati Medical Center for their continued support.Ethics ApprovalIRB 2019-0610ReferencesPinato DJ, Gramenitskaya D, Altmann DM, Boyton RJ, Mullish BH, Marchesi JR, et al. Antibiotic therapy and outcome from immune-checkpoint inhibitors. J Immunother Cancer 2019;7:287.Ueda K, Yonekura S, Ogasawara N, Matsunaga Y, Hoshino R, Kurose H, et al. The impact of antibiotics on prognosis of metastatic renal cell carcinoma in japanese patients treated with immune checkpoint inhibitors. Anticancer Res 2019;39:6265–71.Elkrief A, El Raichani L, Richard C, Messaoudene M, Belkaid W, Malo J, et al. Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors. Oncoimmunology 2019;8:e1568812.Ruiz-Patiño A, Barrón F, Cardona AF, Corrales L, Mas L, Martín C, et al. Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non-small cell lung cancer (AB-CLICaP). Thorac Cancer 2020;(9):2552-2560.Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019;5(12):1774-1778.Panda S, Khader IE, Casellas F, Vivancos JL, Cors MG, Santiago A, et al. Short-term effect of antibiotics on human gut microbiota. PLoS ONE 2014;9.