Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Neoadjuvant Atezolizumab With Gemcitabine and Cisplatin in Patients With Muscle-Invasive Bladder Cancer: A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Neoadjuvant gemcitabine and cisplatin (GC) followed by radical cystectomy (RC) is standard for patients with muscle-invasive bladder cancer (MIBC). On the basis of the activity of atezolizumab (A) in metastatic BC, we tested neoadjuvant GC plus A for MIBC. METHODS: Eligible patients with MIBC (cT2-T4aN0M0) received a dose of A, followed 2 weeks later by GC plus A every 21 days for four cycles followed 3 weeks later by a dose of A before RC. The primary end point was non-muscle-invasive downstaging to < pT2N0. RESULTS: Of 44 enrolled patients, 39 were evaluable. The primary end point was met, with 27 of 39 patients (69%) < pT2N0, including 16 (41%) pT0N0. No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). One patient refused RC and two developed metastatic disease before RC; all were considered nonresponders. The most common grade 3-4 adverse event (AE) was neutropenia (n = 16; 36%). Grade 3 immune-related AEs occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo RC because of AEs. Four of 39 (10%) patients had programmed death-ligand 1 (PD-L1)-positive tumors and were all < pT2N0. Of the patients with PD-L1 low or negative tumors, 23 of 34 (68%) achieved < pT2N0 and 11 of 34 (32%) were ≥ pT2N0 (P = .3 for association between PD-L1 and < pT2N0). CONCLUSION: Neoadjuvant GC plus A is a promising regimen for MIBC and warrants further study. Patients with < pT2N0 experienced improved relapse-free survival. The PD-L1 positivity rate was low compared with published data, which limits conclusions regarding PD-L1 as a predictive biomarker.

Evaluation of thrombophilia testing in the inpatient setting: A single institution retrospective review.

BACKGROUND: Thrombophilia workup is typically inappropriate in the inpatient setting as testing may be skewed by anticoagulation, acute thrombosis, or acute illness. OBJECTIVE: To determine adherence of inpatient thrombophilia testing with institutional guidelines. PATIENTS AND METHODS: A retrospective study to evaluate thrombophilia testing practices of adult patients who were admitted to Lehigh Valley Hospital at Cedar Crest with either venous thromboembolism or ischemic stroke in 2019. Testing included inherited and acquired thrombophilia. Patient charts were individually reviewed for three measured outcomes: 1) the number of appropriate thrombophilia testing in the inpatient setting; 2) the indications used for thrombophilia testing; 3) the proportion of positive thrombophilia tests with change in clinical management. RESULTS: 201 patients were included in our study. 26 patients (13%) were tested appropriately in accordance with institution guidelines and 175 (87%) patients were tested inappropriately. The most common reason for the inappropriate testing was testing during acute thrombosis. 28 of the 201 patients had positive thrombophilia tests, but the reviewers only noted 7 patients with change in clinical management-involving anticoagulation change. CONCLUSION: Our study revealed that a majority of inpatient thrombophilia testing did not follow institutional guidelines for appropriate testing and did not change patient management. These thrombophilia tests are often overutilized and have minimal clinical utility in the inpatient setting.

Light chain cast nephropathy caused by plasmablastic lymphoma of the bladder.

INTRODUCTION: Plasmablastic lymphoma (PBL) is a rare form of B-cell lymphoma typically seen in patients with underlying immunosuppression such as HIV, autoimmune disease, and organ transplantation. PBL in HIV-positive patients usually originates from the gastrointestinal tract, with a predilection for the oral cavity. Bladder involvement by PBL is exceedingly rare, and cast nephropathy due to κ light chain-secreting PBL has not been reported previously. CASE REPORT: We report a patient who presented with acute kidney injury (AKI) in the setting of HIV, and was found to have a bladder tumor. Bladder pathology revealed a high-grade PBL with κ light chain restriction. Renal biopsy showed κ light chain cast nephropathy, presumably secondary to κ light chain-secreting PBL. CONCLUSION: Although the prognosis of PBL is poor, our patient recovered from AKI, achieved complete hematologic remission with chemotherapy, and underwent successful autologous stem cell transplant.

Thrombotic Thrombocytopenic Purpura Induced by Immune Checkpoint Inhibitiors: A Case Report and Review of the Literature.

In recent years, the role of immune checkpoint inhibitors (ICI) in cancer treatment has rapidly expanded. In randomized clinical trials, these agents have demonstrated clinical efficacy in extending survival and increasing response rates. Immune-related adverse effects (irAEs) involving various organs have been frequently narrated. Herein, we present a case report of thrombotic thrombocytopenic purpura (TTP) as a rare side effect of nivolumab, plus ipilimumab, in the treatment of metastatic renal cell carcinoma (RCC). A review of the literature for other case reports of TTP during treatment with ICIs was also performed. Our aim is to elucidate the significance of early recognition of this rare adverse effect in patients being treated with this relatively newer class of medications.

Chemotherapy-induced release of circulating-tumor cells into the bloodstream in collective migration units with cancer-associated fibroblasts in metastatic cancer patients.

BACKGROUND: Recent studies have shown that chemotherapy destabilizes the blood vasculature and increases circulating tumor cell (CTC) influx into the circulation of metastatic cancer patients (Met-pa). CTCs are a precursor of cancer metastasis, in which they can migrate as single CTCs or as CTC clusters with stromal cells such as cancer-associated fibroblasts (CAFs) as cell aggregates. METHODS: Blood samples were collected from 52 Met-pa, and the number of CTC and CAF was determined along with the temporal fluctuation of these through the chemotherapy treatment. RESULTS: In this study, CTC level was found to increase two-fold from the initial level after 1 cycle of chemotherapy and returned to baseline after 2 cycles of chemotherapy. Importantly, we determined for the first time that circulating CAF levels correlate with worse prognosis and a lower probability of survival in Met-pa. Based on the CTC release induced by chemotherapy, we evaluated the efficacy of our previously developed cancer immunotherapy to eradicate CTCs from Met-pa blood using an ex vivo approach and demonstrate this could kill over 60% of CTCs. CONCLUSION: Collectively, we found that CAF levels in Met-pa serve as a predictive biomarker for cancer prognosis. Additionally, we demonstrate the efficacy of our therapy to kill primary CTCs for a range of cancer types, supporting its potential use as an anti-metastasis therapy in the clinical setting.

Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: Neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase II randomized trial.

OBJECTIVES: The ECOG-ACRIN Cancer Research Group trial E2511 recently demonstrated a potential benefit for the addition of veliparib to cisplatin-etoposide (CE) in patients with extensive stage small cell lung cancer (ES-SCLC) in a phase II randomized controlled trial. Secondary trial endpoints included comparison of the incidence and severity of neurotoxicity, hypothesized to be lower in the veliparib arm, and tolerability of the addition of veliparib to CE. Physician-rated and patient-reported neurotoxicity was also compared. MATERIALS AND METHODS: Patients randomized to veliparib plus CE (n = 64) or placebo plus CE (n = 64) completed the 11-item Functional Assessment of Cancer Therapy Gynecologic Oncology Group Neurotoxicity (questionnaire pre-treatment, end of cycle 4 [ie 3 months after randomization] and 3 months post-treatment [ie 6-months]). Adherence analysis was based on treatment forms. RESULTS AND CONCLUSION: No significant differences in mean or magnitude of change in neurotoxicity scores were observed between treatment arms at any time point. However, patients in the placebo arm reported worsening neurotoxicity from baseline to 3-months (M difference = -1.5, P = .045), compared to stable neurotoxicity in the veliparib arm (M difference = -0.2, P = .778). Weakness was the most common treatment-emergent (>50%) and moderate to severe (>16%) symptom reported, but did not differ between treatment arms. The proportion of adherence to oral therapy in the overall sample was 75%. Three percent of patients reported clinically significant neurotoxicity that was not captured by physician assessment. Neurotoxicity scores were not different between treatment arms. The addition of veliparib to CE appeared tolerable, though weakness should be monitored. CLINICALTRIALS. GOV IDENTIFIER: NCT01642251.

Platelet mediated TRAIL delivery for efficiently targeting circulating tumor cells.

Several studies have demonstrated the role of platelets in promoting cancer metastasis. Platelets bind to and protect circulating tumor cells (CTCs) from hemodynamic forces and immune cells, and also promote tumor cell arrest in the vasculature and extravasation. Thus, platelets represent a promising vehicle to deliver anticancer therapeutic agents to CTCs. In this study, we developed a novel platelet-mediated TNF-related apoptosis inducing ligand (TRAIL) delivery system to target CTCs and hinder metastasis via "in situ" platelet modification. This platelet-mediated TRAIL delivery significantly reduced the viability of colorectal and breast cancer cells circulating in flowing blood under physiological shear conditions. TRAIL-coated platelets significantly killed over 60% of CTCs in flowing blood from a variety of primary metastatic cancer samples. Platelets have been considered an important player in the regulation of metastasis due to their interaction with cancer cells in the circulation; the current study supports the idea of using platelet-based TRAIL delivery as a promising CTC-targeted cancer therapy.

Randomized Phase II Trial of Cisplatin and Etoposide in Combination With Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511 Study.

PURPOSE: Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC). MATERIALS AND METHODS: Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate. RESULTS: A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable. CONCLUSION: The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.

Isolated Left Ventricular Metastasis from Renal Cell Carcinoma: Diagnostic and Therapeutic Dilemma.

BACKGROUND: The treatment of metastatic renal cell carcinoma (RCC) has been radically changed by the advent of tyrosine kinase inhibitors (TKIs). However, few reports have described their role in cardiac metastases. We present a case of a left ventricular metastasis from RCC that was managed with pazopanib therapy. CASE REPORT: A 74-year-old male with stage I RCC underwent right nephrectomy in 2004 and right lung metastasis resection in 2009. He was well till March 2016, when he presented with chest pain. Cardiac catheterization revealed a highly vascular mass in the apex. Cardiac magnetic resonance imaging revealed a left ventricular mass with full-thickness involvement of the myocardium, and the open cardiac biopsy was consistent with metastatic RCC. The patient was initially treated with pazopanib with response but later developed therapy-related side effects, and the dose was reduced. Due to tumor progression, he is currently on nivolumab instead and is stable. CONCLUSION: RCC with cardiac metastasis poses unique challenges with regard to diagnosis as well as treatment. The use of TKI therapy is associated with cardiotoxicity and has not been adequately studied in cardiac metastasis. Choosing the right treatment for this subgroup of patients continues to pose an ongoing dilemma.

Acquired von Willebrand Syndrome in IgM Monoclonal Gammopathy as the Presentation of Lymphoplasmacytic Lymphoma.

Acquired von Willebrand syndrome (AVWS) is an increasingly recognized entity with numerous potential underlying etiologies. Most commonly implicated are lymphoproliferative, myeloproliferative, cardiovascular, and autoimmune disorders. Unlike inherited von Willebrand disease (vWD), AVWS tends to present at an older age and without a family history of vWD. Treatment is directed at the underlying etiology if one is uncovered, as well as treatment and prevention of bleeding. Here, we present a rare case of AVWS secondary to Waldenström macroglobulinemia which went unrecognized for several years but resolved promptly with treatment. The potential mechanisms of AVWS secondary to monoclonal gammopathies are discussed as well as strategies to treat and prevent bleeding in these patients.