Generation and Characterization of Ex Vivo Expanded Tumor-infiltrating Lymphocytes From Renal Cell Carcinoma Tumors for Adoptive Cell Therapy.

Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance antitumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC. Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion. Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel. The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion.

Plasma KIM-1 Is Associated with Recurrence Risk after Nephrectomy for Localized Renal Cell Carcinoma: A Trial of the ECOG-ACRIN Research Group (E2805).

PURPOSE: No circulating biomarkers are currently available to identify patients at highest risk of recurrence after nephrectomy for renal cell carcinoma (RCC). Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain circulates in plasma. We investigated whether plasma KIM-1 is a prognostic biomarker in patients with localized RCC after nephrectomy. EXPERIMENTAL DESIGN: The ECOG-ACRIN E2805 (ASSURE) trial evaluated adjuvant sunitinib, sorafenib, or placebo in resected high-risk RCC. KIM-1 levels were measured from banked plasma at trial enrollment 4-12 weeks after nephrectomy. Lognormal accelerated failure time models were used to test for association between KIM-1 and disease-free survival (DFS) as well as overall survival (OS). RESULTS: Plasma from 418 patients was analyzed. Higher post-nephrectomy KIM-1 was associated with worse DFS across all study arms after adjustment for Fuhrman grade, T stage, N stage, and tumor histology [survival time ratio 0.56 for 75th vs. 25th percentile of KIM-1; 95% confidence interval (CI), 0.42-0.73; P < 0.001]. The association between KIM-1 and DFS was stronger among patients with pathologic nodal involvement (P interaction = 0.0086). The addition of post-nephrectomy KIM-1 improved the concordance of clinical prognostic models [Stage, Size, Grade, and Necrosis (SSIGN) concordance 0.57 vs. 0.43, P = 0.05; UCLA International Staging System (UISS) concordance 0.60 vs. 0.40, P = 0.0005]. Higher post-nephrectomy KIM-1 was also associated with worse OS after multivariable adjustment (survival time ratio 0.71 for 75th vs. 25th percentile of KIM-1; 95% CI, 0.56-0.91; P < 0.001). CONCLUSIONS: Post-nephrectomy plasma KIM-1 is associated with DFS and OS in RCC, and may be a biomarker for microscopic residual disease.

Hot or Not: Tumor Mutational Burden (TMB) as a Biomarker of Immunotherapy Response in Genitourinary Cancers.

Pembrolizumab was recently approved for treatment of cancers with high tumor mutational burden (TMB). We conduct a focused literature review of TMB as a predictive biomarker. TMB quantifies the sum of nonsynonymous coding mutations (typically single nucleotide substitutions and short insertion-deletions) per megabase of sequenced DNA. As a proxy for expression of immunogenic neoantigens, TMB may be an effective predictive biomarker for response to immune checkpoint inhibitors. However, like other biomarkers in this setting, TMB has many limitations; the effect of this FDA approval in the current management of genitourinary cancers is likely limited to select situations.

From metrics to practice: identifying preventable emergency department visits for patients with cancer.

BACKGROUND: Oncology patients disproportionately utilize the emergency department (ED) for symptom management. At our institution, approximately 1 in 4 visits to the ED by oncology patients led to discharge. We hypothesized that many of the visits leading to ED discharge would be potentially preventable (PP). METHODS: We retrospectively characterized ED discharges of oncology patients. Visits were classified by presenting symptom, type of cancer, and time of ED visit. Chart reviewers were additionally asked whether each case could have been safely managed as an outpatient. RESULTS: We analyzed 100 ED discharges in a 4-month period in 2016 and 2017. Gastrointestinal (GI) complaints, pain, and fever were the most common presenting symptoms for these visits. We rated 44 of 100 ED discharges as potentially preventable. Given we analyzed only ED discharges which comprise about 25% of ED visits for patients with cancer, overall about 10% of all ED visits by these patients may be preventable. We also found that ED visits without a clinic appointment or phone call to the clinic on the day of ED presentation were more likely to be preventable (51% vs 27%, OR 2.9, p = 0.026). CONCLUSIONS: Many ED visits by oncology patients may be preventable and occur for symptoms which can be managed as an outpatient. More of these visits also appear to occur in those who do not reach a clinic member prior to the visit. These findings suggest that improved access to clinics and standardized outpatient symptom management are next steps to consider in preventing ED visits in this vulnerable population.

Disproportionate longer-term opioid use among U.S. adults with mood disorders.

Adults with mood disorders frequently use prescription opioids. The factors associated with this increased use remain unclear. We used the Medical Expenditure Panel Surveys from 2005 to 2011 to measure the association of mood disorders with new opioid use and the transition to longer-term opioid use for a variety of pain conditions before and after controlling for patient characteristics and clinical disability. We analyzed 33,450 adults with likely acute or potentially chronic pain conditions who were not using opioids at baseline. Among respondents with likely acute pain conditions, those with mood disorders initiated opioids more frequently for that pain condition compared with those without mood disorders (19.3%, vs 17.2%, P = 0.01). After initiation, they also transitioned to longer-term opioid therapy more frequently (11.7% vs 5.3%, P < 0.01). Among respondents with potentially chronic pain conditions, adults with mood disorders initiated opioid therapy more frequently for their chronic pain condition (11.5% vs 9.2%, P < 0.01) and transitioned to longer-term therapy more frequently (36.8% vs 19.9%, P < 0.01). After adjusting for sociodemographics and clinical disability, there was no association between mood disorders and new opioid use for likely acute (adjusted odds ratio [aOR] 1.05 [0.92-1.20]) or potentially chronic pain (aOR 0.91 [0.80-1.03]). However, there remained a strong association between mood disorders and the transition to longer-term opioid use for likely acute (aOR 1.77 [1.15-2.72]) and potentially chronic pain (aOR 1.95 [1.42-2.68]). Targeting the transition to longer-term opioid use may help clinicians reduce potentially inappropriate opioid prescriptions in this high-risk population.

Rates of and Reasons for Hospital Readmissions in Patients With Cirrhosis: A Multistate Population-based Cohort Study.

BACKGROUND & AIMS: There have been few population-based studies of the rates of and reasons for readmission to the hospital within 30 days among patients with cirrhosis. METHODS: We identified all adult patients with cirrhosis who were admitted in 2011 to hospitals in California, Florida Massachusetts, Mississippi, New York, and Washington (119,722 unique index admissions with cirrhosis). We analyzed data from the State Inpatient Databases, which are longitudinal all-payer databases. Data were linked to the American Hospital Association's national survey for hospital characteristics. Outcomes included readmission to any hospital within 30 and 90 days, and the reasons for readmission. RESULTS: The 30- and 90-day rates of readmission were 12.9% and 21.2% overall, with limited variation among states. Among patients with more than 3 complications of cirrhosis, 24.2% were readmitted within 30 days and 35.9% were readmitted within 90 days. The presence of hepatic encephalopathy was most strongly associated with readmission within 30 and 90 days (odds ratio, 1.77 for each). Almost 1 in every 4 readmissions was to a different hospital than the one from which the patient was discharged. Among patients with alcoholic liver disease and a history of a complications of cirrhosis, the 2 most common reasons for readmission were acute complications of cirrhosis (in 41.7%) and substance abuse (in 25.0%). Conversely, the most common reasons for readmission of patients with a history of complications of cirrhosis without alcoholic liver disease were acute complications (in 41.0%) and cancer complications (in 16.2%). CONCLUSIONS: A high proportion of patients with cirrhosis are readmitted to the hospital (often to a different hospital) within 30 or 90 days; encephalopathy is most strongly associated with readmission. Reasons for readmission differ based on the cause of liver disease, and there are opportunities for quality improvement.

Multivalent recognition of peptides by modular self-assembled receptors.

Developing nontraditional approaches to the synthesis and characterization of multivalent compounds is critical to our efforts to study and interface with biological systems and to build new noncovalent materials. This paper demonstrates a biomimetic approach to the construction of discrete, modular, multivalent receptors via molecular self-assembly in aqueous solution. Scaffolds presenting 1-3 viologen groups recruit a respective 1-3 copies of the synthetic host, cucurbit[8]uril, in a noncooperative manner and with a consistent equilibrium association constant (K(a)) value of 2 x 10(6) M(-1) per binding site. The assembled mono-, di-, and trivalent receptors bind to their cognate target peptides containing 1-3 Trp residues with K(a) values in the range 1.7 x 10(4)-4.7 x 10(6) M(-1) and in predetermined mono- or multivalent binding modes with 31-280-fold enhancements in affinity and additive enthalpies due to multivalency. The extent of valency was determined directly by measuring the visible charge-transfer absorptivity due to the viologen-indole pair. The predictable behavior of this system and its ease of synthesis and analysis make it well suited to serve as a model for multivalent binding and for the multivalent recognition of peptides by design.