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The antimicrobial potential of switchgrass extractives (SE) was evaluated on cut lettuce leaves and romaine lettuce in planta, using rifampicin-resistant Escherichia coli O157:H7 and Salmonella Typhimurium strain LT2 as model pathogens. Cut lettuce leaves were swabbed with E. coli O157:H7 or S. Typhimurium followed by surface treatment with 0.8% SE, 0.6% sodium hypochlorite, or water for 1 to 45 min. For in planta studies, SE was swabbed on demarcated leaf surfaces either prior to or after inoculation of greenhouse-grown lettuce with E. coli O157:H7 or S. Typhimurium; the leaf samples were collected after 0, 24, and 48 h of treatment. Bacteria from inoculated leaves were enumerated on tryptic soy agar plates (and also on MacConkey's and XLT4 agar plates), and the recovered counts were statistically analyzed. Cut lettuce leaves showed E. coli O157:H7 reduction between 3.25 and 6.17 log CFU/leaf, whereas S. Typhimurium reductions were between 2.94 log CFU/leaf and 5.47 log CFU/leaf depending on the SE treatment durations, from initial levels of ∼7 log CFU/leaf. SE treatment of lettuce in planta, before bacterial inoculation, reduced E. coli O157:H7 and S. Typhimurium populations by 1.88 and 2.49 log CFU after 24 h and 3 h, respectively. However, SE treatment after bacterial inoculation of lettuce plants decreased E. coli O157:H7 populations by 3.04 log CFU (after 0 h) with negligible reduction of S. Typhimurium populations. Our findings demonstrate the potential of SE as a plant-based method for decontaminating E. coli O157:H7 on lettuce during pre- and postharvest stages in hurdle approaches.

Supplementary Table from ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables In Vivo Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma

Purpose:Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno–positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to IHC in an RCC patient-derived tumorgraft (TG) platform.Experimental Design:Eight independent RCC TGs with a wide range of PD-L1 expression (0%–85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared with PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC.Results:ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 postinjection) revealed a statistically significant association with PD-L1 IHC assays (P = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness.Conclusions:ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).

Supplementary Figure from ImmunoPET Imaging with 89Zr-Labeled Atezolizumab Enables In Vivo Evaluation of PD-L1 in Tumorgraft Models of Renal Cell Carcinoma

Purpose: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 and its ligand (PD-1/PD-L1) have transformed the treatment paradigm for metastatic renal cell carcinoma (RCC). However, response rates to ICIs as single agents or in combination vary widely and predictive biomarkers are lacking. Possibly related to the heterogeneity and dynamic nature of PD-L1 expression, tissue-based methods have shown limited value. Immuno–positron emission tomography (immunoPET) may enable noninvasive, comprehensive, and real-time PD-L1 detection. Herein, we systematically examined the performance of immunoPET for PD-L1 detection relative to IHC in an RCC patient-derived tumorgraft (TG) platform. Experimental Design: Eight independent RCC TGs with a wide range of PD-L1 expression (0%–85%) were evaluated by immunoPET. Uptake of 89Zr-labeled atezolizumab ([89Zr]Zr-DFO-ATZ) was compared with PD-L1 expression in tumors by IHC through double-blind analyses. Clinical outcomes of ICI-treated patients whose TGs were examined were analyzed to evaluate the clinical role of immunoPET in RCC. Results: ImmunoPET with [89Zr]Zr-DFO-ATZ (day 6/7 postinjection) revealed a statistically significant association with PD-L1 IHC assays (P = 0.0014; correlation ρXY = 0.78). Furthermore, immunoPET can be used to assess the heterogeneous distribution of PD-L1 expression. Finally, studies in the corresponding patients (n = 4) suggest that PD-L1 signal may influence ICI responsiveness. Conclusions: ImmunoPET with [89Zr]Zr-DFO-ATZ may enable a thorough and dynamic assessment of PD-L1 across sites of disease. The power of immunoPET to predict ICI response in RCC is being explored in an ongoing clinical trial (NCT04006522).

Background As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence. Methods ECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (, In a randomized clinical trial for renal cell carcinoma, adherence to oral therapy was lower (85%) than adherence to placebo (95%). Adherence was also worse among racial/ethnic minorities, patients experiencing certain toxicities, and high volume enrolling sites, highlighting several challenges to address in clinical practice as oral therapies become increasingly common.

BACKGROUND The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. METHODS The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. RESULTS Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33 years; P = .005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P

Active surveillance (AS) may be used in the management of metastatic renal cell carcinoma (mRCC), but consensus regarding its application is lacking. We report an exploratory analysis of prospectively collected data and specimens prespecified in the only modern clinical trial evaluating AS in mRCC. Whole-exome and RNA sequencing were performed for patients providing consent to identify putative biomarkers associated with time on AS (TAS), the primary endpoint. Log-rank tests and multivariable Cox proportional-hazards models were used for analyses. Patients with mutations in either TP53 or SMARCA4 tumor suppressor genes had shorter TAS (7.5 vs 14.2 mo; log-rank p = 0.004). While these patients exhibited features of aggressive disease clinically, the two-gene model was independently predictive in multivariable analyses (hazard ratio 3.30, 95% confidence interval 1.07–10.18; p = 0.038). In conclusion, insight into the underlying RCC biology improves patient selection for AS. If validated, this two-gene model could help in stratifying patients with mRCC and identifying those who are poor candidates for AS. PATIENT SUMMARY: In this study, we analyzed tumors from patients with metastatic kidney cancer enrolled in a clinical trial of imaging surveillance. We found that tumors with mutations in either the TP53 or SMARCA4 gene progressed faster than tumors without these mutations. Thus, patients harboring mutations in these genes benefit from immediate systemic therapy.

Funder: Libor Fund grant from the UK Department of Health, by the British Lung Foundation and by the Asmarley Foundation, Funder: UK Medical Research Council, Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Background: Surgical feeding ostomies (SFO, e.g. gastrostomy) have replaced natural orifice feeding tubes (NOFT, e.g. nasogastric feeding tube) as the preferred route for long-term enteral nutrition. Reports of complication rates for SFO vary. Many hospitalized patients are required to accept SFO before hospital discharge due to skilled nursing facilities (SNFs) policy, and without supportive data. We compare adverse event rates between SFO and NOFT. Methods: A prospective cohort study of enterally fed inpatients using semiweekly focused physical exam, scripted survey, and chart review. Findings: Over the course of nine weeks, 226 unique patients were seen an average of 6.25 times each for a total of 1118 unique observations. Demographic data were comparable between subgroups. There were 148 subjects with NOFT and 113 subjects with SFO. 35 NOFT crossed over to SFO during the study. More NOFT than SFO observations took place in ICUs (p

Introduction This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. Methods Venous and arterial TEEs within ±365 days of diagnosis of ROS1+, ALK+, EGFR+, or KRAS+ advanced NSCLC at five academic centers in the United States and China were captured (October 2002–April 2018). The primary endpoint was incidence of TEE in ROS1+ compared to anaplastic lymphoma kinase (ALK)+, EGFR+, and KRAS+ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers. Results Eligible data from 95 ROS1+, 193 ALK+, 300 EGFR+, and 152 KRAS+ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n = 33), 22.3% (n = 43), 13.7% (n = 41), and 18.4% (n = 28), respectively. In univariate analysis, the odds of a TEE in ROS1+ NSCLC were higher than ALK+, EGFR+, and KRAS+ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1+ compared to EGFR+ and KRAS+ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31–4.57 (p = 0.005), and OR: 2.62, with a 95% confidence interval of 1.26–5.46 (p = 0.01), respectively. Although numerically superior, the odds for a TEE with ROS1+ compared to ALK+ was not statistically significant (OR: 1.45, p = 0.229). Overall survival was not significantly different in patients with or without TEE within ±90 days of diagnosis in the overall study cohort or within each molecular group. Conclusions The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC.

Summary 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.

TPS3169 Background: Aryl Hydrocarbon Receptor (AHR) is a ligand-activated transcription factor that regulates the activity of multiple innate and adaptive immune cells. Kynurenine, generated from tryptophan by IDO1 and TDO2, is a ligand that binds AHR and leads to a net immunosuppressive tumor microenvironment, making AHR an attractive therapeutic target in multiple cancer types. IK-175 is a selective, small molecule inhibitor of AHR being developed as an oral agent. In preclinical mouse tumor models, IK-175 demonstrates antitumor activity as a single agent or in combination with checkpoint inhibitors. AHR immunohistochemistry (IHC) tumor microarray analysis across 15 different tumor types revealed that bladder cancer has the highest level of AHR protein expression and nuclear localization indicative of ligand-bound and active AHR signaling. Therefore, nuclear AHR in urothelial carcinoma tumors is being investigated for potential predictive clinical benefit with IK-175. Methods: This is a first-in-human, phase 1a/b, open-label, multicenter, dose-escalation and expansion study of IK-175 as a single agent and in combination with nivolumab. The primary objectives are to determine the maximum tolerated dose (MTD) and/or maximum administered dose (MAD), identify the recommended phase 2 dose (RP2D), and evaluate the safety and tolerability of IK-175 alone and in combination with nivolumab. Secondary objectives are to evaluate the pharmacokinetics (PK) of IK-175, evaluate pharmacodynamic (PD) immune effects, and assess preliminary antitumor activity. Key exploratory objectives are to evaluate the PD effects on peripheral immune cells and target gene expression, to assess candidate baseline biomarkers, and correlative analyses of tumor AHR nuclear localization with clinical response. The study is exploring tumor AHR nuclear localization by IHC as a predictive biomarker in patients with urothelial carcinoma. A minimum of 10 patients with a positive AHR nuclear localization test (cutoff for positive AHR is 65% tumor cells positive for 2+/3+ nuclear AHR by a validated IHC assay) will be enrolled in the combination arm. IK-175 is administered daily in 21 or 28 day-cycles as a single agent, and in combination with nivolumab (480 mg q4w on Day 1 of every cycle), in adult patients with advanced solid tumors (dose escalation) and urothelial carcinoma (dose expansion). Key eligibility criteria include patients with histologically confirmed solid tumors (including urothelial carcinoma) who have locally recurrent or metastatic disease that have progressed on or following all standard of care therapies deemed appropriate by the treating physician including prior checkpoint inhibitors. Estimated enrollment is 93 patients; the study began in January 2020 and is ongoing. Clinical trial information: NCT04200963.

The optimal management approach to advanced or metastatic renal cell cancer of the clear cell type continues to rapidly evolve. Risk stratification of patients into favorable-, intermediate-, and poor-risk categories is now routinely performed. In selected individuals with low-volume indolent disease, active surveillance may be an appropriate option. Cytoreductive nephrectomy and/or surgical metastasectomy may be also be considered for selected patients after evaluation by a multidisciplinary tumor board. Systemic frontline therapy options now include immune checkpoint inhibitor–based combination (IBC) therapies such as pembrolizumab/axitinib, nivolumab/ipilimumab, and avelumab/axitinib. With unusual exceptions, monotherapy with vascular growth factor receptor tyrosine kinase inhibitors or mTOR inhibitors are no longer appropriate options in the frontline setting. Despite the established efficacy of frontline IBC, most patients will ultimately require additional lines of therapy, and oncologists must think carefully when switching to another therapy, particularly in situations of drug intolerance or apparent disease progression. Systemic therapy options after IBC are generally tyrosine kinase inhibitor–based, and ongoing clinical trials will help optimize the treatment algorithm further. Despite many recent drug approvals for renal cell cancer (RCC), there remains a pressing need to identify new therapeutic targets. Finally, other systemic therapy or supportive care approaches must be considered for special patient populations such as those with poor performance status, end-organ dysfunction, brain metastases, or who have undergone metastasectomy.

389 Background: Emerging data suggest that active surveillance (AS) may be safely implemented in a subset of patients (pts) with metastatic renal cell carcinoma (RCC) and indolent disease to delay the initiation of systemic therapy without undermining long-term survival. However, widespread adoption of AS has been limited by a lack of data on factors portending favorable outcomes. In this study we sought to characterize pts undergoing AS at a large academic medical center to identify factors associated with time on AS. Methods: We identified pts on AS using Kidney Cancer Explorer (KCE), the data management platform of the Kidney Cancer Program at UT Southwestern Medical Center (2005-2020), as well as input from medical oncologists. The AS cohort was defined by (1) having metastatic RCC (determined by either a suspicious lesion > 1cm or a positive biopsy), and (2) the absence of prior systemic therapy. Baseline characteristics and IMDC criteria were evaluated at the outset. Outcomes of interest included progression free survival (PFS), time to systemic therapy (TST), and overall survival (OS). Survival estimates were generated using Kaplan Meier methods. Cox proportional hazard models were used in univariate and multivariate analyses to identify baseline characteristics associated with TST. Results: We identified 37 pts with metastatic RCC undergoing AS; 31 pts (83.8%) had ccRCC, 28 pts (75.7%) had a favorable IMDC prognostic group, 18 pts (48.6%) had one metastatic lesion at baseline, and the cohort had an average tumor burden of 21mm. The majority of pts had clinical or radiologic progression with a median PFS of 10.8 months (95% CI: 8.13-23.31). The median TST was 37 months (95% CI: 24.3-94.9). In total, there were 11 deaths (none of which occurred prior to the initiation of systemic therapy) and median OS after the initiation of AS was 132.5 months (95% CI: 87.3-NR). Multivariate analyses showed that higher numbers of metastatic lesions at baseline were associated with a shorter TST (HR:1.45; 95% CI: 1.03-2.03, p = 0.03). At a median follow-up of 62.5 months, 11/37 (29%) of pts had not yet started systemic therapy. Conclusions: These results expand upon previous studies and support a role for AS to delay systemic therapy in selected pts with metastatic RCC.

Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (>70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in >10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p 70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon.

Importance Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear. Objective To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC. Design, Setting, and Participants This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy. Exposures Receipt of cabozantinib monotherapy at any line of treatment. Main Outcomes and Measures Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib. Results Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed. Conclusions and Relevance In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.MethodsIn order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.ResultsPreviously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.ConclusionsOur results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.

BACKGROUND: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patients with papillary histology.OBJECTIVE: To determine the benefit of CN in synchronous metastatic papillary RCC.DESIGN, SETTING, AND PARTICIPANTS: Using the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database, a retrospective analysis was performed for patients with papillary mRCC treated with or without CN.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Median overall survival (OS) and progression-free survival (PFS) were determined for both patient groups. Cox regression analysis was performed to control for imbalances in individual IMDC risk factors.RESULTS AND LIMITATIONS: In total, 647 patients with papillary mRCC were identified, of whom 353 had synchronous metastatic disease. Of these, 109 patients were treated with CN and 244 were not. The median follow-up was 57.1mo (95% confidence interval [CI] 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2mo (95% CI 12.0-16.1). Median OS for patients with CN was 16.3mo, compared to 8.6mo (pCONCLUSIONS: The use of CN in patients with mRCC and papillary histology appears to be associated with better survival compared to no CN after adjustment for risk criteria. Selection of appropriate candidates for CN is crucial. A clinical trial in this rare population may not be possible.PATIENT SUMMARY: In a population of patients with advanced papillary kidney cancer, we found that surgical removal of the primary kidney tumor was associated with better overall survival.

Objectives Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis. Methods IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma. Results IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA. Conclusion IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients.

Our understanding of the risk of lymphoma in inflammatory bowel disease (IBD) is confounded by conflicting data, the impact of immunosuppressive medications on that risk, and the introduction of newer agents in the management of IBD. As we alter how we strategize, stratify, and combine therapies, this risk will also alter. Recent data is reassuring in downplaying the risk of lymphoma associated with anti-TNF therapies specifically and brings to the forefront legitimate concerns of thiopurine (6-MP, azathioprine) use, especially in young men. This chapter will discuss the impact of IBD and IBD therapies on overall lymphoma risk. We will also discuss the role of Epstein-Barr virus (EBV) in the development of lymphoma and our evolving understanding of the risk of hepatosplenic T-cell lymphoma (HSTCL) with IBD therapies.

BACKGROUND: Brain metastases (BM) occur frequently in patients with metastatic kidney cancer and are a significant source of morbidity and mortality. While historically associated with a poor prognosis, survival outcomes for patients in the modern era are incompletely characterized. In particular, outcomes after adjusting for systemic therapy administration and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors are not well known. METHODS: A retrospective database of metastatic RCC patients treated at UT Southwestern Medical Center between 2006 and 2015 was created. Data relevant to their diagnosis, treatment course and outcomes was systematically collected. Survival was analyzed by the Kaplan-Meier method. BM patients were compared to non-BM patients after adjusting for the timing of BM diagnosis, either prior to or after first-line systemic therapy. The impact of stratification according to IMDC risk group was assessed. RESULTS: 56 of 268 patients (28.4%) with metastatic RCC were diagnosed with brain metastases (BM) prior to or during first-line systemic therapy. Median OS for systemic therapy-naïve BM patients compared with matched non-BM patients was 19.5 vs. 28.7 months (p=0.0117). When analyzed according to IMDC risk group, median OS for patients with BM was similar for favorable and intermediate-risk patients (NR vs NR; and 29.0 vs. 36.7 months, p=0.5254), and inferior for poor-risk patients (3.5 vs 9.4 months, p=0.0462). For patients developing BM while on first-line systemic therapy, survival from the time of progression did not significantly differ by presence or absence of BM (11.8 vs. 17.8 months, p=0.6658). CONCLUSIONS: Survival rates for patients with BM are significantly better than historical reports. After adjusting for systemic therapy, survival rates of patients with BM in good and intermediate-risk groups were remarkably better than expected and not statistically different from patients without BM, though this represents a single institution experience and numbers are modest. MICRO-ABSTRACT: In this study, we analyze survival for metastatic renal cell carcinoma patients with brain metastases compared with disease-matched patients without brain metastases, adjusting for line of systemic therapy and IMDC risk group. We observed that the development of brain metastases did not significant impact survival for favorable and intermediate-risk patients, while poor-risk patients with brain metastases fared worse.

Treatment with radiosurgery prevents neurocognitive decline associated with whole-brain radiotherapy. After review of data of 38 patients treated with radiosurgery for brain metastases from metastatic renal cell carcinoma, the local control at 1 year was 92%. There was no difference in survival on the basis of number of brain metastases. With therapeutic advancements, a greater number of patients might be candidates for radiosurgery. BACKGROUND: Brain metastases (BM) pose a significant problem in patients with metastatic renal-cell carcinoma (mRCC). Local and systemic therapies including stereotactic radiosurgery (SRS) are rapidly evolving, necessitating reassessments of outcomes for modern patient management. PATIENTS AND METHODS: The mRCC patients with BM treated with SRS were reviewed. Patient demographics, clinical history, and SRS treatment parameters were identified. RESULTS: Among 268 patients with mRCC treated between 2006 and 2015, 38 patients were identified with BM. A total of 243 BM were treated with SRS with 1 to 26 BMs treated per SRS session (median, 2 BMs). The median (range) BM size was 0.6 (0.2–3.1) cm and median (range) SRS treatment dose was 18 (12–24) Gy. Treated BM local control rates at 1 and 2 years were 91.8% (95% confidence interval, 85.7–95.4) and 86.1% (95% confidence interval, 77.1–91.7), respectively. BM control declined for larger tumors. Survival after 1-year was 57.5% (95% CI 40.2–71.4) for all patients. Survival was not statistically different between patients with < 5 BM versus ≥ 5 BM. Survival was prognostic based on International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups in patients with < 5 BM. Two patients experienced grade 3 radiation necrosis requiring surgical intervention. CONCLUSION: SRS is effective in controlling BM in patients with mRCC. Over half of treated patients survive past a year, and no differences in survival were noted in patients with > 5 metastases. Prognostic risk categories based on systemic disease (IMDC) are predictive of survival in this BM population, with limited rates of symptomatic radiation necrosis.

INTRODUCTION Giant condyloma acuminata (GCA), also knownbytheeponymBuschke-Lowenstein tumor, is a human papillomavirus (HPV) –associated verrucous carcinoma of the anogenital region. GCAs have a welldifferentiated squamous histology and a slow growth pattern characterized by local invasion. Despite frequent malignant transformation and recurrence after local therapy, they have been reported to have a low metastatic potential. Here we report the case of a patient with metastatic GCA treated with systemic chemotherapy including the epidermal growth factor receptor (EGFR) inhibitor cetuximab.

Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (>70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in >10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p < 0.0001) months. Age >70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon. © 2018 - IOS Press and the authors. All rights reserved

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.

e16102 Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. Four patients experienced any complication, including 3 that were addressed with a single interventional radiology procedure. One patient died of progressive disease > 3 months after surgery, and one patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants attention.

4578 Background: While the CARMENA trial prompts more caution with upfront cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC), 17% of patients in the sunitinib alone arm underwent deferred CN (dCN). Upfront systemic therapy has been proposed as a potential litmus test to identify patients suitable for CN, but data on outcomes are limited. We sought to characterize outcomes of dCN after upfront sunitinib relative to sunitinib alone. Methods: Patients with newly diagnosed mRCC receiving upfront sunitinib were identified from the International mRCC Database Consortium (IMDC) from 2006-2018. All CNs done after initial sunitinib were included, excluding CNs performed after sunitinib failure. The outcomes were overall survival (OS) and time to treatment failure (TTF). Kaplan Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias. Results: The cohort included 708 patients of whom 53 (7.5%) underwent dCN at a median of 6.5 months (IQR 3.5,10.5) from diagnosis. Patients in the dCN group were more likely to have better Karnofsky performance status (KPS), intermediate IMDC risk, fewer metastatic sites, and response to upfront sunitinib (Table). There were 604 deaths during a median follow-up of 63 months. Median OS and TTF with dCN were 43.5 and 19.8 months vs. 9.4 and 4.3 months without, respectively. Upon multivariable analysis, dCN remained significantly associated with OS (HR 0.45, 95%CI 0.31-0.65; p < 0.001) but not TTF (HR 0.73, 95%CI 0.52-1.01; p = 0.056). Conclusions: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted. [Table: see text]

e16112 Background: Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have historically been associated with a poor prognosis. We have previously reported improved outcomes for RCC patients diagnosed with brain metastases prior to or during 1st line systemic therapy among patients treated with modern systemic and local therapies. Here we report outcomes in all mRCC patients regardless of the timing of BM diagnosis. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method from the diagnosis of metastatic RCC, according to BM status and by IMDC risk group. Results: 271 patients with mRCC were identified, including 79 (29.2 %) diagnosed with BM. Clear-cell histology was more common among BM (94.2 v 81.0%, p = 0.01), otherwise patient characteristics were similar. BM were diagnosed prior to systemic therapy (44.3%), or after one or more lines of therapy (one 26.6%, two 13.9%, three 5.1%, four 6.3%, five 3.8%). Among BM patients, 54 (68.4%) received local therapy with stereotactic radiosurgery (SRS) and/or surgical resection, 14 (17.7%) received WBRT alone, and 11 (13.9%) had no CNS-directed treatment. Local therapy consisted of SRS in 43 (54.4%) and surgical resection in 18 (22.8%), with some patients receiving both. Medial OS from metastatic diagnosis for those with BM was not significantly different from those without BM (26.4 v 28.7 mo, p = 0.305). This remained true when analyzed according to IMDC risk factors (see table). Conclusions: OS from the diagnosis of metastatic RCC did not significantly differ with or without BM in a cohort treated with modern systemic and CNS-directed therapies regardless of the timing of BM diagnosis or presence of IMDC risk factors. [Table: see text]

599 Background: Stereotactic ablative radiotherapy (SAbR) is a standard of care for treating renal cell cancer (RCC) cranial metastasis. We describe the effect of SAbR on oligometastatic extra-cranial RCC disease course. Methods: We retrospectively reviewed 49 patients with oligometastatic RCC with 68 extra-cranial lesions. Patients were treated with SAbR with a curative intent from 2007 to 2017. We analyzed local control, systemic therapy free survival (mPFS), and overall survival. Results: With a median follow-up of 28 months (IQR: 16.0-40.3), the 1-year and 2-year overall survival after SAbR was 93.4% (95% CI: 81.0-97.8), and 83% (95% CI: 67.4-91.5) respectively. The median overall survival was not reached. The median time to systemic therapy was 13.4 months from the first SAbR(95% CI: 8.8-27.6). Median times from the first SabR course to second and third line systemic therapy (or death) were 31.8 months and 45 months, respectively. Patients in the favorable risk group by the Heng’s criteria (HR = 8.67, p = 0.04), with nometastatic disease at diagnosis (HR = 10.38, p < 0.01) and with clear cell histology (HR = 6.15, p < 0.01) exhibited better survival, as shown by univariate analysis. Patients with no metastatic disease at diagnosis (HR = 2.56, p = 0.02) and only one metastasis treated with SAbR (HR = 2.36, p = 0.03) also exhibited better systemic therapy-free survival. SAbR had an excellent local control rate of 94% at 2 years with no reported grade 3 or higher toxicity. Conclusions: SAbR is an effective and safe treatment for oligometastatic RCC, offering excellent local control with minimal toxicity. SAbR delayed the start of systemic therapy for this RCC cohort, offering quality of life benefits for patients without adversely affecting the progression on subsequent lines of systemic therapy. These findings call for prospective verification.

4579Background: Cabo shows robust clinical activity in advanced clear cell RCC. nccRCC, a heterogeneous mix of diseases, have been underrepresented in clinical trials and effective systemic therapy...

601 Background: Brain metastases (BM) in RCC have been associated with poor overall survival. Systemic targeted and immunotherapy and the increasing use of stereotactic radiosurgery (SRS) is likely to improve outcomes. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method. BM patients were compared to non-BM patients after adjusting for the timing of BM diagnosis, either prior to or during 1st line systemic therapy (ST). Results: 56 of 248 mRCC patients (22.6%) were diagnosed with BM, 35 (62.5%) prior to and 21 (37.5%) during 1st line ST. 43/56 (77%) received definitive local therapy for BM (surgery 10, SRS 26, or both 7). 9 received WBRT only and 4 had no CNS-directed therapy. All patients received ST. The median OS for ST-naïve BM patients compared with non-BM patients was 19.5 vs. 28.7 months (p = 0.012). Survival for patients developing BM on 1st-line therapy was not significantly different from patients without BM progressing on 1st line ST (11.8 vs. 17.8 months, p = 0.66). BM patients with poor risk mRCC by IMDC criteria did worse than those without BM regardless of line of therapy. Conclusions: Survival for patients with BM and favorable or intermediate risk mRCC is significantly better than historical reports and similar to non-BM patients in our population which was heavily treated with both systemic and local therapies. Patients with BM and poor risk RCC had significantly worse survival, suggesting that risk group should be considered when counseling on prognosis and selecting treatment. [Table: see text]

581 Background: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC), but the role of CN in patients with papillary histology is unclear. Methods: Using the IMDC database, a retrospective analysis was performed on patients with papillary mRCC treated with or without CN. Baseline characteristics and IMDC risk factors were collected. Median overall survival (OS) was determined for both patient groups. Multivariable Cox regression analysis was performed to control for imbalances in individual IMDC risk factors. Results: In total, 353 patients with papillary mRCC with (n = 75) or without (n = 278) a component of clear cell histology were identified. Median follow-up time was 57.1 months (95% CI 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2 months (95% CI 12.0-16.1). Baseline characteristics are in Table 1 and patients who had CN were more likely to be younger, with better KPS, and have sarcomatoid histology. Median OS in patients with CN was 16.3 months (95% CI 13.1-19.2), compared to 8.6 months (95% CI 6.1-12.2; p < 0.0001) in the no CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45-0.85; p = 0.0031). Conclusions: The use of CN in patients with mRCC and papillary histology appears to be associated with improved survival when compared to no CN after adjustment for risk criteria. A clinical trial in this rare population may not be possible but this data does corroborate with clear cell literature. [Table: see text]

In patients with follicular lymphoma (FL), it is unresolved whether peripheral blood (PB) can replace bone marrow (BM) aspirate samples for detection of bcl-2/JH fusion sequences that result from the t(14;18)(q32;q21). We compare here the results of quantitative polymerase chain reaction (q-PCR) analysis for bcl-2/JH involving the major breakpoint cluster region (mbr) on paired PB and BM aspirate samples from 60 consecutive FL patients. There was a significant correlation between the level of bcl-2/JH fusion sequence obtained from PB and BM aspirate samples (r = 0.886), with 82% of samples showing less than one log of difference. Patients who had histological evidence of FL involving concurrent BM biopsy specimens had moderate to high levels of bcl-2/JH in both PB and BM aspirate samples, allowing unequivocal determination of translocation status (median bcl-2/JH to cyclophilin level was 8.014%). In contrast, patients with no detectable FL in their BM biopsy specimens often showed low levels of bcl-2/JH in both PB and BM aspirate samples (bcl-2/JH to cyclophilin median level = 0.006%), in a range similar to background levels that could be detected in patients without FL (n = 15, median bcl-2 mbr/JH to cyclophilin level = 0.002%). We conclude that PB can be used in place of BM aspirate samples to test for the presence of bcl-2 mbr/JH fusion sequence in FL patients and that either PB or BM aspirate testing yields a rough approximation of the degree of BM involvement by FL. However, in patients with minimal levels of bcl-2/JH in PB or BM aspirate samples, confirmation of this result by testing the primary tumor is recommended to confirm the presence of an identical bcl-2/JH fusion sequence and exclude false-positive results.

498 Background: Fourthline targeted therapy efficacy in mRCC is not well characterized and is not reimbursed in many jurisdictions worldwide. Methods: The IMDC consists of consecutive patient series from 35 international cancer centers. It was queried for mRCC patients who received fourth line targeted therapy. Kaplan Meier estimates were used for time to treatment failure (TTF) and overall survival (OS). Results: 594 out of 7498 (8%) mRCC patients initially treated with first line targeted therapy eventually received fourth line therapy from a class of approved agents. Baseline characteristics are displayed in Table 1. The most common fourth line therapies were everolimus 17%, sorafenib 15%, axitinib 13%, pazopanib 13%, sunitinib 13%, nivolumab 7%. IMDC prognostic group distributions (Heng et al JCO 2009) and their associated survivals (both determined from fourth line therapy initiation) were 5% favorable risk (OS 23.1 (14.7-not reached)), 66% intermediate risk (OS 13.8 (11.4-17.5)), and 29% poor risk (OS 7.8 (4.93-12.2)) (OS p

e16103Background: The cumulative incidence of brain metastasis (BM) in metastatic renal cell carcinoma (mRCC) has historically been quoted as 10%. This figure is based on data collected before the ...

e20107Background: Targeting the programmed-death (PD-1) axis has achieved remarkable success in a variety of tumours. The expression and significance of PD-1, PD-L1 and PD-L2 in TETs is unclear. Me...

In patients with follicular lymphoma (FL), it is unresolved whether peripheral blood (PB) can replace bone marrow (BM) aspirate samples for detection of bcl-2/JH fusion sequences that result from the t(14;18)(q32;q21). We compare here the results of quantitative polymerase chain reaction (q-PCR) analysis for bcl-2/JH involving the major breakpoint cluster region (mbr) on paired PB and BM aspirate samples from 60 consecutive FL patients. There was a significant correlation between the level of bcl-2/JH fusion sequence obtained from PB and BM aspirate samples (r = 0.886), with 82% of samples showing less than one log of difference. Patients who had histological evidence of FL involving concurrent BM biopsy specimens had moderate to high levels of bcl-2/JH in both PB and BM aspirate samples, allowing unequivocal determination of translocation status (median bcl-2/JH to cyclophilin level was 8.014%). In contrast, patients with no detectable FL in their BM biopsy specimens often showed low levels of bcl-2/JH in both PB and BM aspirate samples (bcl-2/JH to cyclophilin median level = 0.006%), in a range similar to background levels that could be detected in patients without FL (n = 15, median bcl-2 mbr/JH to cyclophilin level = 0.002%). We conclude that PB can be used in place of BM aspirate samples to test for the presence of bcl-2 mbr/JH fusion sequence in FL patients and that either PB or BM aspirate testing yields a rough approximation of the degree of BM involvement by FL. However, in patients with minimal levels of bcl-2/JH in PB or BM aspirate samples, confirmation of this result by testing the primary tumor is recommended to confirm the presence of an identical bcl-2/JH fusion sequence and exclude false-positive results.