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The relationship between metastatic colorectal cancer (mCRC) and venous thromboembolism (VTE) is poorly defined in the modern era. Our objective was to examine impact of putative risk factors including newer treatments and anti-angiogenic therapy on VTE incidence and survival in a modern older mCRC cohort.This is a SEER-Medicare cohort analysis of mCRC patients diagnosed in 2004-2009. Risk factor analysis was conducted using Cox models adjusted for sex, diagnosis age, race, primary tumor location, comorbidity, and prior VTE history, with cancer treatments as time-varying covariates. Main outcomes were VTE incidence and overall survival.Ten thousand nine hundred and seventy six mCRC cases with mean age 77.9 years (range 65-107), 49.7% women, 83.5% white. There were 1306 VTE cases corresponding to 13.7% incidence at 1 year and 20.3% at 3 years. Independent VTE predictors included female sex (HR 1.27; 95% CI 1.14-1.42), African American race (HR 1.49; 1.27-1.73), prior VTE history (HR 16.3; 12.1-22.1), and right sided cancers (HR 1.16; 1.04-1.29). After adjustment, any therapy and bevacizumab (HR 0.68, 0.58-0.78) in particular were protective. Overall survival was 40.1% (39.4-41.3) at 1 year but improved significantly with any treatment. VTE following diagnosis of mCRC was associated with inferior OS (HR 1.09; 1.02-1.15).In this large contemporary mCRC cohort, effective systemic therapy including anti-angiogenic treatment was associated with lower VTE risk. Overall survival was poor, and modestly worse if a patient had a VTE at any time during treatment.

PURPOSE:Cyberattacks targeting health care organizations are becoming more frequent and affect all aspects of care delivery. Cancer care is particularly susceptible to major disruptions because of the potential of immediate and long-term consequences for patients who often rely on timely diagnostic testing and regular administration of systemic therapy in addition to other local treatment modalities to cure or control their diseases. On October 28, 2020, a cyberattack was launched on the University of Vermont Health Network with wide-ranging consequences for oncology, including loss of access to all network intranet servers, e-mail communications, and the electronic medical record (EMR).METHODS:This review details the immediate challenges faced by hematology and oncology during the cyberattack. The impact and response on inpatient, outpatient, and special patient populations are described. Steps that other academic- and community-based oncology practices can take to lessen the brunt of such an assault are suggested.RESULTS:The two areas of immediate impact after the cyberattack were communications and lack of EMR access. The oncology-specific impact included loss of the individualized EMR chemotherapy plan templates and electronic safeguards built into multistep treatment preparation and delivery. With loss of access to schedules, basic patient information, encrypted communications platforms and radiology, and laboratory and pharmacy services, clinical outpatient care delivery was reduced by 40%. The infusion visit volume dropped by 52% in the first week and new patients could not access necessary services for timely diagnostic evaluation, requiring the creation of command centers to oversee ethical and transparent triage and allocation of systemic therapies and address new patient referrals. This included appropriate transfer of patients to alternate sites to minimize delays. Inpatient care including transitions of care was particularly challenging and addressing patient populations whose survival might be affected by delays in care.CONCLUSION:Oncology health care leaders and providers should be aware of the potential impact of a cyberattack on cancer care delivery and preventively develop processes to mitigate the impact.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC.The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (2.2 to4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival.A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations.Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.

Despite mounting interest in the non-operative management (NOM, also known as watchful waiting) of rectal adenocarcinoma, limited guidance exists regarding appropriate patient selection and procedures. In this literature review targeting patients with operable adenocarcinoma of the rectum, we sought to evaluate NOM in terms of patient selection, management approaches, and outcomes with regard to both quality of life (QoL) and oncologic outcomes. Despite a lack of randomized evidence comparing NOM (performed via active surveillance following neoadjuvant chemotherapy and radiation) to neoadjuvant therapy followed by planned surgery, given that the vast majority of local, regional, and distant recurrences occur early in follow-up, the available evidence points to similar oncologic outcomes and possible QoL improvement. Due to the high chance of surgical salvage in the case of locoregional recurrence, close multidisciplinary follow-up is essential. Under the care of an experienced multidisciplinary lower gastrointestinal team, NOM is feasible, is safe, and has the potential for improved QoL. A potential algorithm for clinically implementing NOM is described within this review.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti–programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. Key Points Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte–associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.

PURPOSE: Guidelines recommend venous thromboembolism (VTE) risk assessment in outpatients with cancer and pharmacologic thromboprophylaxis in selected patients at high risk for VTE. Although validated risk stratification tools are available, < 10% of oncologists use a risk assessment tool, and rates of VTE prophylaxis in high-risk patients are low in practice. We hypothesized that implementation of a systems-based program that uses the electronic health record (EHR) and offers personalized VTE prophylaxis recommendations would increase VTE risk assessment rates in patients initiating outpatient chemotherapy. PATIENTS AND METHODS: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) was a multidisciplinary program implemented by nurses, oncologists, pharmacists, hematologists, advanced practice providers, and quality partners. We prospectively identified high-risk patients using the Khorana and Protecht scores (≥ 3 points) via an EHR-based risk assessment tool. Patients with a predicted high risk of VTE during treatment were offered a hematology consultation to consider VTE prophylaxis. Results of the consultation were communicated to the treating oncologist, and clinical outcomes were tracked. RESULTS: A total of 918 outpatients with cancer initiating cancer-directed therapy were evaluated. VTE monthly education rates increased from < 5% before VTEPACC to 81.6% (standard deviation [SD], 11.9; range, 63.6%-97.7%) during the implementation phase and 94.7% (SD, 4.9; range, 82.1%-100%) for the full 2-year postimplementation phase. In the postimplementation phase, 213 patients (23.2%) were identified as being at high risk for developing a VTE. Referrals to hematology were offered to 151 patients (71%), with 141 patients (93%) being assessed and 93.8% receiving VTE prophylaxis. CONCLUSION: VTEPACC is a successful model for guideline implementation to provide VTE risk assessment and prophylaxis to prevent cancer-associated thrombosis in outpatients. Methods applied can readily translate into practice and overcome the current implementation gaps between guidelines and clinical practice.

358 Background: In a primary analysis of the STAMPEDE protocol, the addition of Abiraterone acetate to androgen deprivation therapy (ADT) in men with castration sensitive, high-risk, non-metastatic prostate cancer was associated with significantly higher rates of metastasis-free survival compared with ADT alone. However, the cost-effectiveness of Abiraterone in this population remains unaddressed. Methods: A decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICERs) associated with ADT with or without Abiraterone. This analysis was performed from a United States healthcare sector perspective. We estimated drug acquisition costs using the Federal Supply Schedule. Given current heterogeneity in prescription drug coverage, we used both brand-name and generic drug prices. The willingness-to-pay (WTP) threshold was $100,000 per QALY. Analyses were performed over the published STAMPEDE trial with median follow-up duration of 72 months. Model input parameters were based on the STAMPEDE trial data as well as best available and most recent data provided in the published literature. Sensitivity analyses explored uncertainty with regard to the model assumptions. Results: Using brand-name pricing, the addition of Abiraterone to ADT was associated with an increase in net costs by $217,616, and an increase in QALYS by 0.79. Therefore, the ICER associated with brand-name Abiraterone was $277,156 per QALY. Sensitivity analyses revealed that the monthly price of Abiraterone would need to be less than or equal to $2,581 in order to be cost-effective at a WTP threshold of $100,000 per QALY. In contrast, generic Abiraterone was associated with an increase in net costs by $45,325, and a cost-effective ICER of $57,726 per QALY. Conclusions: Abiraterone for high-risk non-metastatic prostate cancer is cost-effective using generic pricing. However, current brand-name pricing is roughly four times the threshold of cost-effectiveness, underscoring the need to increase access to generic drugs in the United States.

Purpose of Review With increased therapeutic options in rectal cancer, a central question has become how to tailor therapy to patient preferences to avoid both over and under treatment. Total Neoadjuvant Therapy (TNT), defined as delivering all planned chemotherapy and radiation therapy (RT) before surgery, was developed with the primary goal of improving overall survival through early elimination of micrometastatic disease. In this narrative review assessing patients with operable adenocarcinoma of the rectum, we sought to evaluate TNT versus alternative options with regard to both quality of life (QoL) and oncologic outcomes. Recent Findings Survey data of patient preferences reveal that an increased focus on QoL when discussing options is essential. While evidence favors TNT improving distant metastases-free survival, this has not yet translated to a clear OS benefit. The improved pathologic complete response rate with TNT compared to short course RT or chemoradiation alone suggests proceeding to surgery might result in overtreatment, lending support to a Watch-and-Wait (W&W) option for patients with a goal for non-operative management (NOM) if a clinical complete response (cCR) is achieved. Similarly, for select low-risk patients, surgery may be the only local therapy required allowing for safe omission of RT. Conclusions In the treatment of rectal cancer, the future appears to be moving towards one local therapy. As an alternative to TNT, there is growing support for the concept we define herein as total definitive therapy (TDT) instead: chemoradiation followed by consolidation chemotherapy, saving surgery only for incomplete responders rather than as part of the initial treatment plan. Also, selective use of RT should be considered for low-risk patients. By thoroughly assessing how these treatment de-escalation options compare to more traditional treatment algorithms, this narrative review provides guidance on how to honor patient preferences for QoL by avoiding treatments that might offer negligible benefits in oncologic outcomes.

Introduction Drug options for VTE prophylaxis are increasing for ambulatory cancer patients and data regarding anticoagulant-drug interactions and their relationship to VTE and bleeding are needed to improve care. Methods Over one year, 108 cancer patients with high VTE risk were prospectively identified. Potential anticoagulant-drug interactions were ascertained by chart review and graded on need for intervention. Providers selected anticoagulant prophylaxis based on potential drug interactions and patient-provider discussion. A cross-sectional analysis was performed thereafter to evaluate VTE and bleeding endpoints within one year of anticoagulant initiation. Results The average number of potential drug interactions per patient was higher for warfarin than others (3.04 vs. 1.28 (apixaban), 1.02 (rivaroxaban), and 0.98 (LMWH)). The severity of the interactions based on grade was, for apixaban: 1.6% grade X, 50.8% grade D, and 47.5% grade C; for rivaroxaban: 2.1% grade X, 64.9% grade D, 33.0% grade C; for LMWH, 0% grade X, 66.7% grade D, 33.3% grade C; and for warfarin, 0% grade X, 29.4% grade D, 70.6% grade C. At the end of the investigational period, 11 bleeds and 7 VTEs were reported. Drug combinations significantly associated with an increased bleeding risk were crizotinib with apixaban or rivaroxaban and PPIs with warfarin. The use of sulfamethoxazole-trimethoprim with warfarin was associated with an increased VTE risk. Conclusions DOACs had fewer DDIs than warfarin, although interaction severity differed between anticoagulants. Some anticoagulant-drug interactions were associated with bleeding or VTE. Although not powered for analysis, DDI severity did not affect bleeding rates and inversely correlated with VTE risk.

Prostate cancer is screened by testing circulating levels of the prostate-specific antigen (PSA) biomarker, monitoring changes over time, or a digital rectal exam. Abnormal results often lead to prostate biopsy. Prostate cancer positive patients are stratified into very low-risk, low-risk, intermediate-risk, and high-risk, based on clinical classification parameters, to assess therapy options. However, there remains a gap in our knowledge and a compelling need for improved risk stratification to inform clinical decisions and reduce both over-diagnosis and over-treatment. Further, current strategies for clinical intervention do not distinguish clinically aggressive prostate cancer from indolent disease. This mini-review takes advantage of a large number of functionally characterized microRNAs (miRNA), epigenetic regulators of prostate cancer, that define prostate cancer cell activity, tumor stage, and circulate as biomarkers to monitor disease progression. Nanoparticles provide an effective platform for targeted delivery of miRNA inhibitors or mimics specifically to prostate tumor cells to inhibit cancer progression. Several prostate–specific transmembrane proteins expressed at elevated levels in prostate tumors are under investigation for targeting therapeutic agents to prostate cancer cells. Given that prostate cancer progresses slowly, circulating miRNAs can be monitored to identify tumor progression in indolent disease, allowing identification of miRNAs for nanoparticle intervention before the crucial point of transition to aggressive disease. Here, we describe clinically significant and non-invasive intervention nanoparticle strategies being used in clinical trials for drug and nucleic acid delivery. The advantages of mesoporous silica-based nanoparticles and a number of candidate miRNAs for inhibition of prostate cancer are discussed.

Despite a lower risk of nausea and vomiting in patients receiving radiotherapy to the upper abdomen (UA-RINV) with prophylactic 5-HT3 antagonist therapy, patients can still experience UA-RINV. The aim of this multicenter phase II study was to assess effectiveness, safety, and tolerability of protracted dual NK1-receptor and 5-HT3 antagonist prophylaxis against UA-RINV. Patients receiving fractionated radiotherapy with radiosensitizing chemotherapy received oral ondansetron 8 mg po q12 h and aprepitant 125/80/80 mg on a Monday, Wednesday, Friday schedules throughout radiotherapy. The primary outcome was complete response (CR) defined as no vomiting or rescue therapy during the entire observation period of radiotherapy (OP). Nausea, vomiting, and use of rescue medication were recorded in a modified version of the MASCC antiemesis tool completed twice weekly. Fifty-five patients were enrolled at 5 sites, 52 of whom were evaluable. 57.7% of patients (30/52, 95% CI 43.2–71.3%) achieved CR on study, with 73.1% (38/52, 95% CI 59.0–84.4%) who did not vomit, and 71.2% (37/52, 95% CI 56.9–82.9%) who did not use rescue medication during the OP. Overall, participants vomited or experienced significant nausea (SN) for an average of 6.8% (95% CI 11.4–21.0) and 8.4% (95% CI 4.2–12.7%) of time on study, respectively. Nausea was common with 32 (61.5%) reporting SN at any time during the OP. UA-RINV remains an important morbidity despite the advent of modern radiotherapy. Aprepitant and ondansetron as dosed in this trial was not superior to standard ondansetron monotherapy.

Background The Khorana Score is a validated risk score for predicting 6-month incidence of cancer-associated venous thromboembolism (CAT) among patients starting chemotherapy. Venous thromboembolism (VTE) risk factors important in the general population, including age, sex, prior VTE, and hospitalization, are not included in this score, their association with VTE in cancer patients is unknown. Objective To examine risk factors for CAT and the impact of incorporating longitudinal hospitalization into risk assessment. Methods Risk factors were recorded among patients starting chemotherapy at a single institution from 2012-14. Hospitalization and time-periods after hospitalization were assessed as time-varying covariates. Logistic regression was used to determine factors related to 6-month CAT risk (the Khorana Score endpoint). Proportional hazard models were used for risk factor identification throughout the 3-year observation period. Results Among 1,583 patients starting chemotherapy (mean age 60, 48% male), 187 developed CAT (11.8%) with 129 (69%) cases occurring within 6 months of starting chemotherapy. In the 6-month analysis, no additional risk factors were associated with CAT. In the 3-year analysis, male sex (HR 1.57, 95%CI 1.21, 2.07), prior VTE (HR 2.12, 95%CI 1.41, 3.18), and hospitalization (HR 2.69, 95%CI 1.92, 3.75) were associated with increased hazard of CAT, adjusting for risk factors in the Khorana score. Conclusions When time-to-event data were incorporated into CAT risk assessment, male sex, prior VTE, and hospitalization were important risk factors. These data highlight the need to consider dynamic methods for assessing VTE risk in cancer patients, with particular attention to the period around hospitalizations.

Key Points Question In men with newly diagnosed, low-volume metastatic prostate cancer, is the addition of prostate radiation therapy to androgen deprivation therapy cost-effective? Findings In this economic evaluation using data from a simulated cohort of 10 000 individuals with low-volume metastatic prostate cancer, a microsimulation model found that the addition of prostate radiation therapy to standard-of-care androgen deprivation therapy was associated with reduced net costs and improved quality-adjusted life-years and was therefore a dominant cost-effective strategy. Meaning These findings support the incorporation of prostate radiation therapy as part of initial treatment for men with low-volume metastatic prostate cancer., Importance Prostate radiation therapy (PRT) is a treatment option in men with low-volume metastatic prostate cancer based on the results of the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Arm H (STAMPEDE-H) trial. However, the cost-effectiveness of this treatment remains unaddressed. Objective To assess the cost-effectiveness of PRT when added to androgen deprivation therapy (ADT) for men with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). Design, Setting, and Participants This economic evaluation used microsimulation modeling to evaluate the cost-effectiveness of adding PRT to ADT. A simulated cohort of 10 000 individuals with low-volume mHSPC was created. Data from men with low-volume mHSPC were extracted and analyzed from January 18, 2019, through July 4, 2020. Transition probabilities were extracted from the STAMPEDE-H study. Health states included stable disease, progression, second progression, and death. Individual grade 2 or higher genitourinary and gastrointestinal toxic events associated with PRT were tracked. Univariable deterministic and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. Health state utility estimates were based on the published literature. Exposures The combination of PRT and ADT using regimens of 20 fractions and 6 weekly fractions. Main Outcomes and Measures Outcomes included net quality-adjusted life-years (QALYs), costs in US dollars, and incremental cost-effectiveness ratios. A strategy was classified as dominant if it was associated with higher QALYs at lower costs than the alternative and dominated if it was associated with fewer QALYs at higher costs than the alternative. Results For the base case scenario of men 68 years of age with low-volume mHSPC, the modeled outcomes were similar to the target clinical data for overall survival, failure-free survival, and rates of PRT-related toxic effects. The addition of PRT was a dominant strategy compared with ADT alone, with a gain of 0.16 QALYs (95% CI, 0.15-0.17 QALYs) and a reduction in net costs by $19 472 (95% CI, $23 096-$37 362) at 37 months of follow-up and a gain of 0.81 QALYs (95% CI, 0.73-0.89 QALYs) and savings of $30 229 (95% CI, $23 096-$37 362) with lifetime follow-up. Conclusions and Relevance In the economic evaluation, PRT was a dominant treatment strategy compared with ADT alone. These findings suggest that addition of PRT to ADT is a cost-effective treatment for men with low-volume mHSPC., This economic evaluation assesses the cost-effectiveness of the addition of prostate radiation therapy to androgen deprivation therapy for men with low-volume metastatic hormone-sensitive prostate cancer.

Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that has been shown to relieve severe opioid-induced constipation (OIC) in patients with advanced disease receiving palliative care. Its efficacy remains unknown in cancer patients who are not terminally ill. The primary aim of this study was to evaluate the efficacy of methylnaltrexone over 48 h in cancer patients who were not terminally ill. In this single-dose phase II trial, cancer patients with a prognosis of ≥3 months and OIC with

Bone pain is a common side effect of pegfilgrastim and can interfere with quality of life and treatment adherence. This study investigated the impact of antihistamine prophylaxis on pegfilgrastim-induced bone pain. This is a two-stage enrichment trial design. Patients receiving an initial dose of pegfilgrastim after chemotherapy were enrolled into the observation (OBS) stage. Those who developed significant back or leg bone pain (SP) were enrolled into the treatment (TRT) stage and randomized to daily loratadine 10 mg or placebo for 7 days. SP was defined by Brief Pain Inventory as back or leg pain score ≥5 and a 2-point increase after pegfilgrastim. The primary end point of TRT was reduction of worst back or leg bone pain with loratadine, defined as a 2-point decrease after treatment compared to OBS. Two hundred thirteen patients were included in the final analysis. Incidence of SP was 30.5 %. The SP subset had a worse overall Functional Assessment of Cancer Therapy-Bone Pain score (33.9 vs. 51.7, p

Background Well-differentiated neuroendocrine tumors (NET) most frequently arise from the gastrointestinal tract (GI), pancreas, and lung. Patients often present as metastasis with an unknown primary, and the clinical management and outcome depend on multiple factors, including the accurate diagnosis with the tumor primary site. Determining the site of the NET with unknown primary remains challenging. Many biomarkers have been investigated in primary NETs and metastatic NETs, with heterogeneous sensitivity and specificity observed. Methods We used high-throughput tissue microarray (TMA) and immunohistochemistry (IHC) with antibodies against a panel of transcriptional factors including NKX2.2, PDX-1, PTF1A, and CDX-2 on archived formalin-fixed paraffin-embedded NETs, and investigated the protein expression pattern of these transcription factors in 109 primary GI (N = 81), pancreatic (N = 17), and lung (N = 11) NETs. Results Differential expression pattern of these markers was observed. In the GI and pancreatic NETs (N = 98), NKX2.2, PDX-1, and CDX-2 were immunoreactive in 82 (84%), 14 (14%), and 52 (52%) cases, respectively. PDX-1 was expressed mainly in the small intestinal and appendiceal NETs, occasionally in the pancreatic NETs, and not in the colorectal NETs. All three biomarkers including NKX2.2, PDX-1, and CDX-2 were completely negative in lung NETs. PTF1A was expressed in all normal and neuroendocrine tumor cells. Conclusions Our findings suggest that NKX2.2 was a sensitive and specific biomarker for the GI and pancreatic neuroendocrine tumors. We proposed that a panel of immunostains including NKX2.2, PDX-1, and CDX-2 may show diagnostic utility for the most common NETs.

The primary tumor side is emerging as a prognostic factor for patients with liver metastatic colorectal cancer (mCRC). In a combined analysis of data from 2 randomized studies, the addition of selective internal radiation therapy to first-line chemotherapy in patients with mCRC was associated with statistically and clinically significant overall survival gains for patients with a right-sided primary tumor. Background: The primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and Methods: Separate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. Results: In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). Conclusion: The addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain. (C) 2018 Elsevier Inc. All rights reserved.

Summary Background Patients with metastatic colon cancer (mCRC) are at increased risk of venous thromboembolism (VTE). Limited preclinical data suggest that the oncogene (KRAS) mutational status of the tumor represents a plausible clinical link to systemic hypercoagulability in cancer patients. Objectives To determine if a tumor genetic characteristic, KRAS mutational status, is associated with an increased risk of VTE in patients with mCRC. Patients/methods A retrospective cohort study of patients with mCRC and KRAS test results was conducted at multiple practice sites across New England in the United States. The primary outcome was a VTE event, defined as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), either 6 months before or at any time after the diagnosis of mCRC. KRAS status (mutated vs. wild type) and other relevant predictors of thrombosis were collected. Results Of 172 histologically confirmed patients with mCRC, 40 developed a VTE (23.3%). Sixty-five patients (37.8%) had a mutant KRAS status. The incidence of VTE and DVT among patients with mutated KRAS was 32.3 and 23.1%, respectively. The corresponding incidence among patients with wild-type KRAS was 17.8 and 9.4%. Odd ratios for the association were 2.21 (95% CI, 1.08–4.53) for VTE and 2.62 (95% CI, 1.12–6.12) for DVT, and remained significant despite adjustment for Khorana score and bevacizumab use. Conclusion Tumor mutant KRAS status is associated with an increased risk of VTE in patients with mCRC. The tumor genetic profile may represent a novel and important risk factor for thrombosis in patients with cancer.

We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a safe, tolerable, and effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophagogastric junction (EGJ). We hypothesized that DCF combined with enhanced surgical control would result in a low rate of local or regional recurrence, and thus reviewed our outcomes with this treatment regimen. A prospectively entered database of all esophageal and EGJ ADC patients resected at a high-volume referral center over 6 years (9/07-9/13) was reviewed for cases treated with curative intent neoadjuvant DCF followed by en bloc resection with extended lymphadenectomy (D2/D3). Recurrences was defined as locoregional (biopsy on endoscopy/regional lymph nodes (LNs)) and distant. Standard statistical techniques were used. Of 279 patients with ADC, 86 (85% male, mean age 63 years (interquartile range 56-70)) underwent preoperative DCF and curative intent resection for locally advanced ADC (cT3 93%; cN+ 69%) of the EGJ (54%) or distal esophagus (46%). After median follow-up of 40 months, the overall 5-year survival was 54% and 43 (52%) had recurred at a median time of 14 months. Sites of recurrence included locoregional only in 2 of 45 (4%), distant only in 40 of 45 (89%), and locoregional and distant in 3 of 45 (7%). The present study demonstrates favourable oncologic outcomes with low local/regional recurrence and an excellent overall 5-year survival after neoadjuvant DCF for esophageal and EGJ ADCs. Because the majority of recurrences were distant, our data support the notion that efforts to improve outcomes in these patients should concentrate on enhancing systemic, rather than local, therapy.

Background: Recent clinical trials have evaluated the safety and efficacy of direct oral anticoagulant (DOAC) therapy for venous thromboembolism (VTE) prophylaxis in cancer outpatients at high risk for thrombosis. Bleeding risk in these trials were approximately 2% over the first 6 months of therapy. For individual patients, the utility of prophylactic anticoagulation (AC) depends on an acceptable safety profile between bleeding and thrombosis. We investigated whether ambulatory cancer patients on contemporary cancer-directed therapies and prophylactic AC had an increased risk of major bleeds over the first 6 months of therapy. Methods: As part of a single-center prospective cohort study, we assessed consecutive ambulatory patients initiating cancer-directed treatment, risk-stratified these patients for VTE using the Khorana score and educated them about VTE. High risk patients (Khorana score ≥3) were offered prophylactic AC. Major bleeding events and minor bleeding events (based on ISTH standard definitions) were prospectively captured via billing code screening and confirmed by physician review of the medical record. Logistic regression was used to compare the odds of developing a major bleed within 6 months in those who received prophylactic AC compared to those that did not. Results: A total of 1,210 patients were enrolled from October 2015 - June 2018, of which, 640 were women (52.9%). The most common cancers were gastrointestinal 270 (22%), lung 213 (18%), and breast 198 (16%). There were 393 patients (32%) with a Khorana score of 0, 706 (58%) with a Khorana score of 1-2, and 111 (9%) with a score of ≥3. A total of 421 patients received any AC (LMWH or DOAC). Of these, 282 received a prophylactic dose anticoagulant and 139 were receiving a full dose anticoagulant prior to enrolling for other medical reasons. Prophylactic dose anticoagulants prescribed included apixaban in 107 (41%), rivaroxaban in 6 (2.3%), enoxaparin in 119 (45.7%), and other heparin products in 50 (19.2%). A total of 27 (2.33%) major bleeds and 22 (1.81%) minor bleeds occurred within the first 6 months of starting therapy. Of these bleeding events, 8 (2.8%) occurred in those on prophylactic AC, and 6 (4.3%) occurred in those on full dose AC. The odds ratio (OR) of developing a major bleed on any type of AC was 1.78 [CI 0.817-3.88]. The OR of major bleeding on prophylactic AC was 1.49 [CI 0.64-3.479]. The OR of major bleed was highest in lung cancer patients on prophylactic AC (OR 2.81, CI 1.27-6.25). Men, when compared to women, were more likely to bleed on prophylactic AC in the first six month (OR 0.2; CI 0.07-0.52). The OR for major bleed with each 1 year increase in age was 1.02 (CI 0.99, 1.06). The OR of bleeding with a high risk Khorana score (≥3) compared to a lower score was 1.04 (CI 0.73-1.50). Conclusion: During the first six months of therapy, prophylactic AC was associated with an increased risk of major bleeding events in patients on cancer-directed therapy. In this study, the rate of major bleeding was similar as compared to published clinical trials. Neither age nor higher Khorana score were associated with an increased risk of major bleeds in patients on prophylactic AC. The finding that men, when compared to women, and patients with lung cancer may have an increased risk of major bleeding while on prophylactic AC and cancer-directed chemotherapy suggests these groups may warrant both increased education and monitoring to ensure safety while on prophylactic AC. Disclosures No relevant conflicts of interest to declare.

Background Although perioperative chemotherapy for esophagogastric adenocarcinoma (ADC) improves survival, the overall poor prognosis suggests that further refinement of treatment is required. Docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) is effective for metastatic ADC of the upper gastrointestinal (GI) tract; we thus sought to investigate the efficacy of this regimen in patients with resectable disease. Patients and methods Patients with resectable ADC of the upper GI tract received DCF [docetaxel (Taxotere) 75 mg/m2 I.V. day 1, cisplatin 75 mg/m2 I.V. day 1, 5-FU 750 mg/m2 continuous infusion for 120 h, every 3 weeks] for three cycles before and after resection. Primary end point was complete resection; secondary end points were response, toxicity, surgical morbidity, and overall survival. Results Forty-three patients with ADC of the esophagus (11), gastroesophageal junction (25), or stomach (7) started treatment and 86% completed all preoperative cycles with grade 3–4 toxicity arising in 47%. Metabolic response to chemotherapy (reduction in maximal standard uptake value >35%) was achieved in 25/33 (76%) patients. Surgery was carried out in 41/43 and complete resection was achieved in all 41 patients with pathologic complete response in 4/41. Postoperative chemotherapy was started in 29 patients and completed in 24. Three-year overall survival was 60%. Conclusion Perioperative DCF is a tolerable and highly effective regimen for the treatment of esophagogastric ADC.

9062Background: MET amplification (amp) has been reported in a subset of NSCLC with the frequency varying depending on the definition used. Crizotinib, an ALK/ROS1/MET inhibitor approved in ALK- or ROS1-positive NSCLC, also has proven clinical activity in cases of MET exon 14 alterations and MET amp. Here we present an updated analysis of crizotinib in pts with low, medium (med), and high (hi) levels of MET amp in advanced NSCLC. Methods: In this ongoing, open-label, multicenter, phase 1 trial (NCT00585195), MET amp was locally tested; pts with MET/CEP7 ratios ≥1.8 were eligible. Pts received crizotinib 250 mg BID and were assigned to categories based on low (≥1.8–≤2.2), med ( > 2.2– 2.2– < 4 and ≥4; data were then reanalyzed to better delineate predictive biomarkers of response. Selected endpoints included best overall response (BOR) per RECIST v1.0, time to tumor response (TTR), progression-free survival (PFS), duration of respo...

Background: The Khorana VTE risk score is a validated tool to predict the 6 month VTE rate for patients starting chemotherapy. It includes cancer type, obesity, anemia, leukocytosis, and thrombocytosis. Patients with cancer are living longer, and VTE risk continues beyond 6 months. The influence of known VTE risk factors that are not included in the Khorana score on VTE risk in cancer patients, such as hospitalization (which varies over time), older age and prior history of VTE is not known. Methods: Among patients with cancer starting chemotherapy from 2012-14 at the University of Vermont Cancer Center, VTE was ascertained for up to 3 years using ICD codes and confirmed by manual chart review. Prior VTE was defined as VTE >3 months prior to starting chemotherapy and body mass index (BMI) and laboratory values were assessed within 1 week prior to starting chemotherapy. We performed two series of analyses. In the first, logistic regression was used to assess the performance of the Khorana score for VTE prediction within 6 months of chemotherapy start before and after the addition of the VTE risk factors of age and prior VTE. In a second analysis, we used Cox proportional hazard models (which incorporate time-to-event data) and all VTE events, with up to 3 years of follow-up, and additionally assessed hospitalization and time-periods after hospitalization as time-varying covariates. The area under the receiver operating characteristic curve (AUC) of the Khorana score was then determined before and after addition of significant traditional risk factors found in univariate analysis. Results: Among 1,583 patients with a mean age of 60 and 48% male, 187 developed VTE (11.8%) with 129 cases occurring within 6 months of chemotherapy start. Cancer types in the study included 229 breast (14.5%), 186 lung (11.8%), 174 lymphoma (11%), 105 gynecologic (6.7%), 71 pancreas (4.4%), 30 bladder (1.9%), 18 testicular (1.1%), 17 stomach (1%) and 753 other types of cancer (47.6%), including cancer types not included in the original Khorana score. The table shows the unadjusted and adjusted associations of risk factors with VTE, assessing both the first 6 months of chemotherapy and the entire 3 year study period. In the 6-month analysis, none of the traditional risk factors were significantly associated with VTE (Table). The c-statistic for the Khorana model was 0.61 (95% CI 0.56, 0.65). In the 3-year analysis, male sex, prior VTE, and hospitalization as a time-varying exposure were associated with an increased hazard of VTE (Table). Hospitalization, both within the past 90 days (HR 2.87, 95% CI 2.06, 4.00) and the past 30 days (HR 3.09, 95% CI 2.12, 4.51) was associated with VTE, while the time period encompassing hospitalization itself (HR 1.75, 95% CI 0.72, 4.28) did not reach statistical significance. The C-index for the Khorana score over 3 years was 0.59, and with addition of male sex and prior VTE this was 0.61. Conclusions: In a real-world patient population, the Khorana score was again validated for predicting 6-month rate of VTE after initiating chemotherapy. Further, patients remained at risk of VTE beyond 6 months, and when time-to-event data were incorporated into risk assessment, male sex, prior history of VTE, and hospitalization were important risk factors. These data demonstrate that risk factors for cancer-related VTE vary over time and highlight the need to re-evaluate VTE risk of the course of a patient's treatment. Disclosures No relevant conflicts of interest to declare.

Human leukocyte antigens (HLAs) present foreign antigens to the immune system and may be important determinants of cervical neoplasia. Previously published associations between HLA and cervical neoplasia exhibit considerable variation in findings. The biomarkers of cervical cancer risk (BCCR) case-control study addressed the role of specific HLA alleles as cofactors in the development of high-grade cervical intraepithelial neoplasia (HG-CIN) based on the most consistent evidence from published literature. Cases (N 5 381) were women with histologically-confirmed HGCIN attending colposcopy clinics and controls (N 5 884) were women from outpatient clinics with normal cytological screening smears. Subjects were mainly of French-Canadian descent. Cervical specimens were tested for human papillomavirus (HPV) DNA and HLA genotypes by PGMY L1 consensus primer PCR and a PCR sequence-specific primer method, respectively. Unlike other studies, the DQB1*03 and DRB1*13 allele groups were not associated with risk of HG-CIN. The B7-DRB1*1501-DQB1*0602 haplotype was associated with a 41% overall reduction in HG-CIN risk (odds ratio [OR] 5 0.59; 95% confidence interval [CI]: 0.36– 0.96), and an 83% reduction in risk of HG-CIN among HPV 16 or HPV 18-positive subjects (OR 5 0.17; 95%CI: 0.05–0.54). Paradoxically, however, the same haplotype was associated with HPV 16/18 infection risk among controls (OR 5 8.44, 95%CI: 1.12– 63.73). In conclusion, the B7-DRB1*1501-DQB1*0602 haplotype was protective against HG-CIN, especially in individuals infected with oncogenic HPV, but the mechanism of the association seems to involve multiple steps in the natural history of HPV and CIN. ' 2008 Wiley-Liss, Inc.

Background. Cancer patients often display procoagulant activity and are at a risk for developing venous thromboembolism (VTE). Multiple mechanisms may explain this procoagulant state, such as tumor cell expression of tissue factor (TF), host tissue response to tumor formation and also contributions from comorbid factors and treatment. We previously observed elevated levels of traditional biomarkers of coagulation (such as D-dimer, CRP, etc.) in patients with advanced cancer on therapy enrolled in a randomized trial comparing rosuvastatin versus placebo. In this study, we evaluated the frequency and concentration of endogenous plasma TF, Factor (F)XIa and FIXa in the cancer patient population analyzed for traditional coagulation biomarkers. The choice of new analytes was based on previous studies in which these 3 proteins were detected and quantitated in patients with cardiovascular diseases, inflammation, and trauma - often present over the course of several days to even weeks. By our knowledge, there are no published studies of the presence of FXIa and/or FIXa in cancer patients. Methods. Thirty-seven adult cancer patients receiving systemic therapy were originally enrolled in a randomized crossover trial comparing effects of rosuvastatin versus placebo on biomarkers of VTE. Inclusion criteria included locally-advanced or metastatic cancer, estimated survival time of greater than 6 months, and anticipated duration of therapy of at least 3 months. Patients on antithrombotic or statin therapy were excluded. Blood was collected on up to 4 occasions; at the start and end of each of 2 treatment periods corresponding to 2 cycles of systemic therapy with a 3-4 week washout period. Citrate plasma was prepared, frozen and stored at -80C. The assay, performed in previously unthawed and contact-pathway inhibited plasma, is based on a response of the lag phase of thrombin generation to corresponding monoclonal inhibitory antibodies (αFXIa-2, αFIXa-91 and αTF-5; all at 0.1 mg/mL). Concentrations of TF, FXIa and FIXa were calculated from corresponding calibration curves built by titrating purified proteins into multi-donor pooled plasma from healthy individuals. Results. A total of 116 blood samples were collected (not all patients were able to complete their regime) and analyzed for endogenous levels of TF, FXIa and FIXa (see table). Overall, rosuvastatin treatment did not have any significant impact on the levels and frequency of these 3 proteins. For the samples obtained from each patient's first blood draw (n = 37) there was a weak correlation between FXIa and FIXa levels (R = 0.37, P = 0.02) and a moderate correlation between FXIa and TF levels (R = 0.57, P < 0.001), while no correlation between FIXa and TF was observed (R = 0.02, P = 0.91). Conclusions. 1) A portion of patients with advanced cancer had active TF in their plasma while the majority, for the first time reported, had active FXIa and FIXa; 2) No pronounced differences were observed between the frequency and concentrations of these proteins at baseline versus later time-points; 3) There was a weak correlation between FXIa and FIXa and a moderate correlation between FXIa and TF, suggesting the TF-pathway is driving the majority of FXIa generation, although contribution from the contact pathway cannot be excluded; 4) Rosuvastatin treatment did not lead to any significant changes in the levels of TF, FXIa and/or FIXa. Table Table. Disclosures No relevant conflicts of interest to declare.

Background:The relationship between metastatic colorectal cancer (CRC) and venous thromboembolism (VTE) is not well defined in the modern treatment era. Previous population-based studies date back to a period marked by inpatient intravenous heparin therapy and inferior survival due to paucity of therapeutic anti-cancer options, and before the advent of newer therapies including oxaliplatin, irinotecan, and anti-angiogenic treatment with bevacizumab. The objectives of this retrospective study were to examine the impact of multiple putative risk factors on VTE incidence in a large representative modern cohort of older patients with metastatic CRC. Methods:We performed a retrospective analysis of SEER-Medicare data on elderly patients with metastatic CRC diagnosed in 2004-2011. VTE and associated risk factors were analyzed using multivariate Cox proportional hazards models adjusted for sex, age at diagnosis, race, ethnicity, tumor anatomy (left/right/unknown), calendar year of diagnosis, Charlson comorbidity score, location of SEER registry and urban residence, with time-varying covariates for use of cancer therapies. Results:Of 339,778 records, 11,086 metastatic colon cancer cases were identified. 1,338 cases had VTE with a cumulative incidence of 13% at 1 year and 19% at 3 years. The mean age was 77.9 years (range 65-106). 49.7% were women and 83.5% white. 60.5% had a Charlson comorbidity score of zero at diagnosis; 6% had scores of 6-18. Significant predictors of VTE included female sex (Hazard Ratio (HR) 1.22; 95% Confidence Interval (CI) 1.10, 1.36; P Conclusion: The higher incidence of VTE seen in right sided colon cancers may be related to biologically aggressive tumors associated with poor survival as reported in recent studies. The lower risk of VTE in older, sicker patients was unexpected and may reflect the effect of competing mortality. In this large contemporary cohort, anti-angiogenic therapy was not associated with a higher risk of VTE; the apparent protective effects of bevacizumab and irinotecan may represent treatment assignment bias. Disclosures No relevant conflicts of interest to declare.

Human herpes virus 6 (HHV-6) can become reactivated in immunosuppressed individuals typically within the first 50–100 days following an allogeneic stem cell transplant [1,2]. Invasion of neural tis...

To determine whether metabolic or pathological response to preoperative chemotherapy can predict the relapse-free survival of gastroesophageal adenocarcinoma patients treated on a perioperative chemotherapy protocol. The prospectively collected data of a recently reported phase II trial of perioperative DCF chemotherapy (docetaxel/cisplatin/5-fluorouracil) were analyzed. Median relapse-free survival (RFS) was compared with the Wilcoxon rank-sum test between responders and non-responders according to defined metabolic (reduction in maximum standard uptake value of at least 35 %) and pathological (greater than 50 % tumor regression or ypN(0) status) criteria. A double-sided p value equal or inferior to 0.05 was considered significant. Patients were followed for a median of 807 days (95 % CI: 607-896). RFS was 576 days in metabolic non-responders versus not reached in metabolic responders (p 0.009) and 562 days in ypN+ versus not reached in ypN(0) patients (p 0.045). No statistically significant RFS difference was seen between low and high pathologic responders classified according to tumor regression criteria, although a trend was observed in favor of high pathologic responders. Simple metabolic and pathologic criteria used for the assessment of response to the preoperative part of perioperative chemotherapy can help to estimate the outcome of gastroesophageal adenocarcinoma patients.

Advanced cancer care planning is encouraged to achieve individualized care. We hypothesized that in-advance end-of-life (EOL) discussions and establishment of do-not-resuscitate (DNR) status prior to the terminal admission would be associated with better quality of inpatient EOL care. We conducted a post-mortality survey, utilizing the validated Toolkit of Instruments to Measure End-of-Life Care. Primary caregivers (PCGs) of the advanced cancer patients who died at our institution between January 2009 and December 2010 were contacted more than 3 months after the patients’ death. The endpoints included overall score for EOL care (0–10; 10 = best care), problem scores of six domains (0–1; 1 = worst problem), and score for supporting family’s self-efficacy (knowing what to expect/do during the dying process) (1–3; 3 = greatest support). Of 115 PCGs contacted, 50 agreed to participate (43.5 %). Patients with EOL discussions (n = 20), as compared to those without (n = 29), had higher rating of overall EOL care (9.7 vs. 8.7; p = 0.001): lower problem scores in “informing and promoting shared decision-making” (0.121 vs. 0.239; p = 0.007), “encouraging advanced care planning” (0.033 vs. 0.167; p = 0.010), “focusing on individual” (0.051 vs. 0.186; p = 0.014), “attending to emotional/spiritual needs of family” (0.117 vs. 0.333; p = 0.010), and “providing care coordination” (0.100 vs. 0.198; p = 0.032), and greater support for family’s self-efficacy (2.734 vs. 2.310; p

PURPOSE: To provide detailed description and illustration of the lens changes found in hereditary hyperferritinemia-cataract syndrome, a newly reported autosomal dominant condition. METHODS: Observational case reports. A 19-year-old man was referred for evaluation of possible hereditary hyperferritinemia-cataract syndrome. His serum ferritin level was increased at 1291 μg/L during a routine screening examination. Genetic analysis revealed mutation G51C on chromosome 19, predicting an altered iron response element in L-ferritin mRNA. Subsequent evaluation of his 46-year-old father revealed similar findings. RESULTS: Multiple breadcrumb-like nuclear and cortical lens opacities were seen in this father-son pair. These cases represent the first detailed description and illustration of hereditary hyperferritinemia-cataract syndrome cataracts in the ophthalmic literature. CONCLUSION: Hereditary hyperferritinemia-cataract syndrome can be associated with distinct breadcrumb-like lens opacities. Recognition of these characteristic cataracts may aid identification and study of patients with this unusual disorder and provide insight into mechanisms of cataract formation.

With a median age at diagnosis of 71 years old and the aging of the US population, colon cancer commonly occurs in the elderly. Adjuvant chemotherapy has been standard of care for stage III disease following complete surgical resection since 1990, but insufficient numbers of patients over 75 years old are participating in clinical trials, and a disparity persists in the administration of standard adjuvant therapy between younger and older Americans despite a meaningful survival advantage for most patients. A large pooled analysis of seven clinical trials supports the administration of adjuvant chemotherapy to otherwise-fit elderly patients, and registry studies have confirmed similar benefits in Medicare beneficiaries. Otherwise-fit elderly patients enrolled in clinical trials do not appear to have more side effects aside from myelosuppression and fatigue. In this review, I discuss the potential benefits and harm of adjuvant therapy in older patients, with a focus on the role of comorbid illness in individualizing decision-making, current standard drug options in the adjuvant setting, and barriers to treatment. Although chronologic age alone should not be an exclusion criterion, more work is needed to establish an optimal and efficient strategy for choosing who would benefit most from adjuvant treatment following surgical resection.

Introduction and Objective: MicroRNAs (miRNA) are well documented to regulate cancer cell activity by targeting tumor suppressors and oncogenes, modulating signaling pathways to promote tumor progression and metastasis. Given the recent knowledge that miRNAs are secreted from normal and prostate cancer cells and circulate at measureable levels, the goal of this study was to identify circulating miRNAs (c-miRNA) in patient serum predictive of prostate cancer risk, prognosis and response to current standards of therapy. Methods: Blood samples were collected from 35 consented men (27 with Prostate Cancer (PCa) and 8 cancer−free age matched individuals) at the University of Vermont Medical Center. A standardized protocol for archived and freshly drawn sample analyses is detailed in Farina et al J Cell Biochem 2014. Serum samples were divided into 1 ml aliquots and frozen only once prior to RNA isolation using the miRNeasy Serum/Plasma kit (QIAGEN). Global profiling was performed with Affymetrix microRNA v4.0 microarray, having over 2500 mature human miRNAs. Three outlier samples (due to secondary complications) were removed prior to data analyses including Principal Component Analyses (PCA), hierarchical clustering, and differential expression. MicroRNAs detected in either all PCa patients or controls were analyzed for putative biological activity by Gene Ontology and Biological Pathway analyses of their predicted gene targets. Results: The PCA generally grouped PCa patients and cancer−free individuals separately. Two miRNAs are consistently elevated in serum of all men screened and may serve as novel endogenous control genes. Four miRNAs are detected in all PCa patients but not in all cancer−free men, while 42 miRNAs are expressed in all cancer−free individuals but not in all men with cancer. Thus, there is a greater loss of c-miRNAs in PCa patients than gain. Enriched KEGG pathways targeted by these miRNAs include Prostate Cancer as well as ErbB, Wnt, TGF-beta, and MAPK signaling pathways. In addition, 12 of the 29 most significantly deregulated c-miRNAs between patients with PCa and cancer-free individuals are differentially secreted in normal prostate epithelial cells (RWPE-1) as compared to PCa cell lines (LNCaP and PC-3). Conclusion: Together, these data suggest that c-miRNAs secreted from PCa cells promote cancer progression through known signaling pathways. While we consider these findings preliminary until a larger sample set is screened, we conclude that the measurement of circulating miRNAs will become valuable biomarkers. Citation Format: Nicholas H. Farina, Jon E. Ramsey, Areg Zingiryan, Steven Ades, Mark K. Plante, Gary S. Stein, Janet L. Stein, Jane B. Lian, Scott D. Perrapato. Serum miRNAs associated with prostate cancer: correlation to deregulated signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4003. doi:10.1158/1538-7445.AM2015-4003

The cardiotoxic effects of anthracycline (ANT)-based chemotherapy are well documented. Biomarkers may be useful for detection of early cardiotoxicity before changes in left ventricular ejection fraction (LVEF) can be observed. To determine the predictive values of troponin I (Beckman), high

In murine erythroleukemia (MEL) A20 cells (grown in 20 ng/ml adriamycin), mutation(s) producing 10-fold adriamycin (doxorubicin) resistance emerged via an unknown mechanism. Exposure of A20 cells to further stepwise increasing concentrations of ADR in combination with MDR modulators (PSC833 and verapamil) aimed to amplify the undetermined A20 mechanism while controlling P-glycoprotein (P-gp) overexpression. The growth of the derived cell lines A30P, A40P and A60P (grown in 30, 40 and 60 ng/ml ADR with PSC833 and verapamil) was initially slow, but eventually reached near WT rates. The new cell lines A30P and A40P were only 1.3- and 1.6-fold more resistant to adriamycin than PC4 A20. Resistance to vincristine was unchanged, but resistance to etoposide (VP-16) was 3.7-fold higher in A40P than A20 (itself 97-fold higher than wild-type). Expression of mdr3 and mrp mRNA tested by RT-PCR showed no increase. Daunorubicin and etoposide accumulation was not different among the cell lines, and no changes were detected in the number of daunorubicin fluorescent lysosomes. In comparison to WT, reduced topoisomerase IIalpha (EC 5.99.1.3) activity (20%) and protein expression (80%) was similar to the parental A20 cells. No mutations in the coding sequence of topoisomerase IIalpha could be located to account for the high etoposide resistance levels. The inhibitor combination of verapamil and PSC833 prevented the emergence of transporter mediated MDR, but not ADR selection of cell lines highly resistant to etoposide.

9628 Background: Bone pain is a common side-effect of pegfilgrastim and can interfere with a patient’s quality of life and treatment adherence. Antihistamine therapy may have analgesic activity in ...

e15044 Background: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a highly effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophago-gastric junction (EGJ). However there is ongoing debate whether chemotherapy alone provides adequate local or regional control. We hypothesized that DCF combined with enhanced local surgical control would result in a low rate of local or regional recurrence. Methods: A prospective entered database of all esophageal/EGJ ADC pts resected at a high volume referral center was reviewed for cases treated with neoadjuvant DCF (Docetaxel 75mg/m2, Cisplatin 75mg/m2, 5FU 750mg/m2x120 hrs CIV) Q3weeks x3, followed by en-bloc resection with extended lymphadenectomy (D2). Follow up included physical exam Q3m x 2 yrs then Q6m, and endoscopy and CT chest/abdo/pelvis performed Q6 m. Recurrence was defined as: Local = biopsy on endoscopy; Regional = regional lymph nodes; Distant = distant organ or non-regional lymph nodes. Data presented as Median (Range). Results: Of 281 pts in the database, 89 (75%male, 63yrs(24-80)) underwent pre-op DCF and resection for locally advanced ADC (cT3 93%;cN+ 73%) of the EGJ (51%) or distal esophagus (49%) from 3/07-10/12. After overall follow-up of 37(6-72) months, 37 (42%) have recurred at 15(6-33) months. Sites of recurrence include Distant only in 29/37, Regional only in 5/37, and Regional and Distant in 3/37. First site of distant recurrence was peritoneum (14/37), liver (10/37), non-regional lymph nodes (10), brain/ovary/pleura (2 each), and bone(1). No patient had local recurrence alone. 3/5 patients with regional recurrence underwent salvage chemoradiotherapy and are alive without disease at 36 months (30-47) after recurrence. Conclusions: En-bloc resection with extended lymphadenectomy after DCF for locally advanced ADC of the esophagus and EGJ is associated with a low rate of local and regional recurrence. As vast majority of recurrences are distant, our data supports the notion that efforts to improve outcomes in these pts should concentrate on enhancing systemic, rather than local, therapy.

e15106 Background: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule associated protein like 4 (EML4) and ALK genes on chromosome 2 is present in a subset of non-small cell lung cancer (NSCLC) patients. ALK mutated lung cancers demonstrate a significantly higher incidence of signet ring cell histology than compared to ALK-negative tumors. Based on the histological similarities of ALK positive NSCLC and signet ring cell carcinomas (SRCC) of the GI tract, we hypothesized that gastric and/or esophageal SRCC may also harbor ALK translocations. Methods: Thirty-five formalin-fixed, paraffin-embedded (FFPE) tissue specimens of SRCC originating from esophageal, GE junction or gastric locations were obtained from the Fletcher Allen Healthcare (Burlington, Vermont) tissue bank following Internal Review Board guidelines. Confirmation of SRCC or adenocarcinoma with signet ring cell features was confirmed by a board certified, gastrointestinal pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis using an ALK (2p23) break-apart probe (Kreatech Diagnostics). Results: The FISH analysis revealed no evidence of ALK translocation: all thirty-five (100%) SRCC specimens showed intact (yellow) ALK FISH signals. Conclusions: These data indicate that despite histological similarities between SRCC of the GI tract and ALK positive NSCLC, ALK translocations are unlikely to be a significant contributor to gastric and esophageal SRCC molecular etiology. Further genomic investigations are on-going. This study was performed with funding received from the Lake Champlain Cancer Research Organization.

95 Background: Perioperative chemotherapy improves outcomes of surgery for upper GI cancer. Some patients have rapid recurrence. We hypothesized that any type of response to chemotherapy would predict better disease-free survival (DFS). Methods: From May 2007 to Sep 2009, 43 patients with operable adenocarcinoma of the esophagus, stomach or gastroesophageal junction went on a multicenter phase II trial. 3 cycles of docetaxel/cisplatin/5FU were given pre and post surgery. We compared DFS between responders and nonresponders after 3 cycles. Clinical response was defined as improvement of ≥ 2 points on a dysphagia score (0: normal swallowing, to 4: total obstruction), metabolic response as ≥ 35% reduction of maximum SUV by PET scan. Lack of nodal involvement or significant histologic regression (less than 50% viable tumor) was considered pathologic response. Log-rank test was used for univariate analysis, Cox regression model for multivariate analysis. All p values are double sided, median follow-up from surgery is 808 days. Results: Clinical response data for 29/40 patients: 26 responses (90%). Median DFS was 405 days for clinical responders vs. 210 days for nonresponders (p= 0.018). Metabolic response data for 28/40 patients : 22 responses (70%). Median DFS was 276 days in metabolic nonresponders, and has not been reached in responders (p = 0.009). 14 patients had no nodal involvement at resection (N0) and had longer DFS (median not reached) than the 26 with N+, who had median DFS of 562 days (p = 0.045). A nonsignificant trend (p = 0.192) was seen in favor of the 20 with significant tumor regression (DFS 565 days) compared to the 20se without it (median DFS not reached). All results were supported by multivariate analysis. Conclusions: These preliminary results indicate that clinical, metabolic and pathologic responses may be individually predictive of longer DFS in patients receiving perioperative chemotherapy for upper GI adenocarcinoma. This requires confirmation in larger datasets. The optimal management of nonresponders is unclear at present. Acknowledgements: Biostatistics Unit (McGill University Health Centre) and Cedars Cancer Institute (Henry R Shibata Fellowship to Dr Alcindor).

e16631 Background: Improvement of dysphagia in pts with esophagogastric adenocarcinoma (EGC) is a crude sign of local tumor response to chemotherapy, however its impact on survival is unknown. We s...

Abstract 3178 Background: HMG CoA reductase inhibitors (statins) were recently reported to reduce the rate of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for a reduction in VTE risk is unknown. We studied cross-sectional associations of statin use with hemostatic factors related to venous thrombosis risk in a large cohort of healthy people. Methods: Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins. Twenty three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women) and major cardiovascular risk factors. Results: The table shows that those using statins had significantly lower levels of D-dimer, C-reactive protein and factor VIII than non-users. Homocysteine and von Willebrand factor did not differ by statin use. Specific adjustment for LDL and triglycerides did not attenuate the observed differences in these factors by statin use. Conclusions: Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest mechanisms whereby statins might lower VTE risk. These associations were not explained by lipid levels on treatment. A prospective study linking these biochemical differences to VTE outcomes is warranted. Disclosures: No relevant conflicts of interest to declare.

4075 Background: Docetaxel, cisplatin, and 5FU (DCF) has been shown to be an effective regimen for metastatic adenocarcinoma (ADC) of the foregut. We have completed accrual to a phase II trial of p...