Citations

209 Background: Predictive markers of response to AA are not known. In a prior study, we found that 8 single nucleotide polymorphisms (SNPs) from 4 candidate hormone-related genes (JAK2, TRMT11, NKX3-1 and HSD17B12) were associated with response to AA in HSPC in a North American cohort of 519 subjects. We attempt to replicate these findings in a cohort of Portuguese patients. Methods: The Portuguese cohort consisted of 308 HSPC patients, and the primary endpoint was time to AA failure, defined as time from initiating continuous AA to two serial PSA increases over the nadir, initiation of chemotherapy for progressive disease, or clinical or imaging based progression, whichever came first. For each SNP, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for time to AA failure using a recessive model with adjustment for Gleason score (GS). Results: The median age of the Portuguese cohort was 69 years (range 43, 85). The GS distribution was 35% subjects with GS≥8; 35% with GS=7 and 30% with GS<7. Median time to AA failure for the cohort was 1.8 years (IQ range: 0.3, 3.6). Association of each SNP with time to AA failure is shown in the Table. None of the SNPs replicated. However, there was a suggestive inverse association for rs10503733 (NKX3.1) with time to AA failure (P=0.07). Conclusions: While we were not able to replicate our initial findings, there was an unexpected association with rs10503733 (NKX3.1 gene) that may warrant additional clinical validation. [Table: see text]

658 Background: In patients (pts) with mCRC with an asymptomatic primary tumor, there is limited evidence regarding the indication for primary tumor resection. The primary objective was to evaluate the prognostic value of primary tumor resection in synchronous mCRC pts. Methods: In this IPD analysis, a total of 3,423 pts from 8 first-line randomized trials (RCTs) with systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Five RCTs included targeted (anti-VEGF and/or anti-EGFR) agents. Synchronous mCRC was defined as distant metastases occurring ≤ 6 months of the initial CRC diagnosis. Overall survival (OS) and progression-free survival (PFS) were compared by stratified multivariate Cox models. Results: There were 710 (21%), 1,705 (50%) and 1,008 (29%) pts with non-resected and resected synchronous mCRC and metachronous mCRC, respectively. Compared to the non-resection group, pts in the synchronous resection group were associated with female gender, colon tumor, isolated liver/lung involvement, single metastatic site, and lower LDH (all p<.001). Adjusted for age, gender, performance status and prior chemotherapy, the non-resection group had a significantly worse median OS (16.4m) compared to the resection (22.2m; HR 1.60, 95% CI 1.43-1.78) and metachronous (22.4m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, PFS was significantly worse for the non-resection group (7.9m) compared to the resection (9.7m; HR 1.31, 95% CI 1.19-1.44) and metachronous group (8.9m; HR 1.47, 95% CI 1.30-1.66). Similar trends were observed in pts treated with non-targeted vs targeted agents, and anti-VEGF vs anti-EGFR therapy. In a subset analysis (n= 526), the observed associations remained after additional adjustment for primary tumor location, liver/lung involvement, number of metastatic sites, BMI and LDH. Conclusions: In this largest IPD analysis of mCRC trials to date, primary tumor resection is associated with better OS and PFS in synchronous mCRC pts. These results may be subject to bias since reasons for (non)resection were not available. Prospective RCTs on this topic are ongoing.

656 Background: Patients (pts) with peritoneal metastases from CRC (pmCRC) have reduced OS compared to mCRC pts without peritoneal involvement. Here we further investigated the impact of number and location of metastases among pts receiving first-line systemic chemotherapy. Methods: Individual patient data were available on 9,265 pts (median age 64; 63% male; 93% ECOG PS 0-1; 68% colon primary tumor; brain metastases excluded) enrolled onto 12 first-line randomized trials (4 tested targeted regimens). Stratified multivariable Cox models were used to assess the associations with overall survival (OS); adjusted hazard ratios (HRadj) and 95% confidence intervals are reported (CI). Results: There were 7,963 (86%) pts with non-pmCRC (3,904 with one disease site; 4,059 with ≥2 disease sites), 191 (2%) pts with isolated pmCRC, and 1,111 (12%) non-isolated pmCRC. These groups were similar in age, race, and use of targeted chemotherapy. Compared to non-pmCRC, pts with pmCRC were more likely to be female (41% vs. 36%, p<.001), have colon primary tumors (85% vs. 67%, p<.0001), and have PS2 (10% vs. 6%, p<.0001). Compared to isolated pmCRC, pts with solitary non-peritoneal sites (both M1a) had significantly better OS (HRadj=0.78; CI, 0.64-0.94, p=.009) while pts with ≥2 non-peritoneal sites had similar OS (HRadj=1.06; CI 0.88-1.28, p=.535). OS of pts with pmCRC with a single other disease site (n=446) was similar to isolated pmCRC (HRadj=1.13; CI 0.91-1.40, p=.28), but those with pmCRC + ≥2 additional disease sites (n=665) had shortest survival (HRadj=1.44; CI 1.17-1.77, p<.001). A combination of peritoneal and liver metastases (n=821; HRadj=1.37, CI 1.12-1.67, p=.002) was associated with poorer survival compared with isolated pmCRC; but combination with extrahepatic sites (n=290; HRadj=1.15, CI 0.91-1.45, p=.25) was not. Conclusions: pmCRC pts have significantly worse survival than those with other solitary site mCRC. Among those with multiple disease sites, poorer survival is a function of increased number of metastatic sites and peritoneal involvement, which indicates prognostic heterogeneities among M1b pts.

158 Background: Esophageal cancer patients (pts) require multidisciplinary management involving thoracic and general surgeons, medical and radiation oncologists, gastroenterologists and psychiatrists. Pts navigate complex medical discussions and endure challenges to nutrition, body image, swallowing mechanics, energy level and weight, mood, and performance status. Coordination of care is complicated by multiple sites of pt entry, complex scheduling requirements, and incomplete information at multidisciplinary consultation. A nurse navigator to coordinate the patient experience may optimize treatment and improve outcomes, quality of life and patient satisfaction. Methods: The nurse navigator evaluates all pt records prior to initial appointment and coordinates scheduling, records acquisition, testing and specialty appointments. The nurse navigator serves as a liaison with pts throughout the course of care and provides a patient navigation book (PNB) as a central source for patient-directed information and record keeping. Benchmarks compared before and after creation of the nurse navigator position include: (1) time from appointment request to multidisciplinary evaluation and start of treatment; (2) completeness of medical records and data (scans, pathology slides); (3) patient awareness of support services for themselves and caregivers; (4) utilization of the PNB; (5) number and frequency of interim hospitalizations and emergency room visits; (6) patient, caregiver, and physician satisfaction. Results: From January to July 2012, 27 gastroesophageal cancer pts have been followed by the nurse navigator. Most of these patients remain on active treatment, hence benchmark analysis is ongoing. Metrics thus far suggest improvement in time to treatment start and awareness of patient resources, use of the PNB and patient satisfaction. Conclusions: Esophageal cancer pts undergo complex and toxic multimodality therapy with curative intent. A dedicated nurse navigator may improve the patient experience, optimize adherence to guideline based therapy and appropriate timeframes and provide continuity to pts undergoing multidisciplinary treatment.

Background and PurposeAngiotensin II (Ang II), whose generation largely depends on angiotensin‐converting enzyme (ACE) activity, mediates most of the renin‐angiotensin‐system (RAS) effects. Elastase‐2 (ELA‐2), a chymotrypsin‐serine protease elastase family member 2A, alternatively generates Ang II in rat arteries. Myocardial infarction (MI) leads to intense RAS activation, but mechanisms involved in Ang II‐generation in resistance arteries are unknown. We hypothesized that ELA‐2 contributes to vascular Ang II generation and cardiac damage in mice subjected to MI.Experimental ApproachConcentration‐effect curves to Ang I and Ang II were performed in mesenteric resistance arteries from male wild type (WT) and ELA‐2 knockout (ELA‐2KO) mice subjected to left anterior descending coronary artery ligation (MI).Key ResultsMI size was similar in WT and ELA‐2KO mice. Ejection fraction and fractional shortening after MI similarly decreased in both strains. However, MI decreased stroke volume and cardiac output in WT, but not in ELA‐2KO mice. Ang I‐induced contractions increased in WT mice subjected to MI (MI‐WT) compared with sham‐WT mice. No differences were observed in Ang I reactivity between arteries from ELA‐2KO and ELA‐2KO subjected to MI (MI‐ELA‐2KO). Ang I contractions increased in arteries from MI‐WT versus MI‐ELA‐2KO mice. Chymostatin attenuated Ang I‐induced vascular contractions in WT mice, but did not affect Ang I responses in ELA‐2KO arteries.Conclusions and ImplicationsThese results provide the first evidence that ELA‐2 contributes to increased Ang II formation in resistance arteries and modulates cardiac function after MI, implicating ELA‐2 as a key player in ACE‐independent dysregulation of the RAS.

ABSTRACTIntroduction: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. Methods: Herein we report on the clinical, serologic, electrophysiologic, and pathologic evaluations of a 29‐year‐old woman with GATA2 haploinsufficiency and active Epstein–Barr virus (EBV) infection complicated by subacute painful neuropathy. Results: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy. Lumbar spine MRI showed thickening and enhancement of the cauda equina nerve roots. Serum and cerebrospinal fluid anti‐IgG and IgM EBV capsid and nucleic acid antibodies were positive. Sural nerve biopsy showed microvasculitis and an increased frequency of fibers with segmental demyelination. Intravenous immunoglobulin and steroids improved the patient's neuropathy. Conclusion: GATA2 mutation–related immunodeficiency may predispose to EBV‐associated subacute demyelinating polyradiculoneuropathy by both viral susceptibility and immune dysregulation. In patients who present in this manner, immunodeficiency syndromes should be considered when lymphomatous infiltration is excluded. Immunotherapy can be helpful. Muscle Nerve 57: 150–156, 2018

AbstractMalignancy represents substantial morbidity and mortality in patients with primary sclerosing cholangitis (PSC). This subset of patients has been proven to be at increased risk for developing cholangiocarcinoma, gallbladder carcinoma and colorectal cancer in those with overlapping inflammatory bowel disease. Herein, we review the prevalence of these malignancies and recommend screening tools and current knowledge to reduce the disease burden in this population. Cholangiocarcinoma is the most dominant malignancy affecting PSC patients, with a lifetime risk ranging from 5% to 20%. We advocate for serial US or MRI/MRCP and CA 19‐9 to screen for cholangiocarcinoma. Gallbladder cancer has a lifetime risk around 2% in this population and we agree with annual imaging for lesions as recommended by national guidelines. Patients with PSC and concomitant IBD are at increased risk of colorectal carcinoma from time of diagnosis and therefore should likely undergo annual surveillance. The low rates of hepatocellular cancer and pancreatic cancer indicate surveillance for these malignancies is less advantageous.