Citations

AbstractObjectivesRapid response teams (RRTs) respond to signs of deterioration to avoid morbidity and mortality. Early RRT activation (eRRT) in patients admitted from the emergency department (ED) is associated with significantly increased mortality. Predicting these events may represent an opportunity to identify patients who would benefit from further resuscitation, aid disposition decision‐making, or improve communication between ED and inpatient providers. We aimed to create a clinical prediction instrument to quantify the risk of eRRT.MethodsWe performed an observational cohort study of patients admitted to a non–intensive care unit (ICU) setting who triggered eRRT from January 2009 to December of 2012 compared to those who did not trigger eRRT. Age, sex, ED vital sign measurements, and final ED diagnosis by ICD‐9 code were evaluated in a multivariable logistic regression model. The performance of prediction models was assessed using discrimination summarized by area under a receiver operating curve (AUC) and calibration with the Hosmer and Lemeshow goodness‐of‐fit test. The final model was used to create a simplified scoring system.ResultsThe eRRT group consisted of 474 patients who were compared to 2,575 patients in the reference group. Age and sex did not add significant discrimination to the model and were eliminated from the simplified, final model. This model, which included vital signs and diagnosis category, was found to have an AUC of 0.754 (95% confidence interval [CI] = 0.730 to 0.778) and was used to create a simplified scoring system. The odds ratio for the association of a 1‐unit increase in risk score with eRRT was 1.37 (95% CI = 1.32 to 1.41; p < 0.001). When internally validated, the score was found to have an AUC of 0.759 (95% CI = 0.735 to 0.753). Calculated scores ranged from −3 to 18, which corresponded to predicted probabilities of eRRT ranging from 5.1% to 72.2%.ConclusionsIn summary, the PeRRT score is a simple tool that can be referenced by emergency providers at the bedside to quantify the risk of early RRT activation and potential deterioration, helping to answer the question, “How likely is my patient to trigger an RRT activation in the next twelve hours?” Given that patients who trigger eRRT have an elevated risk of morbidity and mortality, higher scores should result in resuscitative intervention, further observation in the ED, consideration of ICU admission, or direct enhanced communication between ED and inpatient providers. A prospective multicenter study is required to further validate this instrument.

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Abstract Background: Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma. Methods: We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality. Results: We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P &lt; 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry–European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4. Correlated variants in 7p15.3 clustered around an enhancer at the 3′ end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10−7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7. Conclusions: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles. Impact: A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609–18. ©2016 AACR.

Objectives To describe the clinicopathological features associated with increased risk of renal fossa recurrence ( RFR ) after radical nephrectomy ( RN ) and to describe the prognostic features associated with cancer‐specific survival ( CSS ) among patients with RFR treated with primary locally directed therapy, systemically directed therapy or expectant management. Patients and Methods The records of 2 502 patients treated with RN for unilateral, sporadic, localized renal cell carcinoma ( RCC ) between 1970 and 2006 were reviewed. CSS after RFR was estimated using the Kaplan–Meier method. Associations with the development of RFR and CSS after RFR were evaluated using Cox proportional hazards regression models. Results A total of 33 (1.3%) patients developed isolated RFR ( iRFR ) and 30 (1.2%) patients developed RFR in the setting of synchronous metastases after RN (study cohort, N = 63). The median follow‐up for the series was 9.0 years after RN and 6.0 years after RFR diagnosis. On multivariable analysis, advanced pathological stage ( pT 2: hazard ratio [ HR ] 4.36, P = 0.004; pT 3/4: HR 4.39, P = 0.003) and coagulative necrosis ( HR 2.71, P = 0.006) were independently associated with increased risk of iRFR . The median time to recurrence was 1.5 years after RN among the 33 patients with iRFR , and 1.4 years among all patients. Overall, the median CSS was 2.5 years after diagnosis of iRFR , 1.3 years after RFR in the setting of synchronous metastases, and 2.2 years overall. After primary locally directed therapy (surgery, ablation or radiation), systemic therapy or expectant management, the 3‐year CSS rates among patients with iRFR were 63%, 50% and 13% ( P = 0.001) and were 64%, 50% and 28% ( P = 0.006) among all patients, respectively. On multivariable analysis, when compared with observation, locally directed therapies were associated with a significantly decreased risk of death from RCC ( HR 0.26, P < 0.001). Conclusions Renal fossa recurrence is a rare event after RN for RCC and portends a poor prognosis, even in the absence of synchronous metastases. Development of iRFR is associated with advanced stage and aggressive tumour biology. Patients who underwent primary locally directed therapy had superior CSS compared with those treated with expectant management, supporting the use of aggressive local treatment in carefully selected patients with RFR . Future research is needed to determine the optimum role and sequencing of combined therapy in patients with this rare entity.

Abstract PURPOSE: Previous mutational analyses have failed to identify a predictive or prognostic marker for pulmonary carcinoid tumors (PCT). The heterogeneity of PCTs coupled with a lack of detailed information about the tumor biology, impedes patient stratification into groups based on tumor phenotypes or treatment response. We sought to use high-throughput next-generation sequencing to improve prognostication. METHODS: We stratified 37 patients with resected PCTs as low risk (n = 17) and high risk (n = 20) based on a 5 year long follow up for recurrence. Patients with no recurrence within 5 years from initial treatment were deemed low risk. Macrodissection was followed by genomic DNA isolation and next-generation sequencing was performed using an Illumina Mate Pair library protocol. Sequence reads were mapped to the human genome, and primers spanning the fusion junctions were used for validation polymerase chain reaction. RESULTS: Carcinoids commonly harbor rearrangements (median 3.5, range 1-167). Large chromosomal gains or losses were found in 24 of the cases (64.8%). We developed a prognostic score that included the total amount of genetic alterations (deletions and translocations). ROC analysis revealed an AUC of 0.76. High risk patients had a mean score of 20 and low risk patients had a mean score of 5.45 (p value = 0.03, Welch Two Sample t-test). Further analysis of the specific genetic alterations harbored by high and low risk PCTs and correlation with the pathologic and immunohistochemical information is currently underway. CONCLUSION: Large chromosomal rearrangements and aneuploidy portend a poor prognosis for patients with PCTs. Mate Pair sequencing of PCTs provides valuable prognostic information for this highly heterogeneous group of cancers. Citation Format: Konstantinos Leventakos, Aaron S. Mansfield, Stephen J. Murphy, Sarah H. Johnson, Sarah E. Kerr, Marie Christine Aubry, George Vasmatzis, Julian R. Molina. A prognostic model for pulmonary carcinoid tumors based on large chromosomal alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4513.

Abstract Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel treatment. There is conflicting data on the benefits and harms of supplement use for the treatment and prevention of CIPN. We examined dietary supplement use before diagnosis and during treatment in relation to CIPN among breast cancer patients registered to a clinical trial (SWOG 0221; ClinicalTrials.gov Identifier: NCT00070564) before diagnosis and during treatment in relation to CIPN. Methods. At trial registration (baseline), breast cancer patients (n = 1,225) completed questionnaires to capture use before and at diagnosis of multivitamins and other dietary supplements. Of these patients, 1,068 completed a 6-month follow-up questionnaire to capture use during treatment. We examined the use of multivitamins, vitamins C, D, E, B6, and B12, folic acid, iron, calcium, glucosamine, and combined fish oil, eicosapentaenoic acid (EPA), omega-3, flaxseed and cod liver oil at these timepoints in relation to CIPN. CIPN was assessed via the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios and 95% confidence intervals were computed using unconditional logistic regression. Results. Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE adjusted OR = 0.60, 95% CI = 0.42-0.87; FACT/GOG-Ntx adjusted OR = 0.78, 95% CI = 0.61-1.00). Although in a similar direction as use prior to diagnosis, multivitamin use during treatment was less strongly associated with CIPN (CTCAE adjusted OR = 0.73, 95% CI = 0.49-1.08; FACT/GOG-Ntx 0.77, 95% CI = 0.60-0.99). Other supplement use, either before diagnosis or during treatment, was not associated with CIPN. Conclusions. Our results indicate that supplement use during treatment may not appreciably affect experience of CIPN symptoms. Future analyses of the relationships between supplement use and survival outcomes will better inform patient decision making. Acknowledgments: supported by R01 CA116395 (CBA); S0221 supported, in part, by National Cancer Institute/Division of Cancer Prevention SWOG NCORP Research Base grant 5UG1CA189974-02; National Cancer Institute (NCI), National Clinical Trials Network (NCTN): CA180888, CA180819; and in part by Amgen, Inc. Citation Format: Gary R. Zirpoli, Susan E. McCann, Lara E. Sucheston-Campbell, Dawn L. Hershman, Gregory Ciupak, Warren Davis, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Robert B. Livingston, Gabriel N. Hortobagyi, Julie R. Gralow, Daniel F. Hayes, G. Thomas Budd, Kathy S. Albain, Christine B. Ambrosone. Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3413.

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.

Purpose To provide evidence-based guidance on the optimum management of chronic pain in adult cancer survivors. Methods An ASCO-convened expert panel conducted a systematic literature search of studies investigating chronic pain management in cancer survivors. Outcomes of interest included symptom relief, pain intensity, quality of life, functional outcomes, adverse events, misuse or diversion, and risk assessment or mitigation. Results A total of 63 studies met eligibility criteria and compose the evidentiary basis for the recommendations. Studies tended to be heterogeneous in terms of quality, size, and populations. Primary outcomes also varied across the studies, and in most cases, were not directly comparable because of different outcomes, measurements, and instruments used at different time points. Because of a paucity of high-quality evidence, many recommendations are based on expert consensus. Recommendations Clinicians should screen for pain at each encounter. Recurrent disease, second malignancy, or late-onset treatment effects in any patient who reports new-onset pain should be evaluated, treated, and monitored. Clinicians should determine the need for other health professionals to provide comprehensive pain management care in patients with complex needs. Systemic nonopioid analgesics and adjuvant analgesics may be prescribed to relieve chronic pain and/or to improve function. Clinicians may prescribe a trial of opioids in carefully selected patients with cancer who do not respond to more conservative management and who continue to experience distress or functional impairment. Risks of adverse effects of opioids should be assessed. Clinicians should clearly understand terminology such as tolerance, dependence, abuse, and addiction as it relates to the use of opioids and should incorporate universal precautions to minimize abuse, addiction, and adverse consequences. Additional information is available at www.asco.org/chronic-pain-guideline and www.asco.org/guidelineswiki .

Ciliated muconodular papillary tumors (CMPTs) are rare peripheral lung lesions, characterized by papillary architecture and ciliated columnar cells admixed with mucinous cells and basal cells. They often have prominent surrounding intra-alveolar mucin, which can lead to diagnostic confusion with mucinous adenocarcinoma. Recognition of the ciliated component is the key to diagnosis of CMPT. The literature contains few reported cases to date, all occurring in East-Asian patients. Although follow-up data are limited, CMPT seems to be an indolent tumor with very good prognosis, leading some to question whether it is a reactive or hamartomatous lesion. However, a very recent molecular study has identified BRAF (40%) and EGFR (30%) alterations in CMPT, supporting a truly neoplastic process. Here for the first time, we report 4 cases of morphologically typical CMPT in western patients, occurring in 1 man (60 y) and 3 women (71 to 83 y). Interestingly, 1 case occurred in background of pronounced small airway disease with necrotizing bronchiolitis and multiple carcinoid tumorlets. We further analyzed 1 tumor using a 50 gene next-generation sequencing oncology panel that identified 2 pathogenic mutations (BRAF V600E and AKT1 E17K). Our study is the first to describe that CMPT can occur in western (non-Asian) patients. Our data confirm BRAF V600E mutation as a probable driver in a subset of these tumors, along with AKT1 mutation, which further supports that CMPT are indolent pulmonary neoplasms.

Inflammation plays a pivotal role in peripheral artery disease (PAD). Cellular adhesion proteins mediate the interaction of leukocytes with endothelial cells during inflammation. To determine the association of cellular adhesion molecules with ankle–brachial index (ABI) and ABI category (≤1.0 vs >1.0) in a diverse population, 15 adhesion proteins were measured in the Multi-Ethnic Study of Atherosclerosis (MESA). To assess multivariable associations of each protein with ABI and ABI category, linear and logistic regression was used, respectively. Among 2364 participants, 23 presented with poorly compressible arteries (ABI > 1.4) and were excluded and 261 had ABI ≤ 1.0. Adjusting for traditional risk factors, elevated levels of soluble P-selectin, hepatocyte growth factor, and secretory leukocyte protease inhibitor were associated with lower ABI ( P = .0004, .001, and .002, respectively). Per each standard deviation of protein, we found 26%, 20%, and 19% greater odds of lower ABI category ( P = .001, .01, and .02, respectively). Further investigation into the adhesion pathway may shed new light on biological mechanisms implicated in PAD.