tbuckley/cabot-search huggingface dataset:
Prognostic value of <i>BRAF</i> V600E and <i>KRAS</i> exon 2 mutations in microsatellite stable (MSS), stage III colon cancers (CC) from patients (pts) treated with adjuvant FOLFOX+/- cetuximab: A pooled analysis of 3934 pts from the PETACC8 and N0147 trials.
Authors: Julien Taieb, Karine Le Malicot, Frederique Madeleine Penault-Llorca, Olivier Bouche, Qian Shi, Stephen N. Thibodeau, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean-Luc Van Laethem, Daniel J. Sargent, Steven R. Alberts, Pierre Laurent-Puig, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2015)

3507 Background: The prognostic value of BRAF and KRAS mutations in resected CC pts remains controversial due to published studies that include stage II & III, microsatellite instability (MSI) and MSS, colon and rectal tumors, and variable treatment regimens. We examined this question in prospectively collected biospecimens from MSS stage III CC pts receiving adjuvant FOLFOX +/- cetuximab. Methods: Tumors were analyzed for BRAF V600E and KRAS exon 2 mutations, only MSS tumors were included. Three groups were defined: BRAF Mutant, KRAS Mutant and double wild-type (WT). The analytic strategy estimated study- and arm-specific prognostic effects to assess homogeneity of results, and then analysis of pooled data. Associations of mutations with time-to-recurrence (TTR), survival after relapse (SAR) and overall survival (OS) were analysed using a stratified Cox proportional hazards model. Multivariate models were adjusted for treatment and covariates (age, sex, tumor grade, T/N stage, tumor location, ECOG PS). Results: Of the 5,577 pts enrolled, 3,934 tumors were MSS and evaluable for BRAF and KRAS; 279 pts were BRAF Mutant, 1,450 KRAS Mutant, and 2,205 WT. Both mutations were linked to shorter TTR and OS vs WT, and results were confirmed in multivariate analyses (table). Median SAR was 2.57, 2.09 and 1.0 year in WT, KRAS Mutant (HR: 1.20- 95%CI: 1.01-1.44, p < 0.0001) and BRAF mutant (HR: 3.01-95%CI: 2.32-3.93, p < 0.0001), respectively. No interaction was found between treatment (with or without cetuximab) and KRAS/BRAFmutations for TTR (p = 0.38) or OS (p = 0.16). Conclusions: In a large pooled analysis of pts with resected stage III MSS colon cancers receiving adjuvant FOLFOX, BRAFV600E or KRAS exon 2 mutations, including codons 12 or 13, are independent predictors of significantly shorter TTR, SAR and OS. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors. TTR OS 3 y rate HR (95% CI) p 3 y rate HR (95% CI) p WT 80.0% 91.4% BRAF V600E 69.7% 1.49 [1.19,1.87] 0.0005 73.9% 1.72 [1.33,2.22] < .0001 KRAS Exon 2 69.5% 1.60 [1.40,1.83] < .0001 86.3% 1.52 [1.29,1.79] < .0001
A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer.
Authors: Tiffany A. Traina, Joyce O'Shaughnessy, Catherine Margaret Kelly, Lee Steven Schwartzberg, Ayca Gucalp, Amy C. Peterson, Iulia Cristina Tudor, Martha Elizabeth Blaney, Joyce Leta Steinberg, Maureen E. Trudeau, Clifford A. Hudis, Peter Schmid
Journal: Journal of Clinical Oncology (2014)

TPS1144 Background: Androgen receptor (AR) expression is observed in 10-30% of patients (pts) with triple-negative breast cancer (TNBC). Experiments using AR+ TNBC cell lines have demonstrated enhanced growth in response to androgen stimulation that is inhibited by enzalutamide (ENZA), a potent oral inhibitor of AR signaling (Richer JK. Abstract presented at the AACR Advances in Breast Cancer Research Meeting, San Diego, CA, 2013 October 3-6 and D'Amato NC. Abstract presented at the SABCS, San Antonio, TX, December 4-8, 2012). AR+ TNBC may represent a subtype driven by AR signaling and which may respond to ENZA. Methods: Women with advanced AR+ TNBC (ER and PgR <1% by IHC and Her2 normal) will receive daily ENZA (160 mg) until disease progression (NCT01889238). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥16 weeks (wks) as assessed by the Investigator and according to RECIST 1.1. Additional EPs include CBR at 24 wks, safety and tolerability, and the relationship between AR signaling and ENZA activity. If the CBR exceeds 2 in 26 pts, the sample size will increase to 62 pts. Any amount of AR expression (local or central) is allowed, submission of tissue is mandatory. Pts may have bone-only non-measurable disease. Brain imaging is required to exclude patients with CNS metastases. Pts with a seizure history are excluded. The primary EP will analyze pts with centrally defined AR+ TNBC (≥10% nuclear staining by IHC) who have ≥1 post-baseline tumor assessment. An ITT analysis will also be reported. The null hypothesis (H0), that the true CBR is 8%, will be tested against a 1-sided alternative. If CBR exceeds 9 in 62 pts in Stage 2, H0will be rejected. This design yields a 1-sided type 1 error rate of 5% and 85% power when the true response rate is 20%. Enrollment is expected to continue through 2014. Clinical trial information: NCT01889238.
Racial disparities on the use of invasive and noninvasive staging in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: J. M. Suga, D. V. Nguyen, S. M. Mohammed, M. Brown, R. F. Calhoun, K. Y. Yoneda, D. R. Gandara, P. Lara
Journal: Journal of Clinical Oncology (2010)

7075 Background: Racial health disparities have been reported in NSCLC staging and therapeutic outcomes (Lathan, et al JCO 2006). We investigated whether such disparities exist in the era of modern noninvasive staging modalities, including PET scan use. Methods: NSCLC pts in the California Cancer Registry (CCR) diagnosed between 1/94 through 12/04 (reported through 10/06) were included. Cases with unknown race/ethnicity, age, or sex were excluded from the analysis. The likelihood of obtaining invasive (thoracoscopy, bronchoscopy, and mediastinoscopy) and noninvasive staging procedures (CT, MRI, PET scans), as well as surgical resection, were analyzed using logistic regression, controlling for age, sex, residence, stage, and socioeconomic status (SES). Results: Of 13,762 NSCLC pts, 12,395 with adequate staging information were included. 10,217 pts (82%) were classified as white, 2,178 pts (18%) were non-white; blacks comprised 738 pts (6%). Mean age was 66 years for non-whites, 68 years for whites. No association was seen between race and the use of either non-invasive (OR 1.02, p=0.76) or invasive staging procedures (OR=0.96, p=0.44). However, compared to white pts, black pts had a lower likelihood of undergoing surgery, regardless of non-invasive (OR=0.6; <0.001) or invasive staging use (OR=0.63, p=0.02). Higher SES predicted for PET scan use (OR=1.15, p=<0.001), but not for CT (p=0.08) or MRI (p=0.6). Except for race, all other demographic variables significantly predicted for invasive staging use. There was no survival difference for those who underwent surgery between whites and non-whites, regardless of non-invasive (hazard ratio HR=0.95, p=0.45) or invasive staging (HR=1.03, p=0.79). Conclusions: In contrast to prior published work, we found no difference in rates of both invasive and non-invasive staging between white and non-white pts in the CCR. However, non-white pts–particularly blacks–were less likely to receive surgery. The reason for the apparent difference in surgical rates between white and non-white pts could not be explained by the variables we evaluated. Thus, other factors such as personal preference or access to care require further investigation. No significant financial relationships to disclose.
High-dose chemotherapy (HDCT) as second salvage treatment in patients with multiple relapsed or refractory germ cell tumors
Authors: J. Beyer, M. Hackenthal, A. Lorch, A. Neubauer, A. Dieing, O. Rick, J. T. Hartmann, C. Bokemeyer
Journal: Journal of Clinical Oncology (2009)

5082 Background: To determine the activity of high-dose chemotherapy (HDCT) as intensification of second salvage treatment (SST) in patients with multiple relapsed germ-cell tumors (GCT). Methods: Databases in Berlin and Marburg (Germany) on patients treated with HDCT between 1989 and 2008 for germ-cell tumors were screened. Among 534 patients overall, 71/534 (13%) patients were identified as scheduled for HDCT having failed at least one previous conventional-dose first-line and first-salvage chemotherapy regimen. Forty-nine patients who had received at least cisplatin- and etoposide as first-line as well as conventional-dose cisplatin as first-salvage treatment and were diagnosed after January 1, 1990, were further analyzed. Results: Median age at SST was 32 years (range 19 to 52 years). Median follow-up for surviving patients was 4 years (range 1,7 to 8,5 years). Histology was pure seminoma in 5/49 (10%) patients and non-seminoma or mixed histologies in 44/49 (90%). The median number of cisplatin-based treatment cycles prior to SST was 7 (range 5 to 11 cycles). Three of forty-nine (6%) patients either progressed or died prior to scheduled HDCT, the remaining 46/49 (94%) received either single or sequential HDCT. The rate of favorable responses to HDCT as intensification of SST was 27/49 (55%). Ten patients are alive without progression. One additional patient is lost-to-follow at four years without progression. The projected overall survival rate at five years after initiation of SST was 17%. Conclusions: HDCT can induce long term remissions even in patients with multiple relapsed GCT. No significant financial relationships to disclose.
MicroRNA-489 Induction by Hypoxia–Inducible Factor–1 Protects against Ischemic Kidney Injury
Authors: Qingqing Wei, Yong Liu, Pengyuan Liu, Jielu Hao, Mingyu Liang, Qing-sheng Mi, Jian-Kang Chen, Zheng Dong
Journal: Journal of the American Society of Nephrology (2016)

MicroRNAs have been implicated in ischemic AKI. However, the specific microRNA species that regulates ischemic kidney injury remains unidentified. Our previous microarray analysis revealed microRNA-489 induction in kidneys of mice subjected to renal ischemia-reperfusion. In this study, we verified the induction of microRNA-489 during ischemic AKI in mice and further examined the underlying mechanisms. Hypoxia–inducible factor–1 α deficiency associated with diminished microRNA-489 induction in cultured rat proximal tubular cells subjected to hypoxia and kidney tissues of mice after renal ischemia-reperfusion injury. Moreover, genomic analysis revealed that microRNA-489 is intronic in the calcitonin receptor gene, and chromatin immunoprecipitation assays showed increased binding of hypoxia–inducible factor–1 to a specific site in the calcitonin receptor gene promoter after hypoxia. Inhibition of microRNA-489 increased apoptosis in renal tubular cells after ATP depletion injury in vitro , whereas microRNA-489 mimics mediated protection. In mice, inhibition of microRNA-489 enhanced tubular cell death and ischemic AKI without significantly affecting tubular cell proliferation. Deep sequencing identified 417 mRNAs that were recruited to the RNA–induced silencing complex by microRNA-489. Of the identified mRNAs, 127 contain microRNA-489 targeting sites, and of those, 18 are involved in the cellular stress response, including the poly(ADP-ribose) polymerase 1 gene implicated in ischemic kidney injury. Sequence analysis and in vitro studies validated poly(ADP-ribose) polymerase 1 as a microRNA-489 target. Together, these results suggest that microRNA-489 is induced via hypoxia–inducible factor–1 during ischemic AKI to protect kidneys by targeting relevant genes.
Vaccination of stage IV melanoma patients with dendritic cells generated <i>ex vivo</i> with type I interferon and loaded with heat-treated killed allogeneic melanoma cells—Preliminary report from the phase II clinical trial
Authors: A. Palucka, J. Nemunitis, J. Weber, H. Ueno, K. Auditore-Hargreaves, J. Fay, J. Banchereau
Journal: Journal of Clinical Oncology (2006)

2582 Background: We have previously demonstrated in phase I clinical trial treating 20 patients with metastatic melanoma that dendritic cells (DCs) loaded with killed allogeneic tumor cells can elicit immune and clinical responses. In that study DCs were generated from monocytes with GM-CSF and IL-4 and activated with a combination of TNF and soluble CD40 ligand. Two patients who had failed previous therapy including DTIC, achieved durable objective clinical responses, one CR and one PR lasting ≥ 20 months. We describe here the development of a high-throughput method for generating DC vaccines with improved immunogenicity and preliminary data from their evaluation in a Phase II trial in metastatic melanoma. Methods: We have initiated a phase II clinical trial (IRB #005–065; BB-IND #12339) enrolling patients with stage IV melanoma who failed first line therapy with DTIC and/or temozolomide with or without IL-2. Patients will receive seven injections of an autologous DC vaccine generated from monocytes by culturing with GM-CSF and Type I interferon and loaded with heat-treated and killed allogeneic Colo829 melanoma cells. Vaccine is generated in a closed system and stored frozen. Patients are vaccinated over 18 weeks. The trial is based on an initial toxicity evaluation in the first 10 patients on top of a 2-stage response rule - 1/19 to continue and 5/30 to accept. The trial is expected to accrue a total of 32 subjects. The primary end-points of this trial are the rate of objective clinical response and the safety/feasibility of the vaccination preparation. Results: To date seven patients were enrolled and begun vaccinations. Vaccine has been successfully generated for all enrolled patients. Thus far, a total of 20 vaccinations have been administered. Vaccinations were safe and tolerable. [Table: see text]
Radiation after lumpectomy for DCIS to reduce the risk of invasive breast cancer: A population-based study
Authors: N. N. Baxter, B. A. Virnig, S. B. Durham, T. M. Tuttle
Journal: Journal of Clinical Oncology (2005)

516 Background: Although randomized trials have demonstrated the efficacy of radiation (RT) in reducing the risk of breast cancer after lumpectomy for Ductal Carcinoma in Situ (DCIS), the use of RT in the population remains relatively low. This study was designed to determine the effectiveness of RT after lumpectomy for DCIS in a population-based fashion using SEER data. Methods: We identified women with DCIS treated with lumpectomy in SEER registry data from 1987 through 1996. We evaluated the effect of RT on development of subsequent invasive breast cancer: the overall rate, the rate of ipsilateral invasive cancer, and the rate of contralateral invasive cancer. Using a proportional hazards model, we evaluated the effect of RT on development of invasive breast cancer over time adjusting for potential confounders. Results: A total of 10,034 women underwent lumpectomy for DCIS in this time period; 5063 underwent lumpectomy only and 4971 underwent RT after lumpectomy. Invasive breast cancer developed in 854 patients; 439 in the ipsilateral breast and 413 in the contralateral breast (laterality unknown in 2 cancers). The actuarial rate of invasive ipsilateral breast cancer at 8 years was 6.2% in the lumpectomy only group and 2.7% in the RT group. The actuarial rate of invasive contralateral breast cancer at 8 years was 4.2% in the lumpectomy only group and 4.0% in the RT group. Lumpectomy only was strongly associated with development of ipsilateral breast cancer over time after adjusting for potential confounders. The adjusted hazards ratio for development of ipsilateral invasive cancer was 0.43 for the RT group, as compared with the lumpectomy only group (95% CI 0.35 to 0.53), indicating that women who did not undergo RT had 2.3 times the risk of developing ipsilateral invasive breast cancer over time. RT after lumpectomy was not associated with development of contralateral invasive cancer. Conclusions: Women with DCIS in the population have a substantial risk of developing invasive breast cancer after lumpectomy. The effectiveness of RT in reducing the risk of ipsilateral cancer in the population is similar to the efficacy of RT found in trials. This supports routine use of RT after lumpectomy for DCIS in the population. No significant financial relationships to disclose.
Looking for tips to find icebergs - surveillance of haemolytic uraemic syndrome to detect outbreaks of Shiga toxin-producing E. coli infection
Authors: D Werber, C Frank, M Wadl, H Karch, A Fruth, K Stark
Journal: Eurosurveillance (2008)

In a recent article, De Schrijver et al. described an outbreak of Verocytotoxin-producing Escherichia coli, syn. Shiga toxin-producing E. coli (STEC), linked to the consumption of ice cream produced at a farm in the province of Antwerp, Belgium. Interestingly, the outbreak was identified through the time-clustering of patients who had developed haemolytic uraemic syndrome (HUS) and from whom STEC O145 was isolated.
Abstract 14903: Cardiac Structure and Function and Outcome of African-Americans Carrying the Amyloidogenic V122i Transthyretin Mutation: The ARIC (Atherosclerosis Risk in Communities) Study
Authors: Candida C Quarta, Joel N Buxbaum, Rodney H Falk, Amil M Shah, Brian Claggett, Dalane Kitzmann, Thomas H Mosely, Ervin R. Fox R Fox, Kenneth R Butler, Scott D Solomon
Journal: Circulation (2013)

Background: Almost 4% of African Americans carry an amyloidogenic transthyretin (TTR) mutation, V122I, which usually manifests over the age of 65 years as a restrictive amyloid cardiomyopathy with ...
Association of opioid requirement and cancer pain with survival in advanced non-small cell lung cancer.
Authors: Dylan Michael Zylla, Michael Kuskowski, Kalpna Gupta, Pankaj Gupta
Journal: Journal of Clinical Oncology (2014)

183 Background: Pain is associated with shorter survival in non-small cell lung cancer (NSCLC). Lung cancer cells express opioid receptors. Opioids promote angiogenesis, tumor growth and metastases, and shorten survival in animal models. Methods: To examine if long-term opioid requirement, independently of chronic pain, is associated with survival, we studied 209 patients treated with chemotherapy for stage IIIB/IV NSCLC. Pain was stratified by proportion of time patients reported specific levels of pain. Opioids were converted to oral morphine equivalents (OME) for comparison. The effects of pain, opioid requirement, and known prognostic variables on survival were analyzed in univariable and multivariable models. Results: Both severity of pain and greater opioid requirement in first 90 days after starting chemotherapy were strongly predictive of shorter survival on univariable analysis. Patients with no/mild chronic pain and requiring &lt;5 mg/day OME during first 90 days had nearly 12 months longer median survival compared to patients requiring ≥5 mg/day OME and/or experiencing more pain. Differences in survival remained remarkably similar when chronic pain and opioid requirement were assessed over the entire clinical course (until death or last follow-up). In multivariable models, both opioid requirement and chronic pain remained independent predictors of survival, after adjustment for age, stage and performance status. Conclusions: Severity of chronic cancer-related pain or greater opioid requirement are associated with shorter survival in advanced NSCLC, independently of known prognostic factors. While pain adversely influences prognosis, controlling it with opioids does not improve survival. Prospective studies should determine if achieving pain control using opioid-sparing approaches improves outcomes.
Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement
Authors: Rita João Guerreiro, Ebba Lohmann, José Miguel Brás, Jesse Raphael Gibbs, Jonathan D. Rohrer, Nicole Gurunlian, Burcu Dursun, Basar Bilgic, Hasmet Hanagasi, Hakan Gurvit, Murat Emre, Andrew Singleton, John Hardy
Journal: JAMA Neurology (2012)

OBJECTIVE To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. DESIGN Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. SETTING Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. MAIN OUTCOME MEASURE Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). RESULTS In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. CONCLUSIONS Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
Review: In obstructive sleep apnea, CPAP and mandibular devices do not differ for reducing blood pressure
Authors: Ken Kunisaki
Journal: Annals of Internal Medicine (2016)

Source Citation Bratton DJ, Gaisl T, Wons AM, Kohler M. CPAP vs mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and meta-analysis. JAMA. 2015;314:2280-93. 26624827