tbuckley/cabot-search huggingface dataset:
Concordance in the relative mortality rates for prostate cancer and gastric cancer in African Americans.
Authors: John Clark Henegan
Journal: Journal of Clinical Oncology (2017)

270 Background: The racial disparity in outcomes for prostate cancer, gastric cancer, and multiple myeloma is demonstrated by these malignancies having the highest age-adjusted mortality rate ratio for black Americans versus white Americans. A variety of factors have been identified as contributing to this disparity, leading to our hypothesis that there would not be concordance, in respect to the mean, when the county-level age-adjusted black: white mortality rate ratio for a malignancy was compared to the other two malignancies. Methods: Publically available information from cancerrates.gov was used to obtain county-level data in regards to race-specific age-adjusted mortality rates for prostate cancer, gastric cancer, and multiple myeloma. Counties with potentially unstable age-adjusted mortality rates were excluded. A malignancy’s age-adjusted mortality rate for blacks was divided by the complementary rate for whites to determine the black: white mortality rate ratio. Across a county, malignancies were compared for concordance in mortality rate ratios relative to the mean ratio for that malignancy. After a preliminary inspection noted that all New Jersey counties had a markedly lower black: white mortality ratio for gastric cancer than other counties in the data set, the New Jersey counties were excluded from analysis and odds ratios for concordance were calculated. Results: All counties (n = 68) had a black: white age-adjusted mortality ratio of &gt; 1 for each malignancy. In the analyzed counties (n = 52), there was a statistically significant concordance in black: white mortality rate ratios for prostate cancer and gastric cancer (OR = 3.26, p = 0.046). The black: white mortality rate ratios for neither prostate cancer (OR = 1.17, p = 0.78) nor gastric cancer (OR = 1.17, p = 0.78) demonstrated a statistically significant concordance with multiple myeloma. Conclusions: The concordance in the black: white mortality rate ratios for prostate cancer and gastric cancer in this dataset indicate that these two malignancies may share common clinical, environmental, or genetic factors in African-Americans. Future research is needed into what common factors may contribute to disparities in these two malignancies.
Rate of never smokers in non small cell lung cancer (NSCLC) patients.
Authors: Lorraine Cheryl Pelosof, Chul Ahn, Alejandra Madrigales, Joan Cox, John D. Minna, Joan H. Schiller
Journal: Journal of Clinical Oncology (2015)

e19007 Background: There has been significant debate about whether the percentage of never smokers is increasing in lung cancer patients (pts). Using our institutions' registry data, our objective was to determine if the rate of never smokers is increasing among lung cancer pts. Methods: We conducted a retrospective study using lung cancer registry data from our university hospital at the University of Texas Southwestern Medical Center and our county hospital, Parkland. These registries were queried year by year between 1990 and 2013 for gender, age at diagnosis, diagnosis of NSCLC or small cell lung cancer (SCLC), and self-reported smoking history. Logistic regression analysis was performed to assess the rate of never smokers in NSCLC (N=5,392) and SCLC (N=792) pts. Results: The percentage of never smokers increased among NSCLC pts between 1990 and 2013 [Table]. Univariate logistic regression demonstrated an increasing proportion of never smokers among NSCLC cases (p<0.0001 for year) and multivariate logistic regression also demonstrates this increase (p<0.0001 for year) after controlling for age and gender. Never smokers were more likely to be female (67%, p<0.0001) and younger (59.6±18.7 yrs old) than smokers (62.0±14.7 yrs old; p= 0.002). The increase in the percentage of NSCLC never smokers was seen at both our university and county hospitals. In contrast, the percentage of never smokers among SCLC cases did not significantly increase during this time period. Conclusions: This study demonstrates an increasing rate of never smokers with NSCLC, but not SCLC, between 1990 and 2013 in a large and demographically diverse population. We recognize the limitations of this retrospective analysis, but the relative constancy of never smokers in SCLC cases suggests our findings are not merely an artifact of better documentation of smoking history. Because the biology and, thus, often the treatment options of lung cancer in never smokers differs from that of smokers, this finding warrants further investigation. Percentage of never smokers. 1990-1995 1996-2000 2001-2005 2006-2010 2011-2013 NSCLC 8.9 8.8 8.8 13.5 17.0 SCLC 1.7 2.3 1.7 4.5 2.8
Genome Engineering and Modification Toward Synthetic Biology for the Production of Antibiotics
Authors: Xuan Zou, Lianrong Wang, Zhiqiang Li, Jie Luo, Yunfu Wang, Zixin Deng, Shiming Du, Shi Chen
Journal: Medicinal Research Reviews (2017)

Antibiotic production is often governed by large gene clusters composed of genes related to antibiotic scaffold synthesis, tailoring, regulation, and resistance. With the expansion of genome sequencing, a considerable number of antibiotic gene clusters has been isolated and characterized. The emerging genome engineering techniques make it possible towards more efficient engineering of antibiotics. In addition to genomic editing, multiple synthetic biology approaches have been developed for the exploration and improvement of antibiotic natural products. Here, we review the progress in the development of these genome editing techniques used to engineer new antibiotics, focusing on three aspects of genome engineering: direct cloning of large genomic fragments, genome engineering of gene clusters, and regulation of gene cluster expression. This review will not only summarize the current uses of genomic engineering techniques for cloning and assembly of antibiotic gene clusters or for altering antibiotic synthetic pathways but will also provide perspectives on the future directions of rebuilding biological systems for the design of novel antibiotics.
Exploring the role of circulating VE-cadherin (VE-C) in metastatic colorectal adenocarcinoma (mCA) patients (pts) treated by bevacizumab (Bev).
Authors: Christelle De La Fouchardiere, Nadia Oussaid, Sylvie Chabaud, Ellen Blanc, Olfa Derbel-Miled, Françoise Desseigne, Pierre Guibert, Matthieu Sarabi, Helena Polena, Pascal Artru, Isabelle Vilgrain
Journal: Journal of Clinical Oncology (2014)

e14614^ Background: No predictive biomarker of tumor response or resistance to Bev has been identified in mCA. VE-C is an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis which was shown to be significantly predictive of the overall survival (OS) for glioma pts. Methods: mCA pts≥ 18 years with ECOG PS ≤ 2, measurable disease and starting a first line by Bev were eligible. The primary endpoint was to evaluate the predictive value of VE-C on the objective tumor response. Assuming 5% α bilateral error, 80% power and a response rate of 40%, 98 pts were needed to highlight an Odds Ratio (OR) = 2 of not responding to Bev between the 2 groups of level of VE-C at Day1 (D1) (cut-off: median). Major secondary objectives were overall survival (OS) and progression-free survival (PFS). Results: Between 05/2010 and 05/2013, 63 pts were included. Median follow-up was 11 months (mo) (95%CI, 8.1-11.7). Median age was 60 years, 14% had ECOG performance status = 2, 86% had colon as primary site, 83% had liver metastasis. 30 pts (47.6%) harbored Ras mutations. Pts characteristics were well balanced between the 2 groups of VE-C levels at D1. Median VE-C rates decreased significantly between D1 (905 ng/ml) and D15 (815 ng/ml). We observed a positive correlation between PCR (protein C reactive), ALP (alkaline phosphatase) and VE-C rate at D1, indicating a potential prognostic value of VE-C. 34 pts (55%) presented an objective response to chemotherapy + Bev. No correlation between response rate and VE-C rate at D1 was seen. Although we have not been able to demonstrate a statistically significant difference in univariate or multivariate analyses, a decrease of at least 10% in VE-C rate between D1 and D15 seems associated with less objective tumor response (OR = 0.415 (95%CI = 0.142-1.205 ; p=0.11). At the time of cutoff analysis, 22 of 63 pts had died and median OS and PFS were 17.2 mo and 14.4 mo respectively. Conclusions: We failed to demonstrate a predictive role of VE-C on objective response rate under antiangiogenic treatment (Bev) in mCA. Updated survival data are awaited in order to correlate VE-C and other biomarkers (such as BMP9 and ALK1) with overall survival. Clinical trial information: NCT01405430.
Evaluation of patient (Pt), treatment, and prognostic factors in urinary tract adenocarcinoma.
Authors: Meena Sadaps, Haris Zahoor, Paul Elson, Hamid Emamekhoo, Kim Schach, Nicole DiBiase Brey, Jihad Kaouk, Georges-Pascal Haber, Michael C. Gong, Ryan Kent Berglund, Venkatesh Krishnamurthi, James Ulchaker, Timothy D. Gilligan, Brian I. Rini, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

408 Background: Adenocarcinoma is a rare histological subtype of urinary tract cancer with limited data regarding risk factors, effectiveness of treatment, and prognostic factors. Methods: To identify prognostic features, we evaluated demographics, treatment, and progression-free and overall survival (PFS, OS) in a retrospective review of 49 pts with adenocarcinoma of the bladder (n=35), ureter (n=1), or urethra (n=13) evaluated at Cleveland Clinic from January 2000 to April 2016. Uni- and multi- variable analyses (UVA, MVA) were used to identify prognostic factors. OS was measured from diagnosis to death and PFS from diagnosis to first of recurrence/progression or death. Results: 25 (51%) pts were women, median age at diagnosis was 62 (33-82), 30 pts (61%) presented with hematuria, and 13/36 (36%) had hydronephrosis. Treatment included cystectomy in 43 pts (88%), neoadjuvant chemotherapy in 3 pts (MVAC, gemcitabine/cisplatin, paclitaxel/cisplatin), adjuvant chemotherapy in 2 pts (gemcitabine), and systemic therapy for advanced or recurrent disease in 6 pts. Overall, 23 pts (47%) recurred/progressed and 31 (63%) died [12 without recurrence/progression]. Estimated median OS and PFS from diagnosis were 38.1 and 24.5 months, respectively. Pts with hydronephrosis at time of diagnosis had shorter PFS (p=0.06) and OS (p=0.007). Among the cystectomy pts, MVA identified pN stage and presence of signet-ring cells or papillary component as the only independent predictors of OS, while pN stage was the only independent predictor of PFS. Combining these factors, 3 prognostic groups for OS were identified (Table). Conclusions: pN stage and morphology are independent predictors of OS in pts with urinary tract adenocarcinoma after radical surgery and can stratify pts into distinct prognostic groups. If validated in larger cohorts, these factors could be used for prognostication, clinical decision making, and trial stratification. [Table: see text]
Association of frailty markers with treatment decision in patients seen in oncogeriatric clinic: Results from the ASRO pilot study.
Authors: Anais Farcet, Laure De Decker, Vanessa Pauly, Frederique Rousseau, Howard Bergman, Catherine Molines, Simon Paternotte, Frederique Retornaz
Journal: Journal of Clinical Oncology (2014)

9552 Background: Comprehensive geriatric assessment (CGA) is the gold standard to help oncologist in choosing the best cancer treatment in their older patients. Some authors recently suggest that the concept of frailty, developed by L Fried, could be a more useful approach in this population. We investigated if frailty markers (FM) are associated with treatment recommendations in an oncogeriatric clinic. Methods: This prospective multicenter study included patients 65 years and older, with solid tumors, referred to the oncogeriatric consultation after a cancer treatment plan. A CGA includes 9 domains (autonomy, comorbidities, medication, cognition, nutrition, mood, neurosensory deficits, falls and social status) was performed. Five FM were assessed (nutrition, physical activity, energy, mobility, strength). Patients were classified as Frail (3 or more FM), pre frail (1 or 2 FM) or not frail (0 FM). Treatment recommendations were classified in 3 categories: Standard treatment, Standard treatment with adaptation, supportive/palliative care. A polytomus logistic regression models were used to analyze factors associated with treatment recommendations. Results: 217 patients, mean age 83 years (± SD 5,3) were included. The most prevalent of the FM were mobility (77%), physical activity (65%), and nutrition (61 %). 42% had at least 3 markers. In univariate analysis, grip strength, physical activity, mobility, nutrition, ADL, IADL, social status, depression, ECOG-PS and sexe were significantly associated with treatment recommendations. In the multivariate analysis, only the number of FM and ADL were significantly associated with treatment recommendations (respectively p=0.001 and p=0.015). Treatment recommendations were significantly different into the 3 FM groups (p=0,001). In the non frail group, standard treatment or standard treatment with adaptation was maintained for more than 90% of patients. In the frail group, a support/palliative care was proposed for 60% of patient. Conclusions: Frailty markers are associated with treatment recommendations in older cancer patients. Longitudinal studies are warranted to better precise their use in geriatric oncology setting.
Phase II study of temsirolimus and erlotinib in patients (pts) with recurrent/metastatic (R/M), platinum-refractory head and neck squamous cell carcinoma (HNSCC).
Authors: Julie E. Bauman, Hugo Arias-Pulido, Sang-Joon Lee, Michael Considine, M Houman Fekrazad, Jason Howard, Justin A. Bishop, Garth T Olson, Dennie V. Jones, Elana J. Fertig, Christine H. Chung
Journal: Journal of Clinical Oncology (2012)

5549 Background: The Epidermal Growth Factor Receptor (EGFR) is a validated target in HNSCC. In R/M disease, primary or acquired resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. We hypothesized that concurrent mTOR blockade may improve efficacy of anti-EGFR therapy and conducted this phase II study. Methods: We evaluated the combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The exact, single-stage phase II design had 80% power (5% significance level) to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 mos with 35 evaluable pts. Correlatives included determination of PIK3CA mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts enrolled. Six pts withdrew prior to first planned response assessment, due to toxicity (5) or death (1), prompting referral to the Data Safety and Monitoring Committee and early closure. Grade ≥ 3 toxicities included fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN edema (2), and neutropenia (1). Among 8 progression-evaluable pt, median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were p16(+); 4/10 were EGFR(+); 11/11 showed no PTEN expression. PIK3CA mut was present in 1/11; the mut(+) pt withdrew after 3 wk for diarrhea/peritonitis with minor response. There were no associations between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory cytokine levels in pre- and post-temsirolimus plasma did not significantly differ or associate with toxicity. Two pts with ≥ 4.4 mos PFS were p16(-) and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated in this population, with toxicities predominant in p16(-) pts. Although the sample size was small, this R/M cohort demonstrated lack of PTEN expression and 9% PIK3CA mut, justifying further investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts.
pAKT expression in paraffin-embedded xenograft tumors after fixation delays and human breast cancer by optimized immunohistochemistry.
Authors: Sherry X. Yang, Diana Nguyen, Larry Rubinstein, Mark E Sherman, Sandra M. Swain, Joseph E. Tomaszewski, James H. Doroshow
Journal: Journal of Clinical Oncology (2012)

10603 Background: With progress in targeting PI3K/AKT pathway in the treatment of a wide range of cancers, it is getting more important than ever for optimization of detection method of AKT kinase, a central effector of the pathway, in archived tissues. Recently, we found that pAKT-S473 (pAKT) significantly predicts paclitaxel benefit in breast cancer (JCO 28: 2974, 2010), in which a good analytical and clinical performance of quantitative pAKT immunohistochemistry (IHC) was demonstrated. The current study evaluates pAKT stability in human breast cancer xenograft tumors after delays in fixation, and assesses a detection window following fixation delays with an established cutoff [staining index (SI) &gt; 2]. Methods: Xenograft tumors with high (MDA-MB-468) and intermediate levels (MDA-MB-231) of pAKT were fixed or snapped frozen in 10% neutral-buffered formalin or liquid nitrogen after delays post-excision. pAKT staining was performed in xenograft tumors and 96 cases of human surgical breast tumors by our optimized and traditional IHCs, and Western blot. Results: The mean SIs were 133, 121, 112, 94, 84, and 66 using optimized, and in contrast were 51, 44, 29, 14, 12, and 6.4 on traditional method at 0, 15, 30, 60, 120 and 180 min (2.6-fold by comparing the optimized with the traditional at baseline) in MDA-MB-468 xenograft tumors. pAKT level was ½ by the optimized, similar to the level detected by Western blot, relative to 1/8 of the baseline by the traditional (10.6-fold) at 180 min. The logarithmic decline rate by the optimal was 3.1 times (95% CI, 2.4 - 3.7) less than that of the traditional (normal approximation; 2-sided P &lt; 0.0001). pAKT expression was observed in 38.5% (37/96 ) of surgical breast tumors, comparable to 38% (606/1581) in a large cohort derived from the NSABP B-28 trial. There was little loss of pAKT in MDA-MB-231 xenograft tumors up to 180 min by IHC and Western blot. Conclusions: The optimized pAKT IHC significantly increases the sensitivity of detection with a large window for positivity. It is suitable for use in archived human specimens although it warrants further standardization and validation among research laboratories and perhaps diagnostic laboratories in the future.
Magnetic resonance imaging-guided focal laser ablation for prostate cancer: A phase I trial.
Authors: Arvin George, Anthony N. Hoang, Soroush Rais-Bahrami, Annerleim Walton-Diaz, Ardeshir Rastinehad, Mohummad Minhaj Siddiqui, Nabeel Ahmad Shakir, Richard Ho, Michele Fascelli, Steven F. Abboud, Raju Chelluri, Maria J Merino, Peter L. Choyke, Baris Turkbey, Bradford J. Wood, Peter A. Pinto
Journal: Journal of Clinical Oncology (2015)

e16128 Background: The majority of patients with low risk prostate cancer (CaP) harbor indolent disease and maybe safely observed on active surveillance (AS). However more than 30% of those on AS will ultimately receive definitive treatment. Focal therapy offers a treatment alternative that may provide oncologic control while avoiding treatment-related morbidity. The objective of this study was to determine the safety and feasibility of magnetic resonance (MR) image-guided focal laser ablation (FLA) of biopsy confirmed and MR visible prostate cancer. Methods: MR image-guided FLA was performed for men with Gleason < 7(3+4) when < 3 cores were positive in a standard 12 core biopsy corresponding to locations of MR lesions, or < 4 cores positive on MR image-guided biopsy. MR localization of biopsy-positive lesions were targeted via a transperineal approach and treated with a laser thermal ablation system. Validated quality of life questionnaires were completed pre-procedure and at each subsequent followup visit. MR-imaging was performed at 6 and 12 month followup with repeat fusion-guided biopsy perfomed at 12 months post-procedure. Results: 15 patients were treated with a mean preoperative PSA of 7.04 (Table 1). 14 patients had complete 1 year followup of which 6 patients had Gleason 6 and 8 patients had Gleason 6 disease. Mean operative time was 3.8 hours per treatment session for 1 lesion ablated. The mean (±Std Dev) IPSS and SHIM scores were 6.5±4.1 and 18.9±6.9 respectively, with no significant differences in SHIM or IPSS at 12 month followup. PSA was significantly lower at 1 year followup versus preoperatively (7.0 vs. 4.5, P = 0.0007).Five Grade 1 adverse events (AEs) were note in 4 patients, consisting of 4 incidences of hematuria and a pressure blister. Grade 2 AEs consisted of a UTI and epididymitis, one of which was unrelated to the procedure. Gleason 6 prostate cancer was identified in 2 prior treated lesions at repeat biopsy, of which 1 was observed and 1 underwent radical prostatectomy. Conclusions: MR-image guided FLA is safe and feasible for men with low risk CaP with acceptable oncologic outcomes at 1 year followup. Focal therapy is a promising alternate treatment that allows for preservation of functional outcomes. Clinical trial information: NCI-11-C-0158.
Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes
Authors: D. H. Munn
Journal: Journal of Clinical Investigation (2004)

During the preparation of this manuscript for publication, an error was introduced into the Results section, in the fourth sentence of the paragraph beginning with "The levels of the APP-derived soluble peptides Aβ40 and Aβ42 in brains of double-transgenic mice and APP [V717I] control animals at the age of 18 weeks were quantified by specific sandwich ELISAs."The correct sentence appears below.We regret this error.In line ADAM10-mo × APP [V717I] , Αβ40 and Aβ42 were reduced by 49% and 20%, and in line ADAM10-hi × APP [V717I] , by 39% and 29%, respectively.