tbuckley/cabot-search huggingface dataset:
Concurrent molecular alterations in KRAS-mutant lung adenocarcinomas and effects on overall survival.
Authors: Gregory J. Riely, Juliana Eng, Helena Alexandra Yu, Meier Hsu, Mark G. Kris, Laetitia Borsu, Magali Cavatore, Angela Yannes, Edyta Brzostowski, Jacklyn Casanova, Agnes Viale, Camelia S. Sima, Donavan T Cheng, Marc Ladanyi
Journal: Journal of Clinical Oncology (2014)

8033 Background: KRAS mutations define the largest subset of oncogene-driven lung adenocarcinomas (25-30%). Among patients with KRAS mutations, their clinical course during treatment is heterogeneous. The presence of concurrent genetic alterations in other oncogenes and tumor suppressors, such as TP53 or STK11 may affect outcomes for patients with KRAS mutant lung cancers. We sought to use a next-generation sequencing-based assay to comprehensively describe concurrent genetic alterations present in KRAS mutant lung cancers and explore the effect of such alterations on patient outcomes. Methods: We studied tumor DNAs from 102 patients with stage IV/recurrent KRAS mutant lung cancers enriched for cases with longer and shorter overall survivals. All patients received standard therapies for advanced lung cancer. We performed massively parallel sequencing (Ion Torrent PGM) of all exons from 65 cancer genes using a custom AmpliSeq panel. The sequence data were analyzed for point mutations and small insertions and deletions using a custom pipeline. We collected clinical characteristics, survival, and concurrent mutations. The association of concurrent mutations and overall survival was evaluated using Kaplan-Meier methodology with log rank test for comparisons. Results: Among these 102 samples in which the KRAS (G12C=47, G12D=23, G12V=12, G12A=9, Other=11) mutation was confirmed by Ion Torrent PGM sequencing, we found 0 to 11 concurrent mutations with a majority of the patients having 1 (24), 2 (30), or 3 (16) mutations in addition to KRAS. The most frequent concurrent mutations included TP53 (21), KEAP1 (13), SMARCA4 (7), and ARID1A (6). There was no difference in median overall survival between patients with or without a concurrent mutation in TP53 (21 vs 25 mos, p=0.84), KEAP1 (19 vs 25 months, p=0.86), SMARCA4 (12 vs 25 months, p=0.14) or ARID1A(22 vs 25 months, p=0.5). Conclusions: This study is the largest reported series of KRAS mutant lung cancers with a broad analysis of concurrent molecular alterations and survival. There was no significant effect on survival for concurrent mutations in the identified cancer associated genes.
Tuberculosis — United States, 2016
Authors: Kristine M. Schmit, Zimy Wansaula, Robert Pratt, Sandy F. Price, Adam J. Langer
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

In 2016, a total of 9,287 new tuberculosis (TB) cases were reported in the United States; this provisional* count represents the lowest number of U.S. TB cases on record and a 2.7% decrease from 2015 (1). The 2016 TB incidence of 2.9 cases per 100,000 persons represents a slight decrease compared with 2015 (-3.4%) (Figure). However, epidemiologic modeling demonstrates that if similar slow rates of decline continue, the goal of U.S. TB elimination will not be reached during this century (2). Although current programs to identify and treat active TB disease must be maintained and strengthened, increased measures to identify and treat latent TB infection (LTBI) among populations at high risk are also needed to accelerate progress toward TB elimination.
Chemotherapy use in lung cancer patients during last three months of life: Current practice in a large Israeli health care organization.
Authors: Ariel Hammerman, Sari Greenberg-Dotan, Erez Battat, Haim Bitterman, Samuel Ariad
Journal: Journal of Clinical Oncology (2014)

e17675 Background: Lung cancer is the second leading cause of cancer-related death in Israel. Aggressive cancer treatment given at late stages of disease raises questions on quality of care, ethical aspects and cost. Objective: To explore the use of anti-cancer chemotherapeutic drugs (CT) in lung cancer patients (pts) that deceased during 2013, within three months of end of life (EOL). Methods: Clalit Health Services (CHS), Israel's largest health-care organization with over 4 million members, serves 52% of the total population. CHSs administrative database was used to extract available clinical and demographic information regarding all of CHS's Lung cancer pts that died during 2013. Data obtained included: cancer diagnoses, demographics, Charlson's comorbidity index and pharmacotherapy provided within 3 months of EOL. Results: 556 CHS pts died from lung cancer in 2013, 184 female (33%). 338 pts received CT within 3 months of EOL (table). Pts that received CT were significantly younger than pts that didn't receive CT within 3 months of EOL (table),no significant difference in gender (table) or Charlson's comorbidity index (p=0.190). CT given (pts, % of total pts that received CT): erlotinib (78, 23.1%), pemetrexed (76, 22.5%), gemcitabine (59, 17.5%) vinorelbin (59, 17.5%), paclitaxel (33, 9.8%), gefitinib (27, 8.0%), docetaxel (25, 7.4%), bevacizumab (22, 6.5%), topotecan (21, 6.2%), crizotinib (4, 1.2%). In 29.6% of pts treated with CT, initiation of the specific CT was within the 3 months of EOL. Conclusions: Our results indicate that CT use in last 3 months of life is frequent in CHSs patients with lung cancer. Further research is required to determine other factors that might influence this use, and to examine whether these patterns of CT prescribing are clinically justified. CT within 3 months of death N (%) No CT within 3 months of death N (%) Total 338 (60.8%) 218 (39.2%) Female 104 (56.5%) 80 (43.5%) p=0.147 Male 234 (62.9%) 138 (37.1%) Median age at death 68 73 p=0.006
UTILIDAD DEL NARROW BAND IMAGING (NBI) EN PROCESADORES EVIS EXERA III DE OLYMPUS Y ENDOSCOPIOS DE ALTA DEFINICIÓN PARA EL DIAGNÓSTICO DE DISPLASIA EN EL ESÓFAGO DE BARRETT
Authors: A Caballero Marcos, Ó Nogales Rincón, A Clemente Sánchez, G Pérez Rial, C Carbonell Blanco, J García Lledó, B Merino Rodríguez, L Pérez Carazo, M López Ibáñez, C González Asanza
Journal: Endoscopy (2015)

Introducción: El narrow banding imaging (NBI) facilita la delineación de patrón mucoso y de microcapilares. Su capacidad para mejorar la detección de displasia en esófago de Barrett (EB) ha sido analizada en diversos estudios basados en procesadores Evis Exera II, evidenciando una concordancia interobservador habitualmente mediocre, con sensibilidades y especificidades subóptimas.
Improvement of cancer care by linking community cancer center oncologists to disease site-specific experts.
Authors: Patricia H. Hardenbergh, Calloway B May, Kimberly Anne Lyons-Mitchell
Journal: Journal of Clinical Oncology (2013)

6641 Background: To improve the quality of cancer care across US by connecting community cancer center oncologists with highly specialized, disease site-specific oncologists through the use of online technology. Methods: Chartrounds.com was developed which allows community oncologists to interact online with disease site-specific oncologists and their peers on a scheduled basis in order to present and review treatment management and specific cases. Disease sites include breast, head and neck, gastrointestinal, gynecologic, prostate, central nervous systems, pediatric, lymphoma, lung cancer and palliative care. At the conclusion of each session, participants are asked to complete a questionnaire which requests feedback on the quality and relevance of the session and the manner in which it might result in practice changes. Results: To date, 825 community radiation oncology physician members from 50 states and 19 countries have enrolled online. In the initial 25-month period (12/2010-1/2013), 35 disease site-specific specialists have lead 256 chart rounds one-hour sessions with an average attendance ratio of 15 community physician members to 1 disease site-specific specialist. On a 5 point scale with 5 representing the greatest impact possible, of 1,756 responses the mean score to feedback questions is as follows: session quality: 4.6, time used effectively: 4.6, discussions relevant to daily practice: 4.6, session is likely to result in a change in practice: 4.0.Members reported that they would make the following changes in their practice: change in clinical management of the radiation patient: 40%, change in the selection of patients for radiation: 10%, change in radiation fields: 15%, change in radiation prescription dose: 10%. Conclusions: The Chartrounds.com program appears to be making an impact on the quality of radiation oncology practices resulting in changes in management and treatment of patients in community cancer centers. Future directions of this project are aimed at continuing to develop the site for medical oncologists and multidisciplinary tumor conferences. This work is funded by the Improving Cancer Care Grant of the ASCO Conquer Cancer Foundation supported by Susan G. Komen for the Cure.
The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.
Authors: Jason John Luke, Larry Rubinstein, Gary L Smith, S. Percy Ivy, Pamela Jo Harris
Journal: Journal of Clinical Oncology (2012)

2606 Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p&lt;.001) and chemo with higher incidence of G4 toxicity (p&lt;.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p&lt;.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]
Phase I clinical trial of the intraperitoneal (IP) administration of a novel nanoparticle formulation of paclitaxel (NTX).
Authors: Stephen K. Williamson, Jo Wick, Julia A. Chapman, Gary Johnson, Greg Reed, Thomas K. Schulz, Holly Smith, Scott Weir, Charles J Decedue, Jahna Howell, Katherine Roby
Journal: Journal of Clinical Oncology (2013)

2558 Background: IP therapy is an attractive option for patients with IP carcinomatosis as many of these malignancies remain confined IP. Agents whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Pre-clinical studies of a novel formulation of nanoparticulate paclitaxel in animal tumor models demonstrated superior activity and substantially reduced systemic toxicity. This allowed for significant IP doses and concentrations, yet yielded very low systemic concentrations of paclitaxel. We report here the results of a Phase I trial of IP administered NTX. Methods: Patients (ECOG≤2) had relapsed, treatment refractory solid IP tumors and adequate organ function. NTX was administered IP as a bolus injection after 500 ml saline followed by IP administration of up to 2 L of saline. We utilized an accelerated dose escalation scheme until one DLT occurred during cycle 1, followed by a standard dose escalation (3+3 design) based on CTCAE V3 toxicities. The pharmacokinetics of IP administered NTX were characterized in plasma and ascites fluid. Secondary objectives were to define the recommended phase 2 dose of NTX, and characterize preliminary activity and toxicity. Results: 20 patients were treated at dose levels from 50 – 275 mg/M2 q 28 days. Primary malignancy was ovarian cancer (74%). Treatment was well tolerated at all dose levels. Common toxicities potentially related to NTX were: gastrointestinal (68%), constitutional (42%), and pain (42%). Average number of cycles received was 2 (range 1 to 6). Best response was stable disease (4 patients, 21%). Median length of disease stability was 99 days (range 85 to 151 days); median time on study patients with stable disease was 313 days (range 142 to 740 days). All Cmax in plasma were less than 35 ng/mL, with ascites fluid Cmax generally greater than 1000 ng/mL. Conclusions: IP NTX is well tolerated. MTD has not yet been reached. Pharmacokinetic data demonstrate significant, persistent IP exposure to paclitaxel with minimal systemic exposure. Accrual at the 275 mg/M2 dose level continues; updated results will be presented. Further clinical development of NTX is indicated. Clinical trial information: NCT00666991.
Lapatinib in advanced chordoma: A phase II study.
Authors: Silvia Stacchiotti, Elena Tamborini, Elena Palassini, Tiziana Negri, Andrea Marrari, Antonella Messina, Carlo Morosi, Beatrice De Troia, Alessandra Longhi, Emanuela Palmerini, Alessandro Gronchi, Silvana Pilotti, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2012)

10026 Background: To report on a prospective Phase II, investigator-driven, collaborative study to explore the activity of lapatinib, a dual EGFR and ErbB2 inhibitor, in EGFR-positive advanced chordomas. Methods: From December 2009 to December 2011, 19 advanced progressing chordoma patients entered this study (mean age: 59 yrs – range = 35-75; PS: 0-3 - ≥2 = 52%; site: sacrum = 68%, spine = 21%, skull base = 11%; disease extent: metastatic = 68%, locally advanced = 32%). EGFR expression was evaluated by immunohistochemistry in all patients. EGFR activation was detected in 15 of 17 evaluable cases by phospho-arrays and/or real-time PCR and/or fluorescence immunostaining. EGFR FISH analysis showed high level of gene gain in 4. HerB2 status is under evaluation. Patients received lapatinib 1500 mg/day (dose intensity in excess of 1250 mg/day), until progression or toxicity. The primary study end-point was response rate (RR) as for Choi criteria extended to MRI. Secondary end-points were RR by RECIST, PFS by Choi, OS, clinical benefit rate (CBR) (CR+PR+SD≥6mos), correlation between EGFR status and response. Results: 16 pts are evaluable for response (3 too early); 4 patients are still on treatment. 3 patients (19%) had a partial response (PR) and 8 (50%) a stable disease (SD) as their best Choi response, corresponding to RECIST SD in all cases. The 3 cases with a PR by Choi had a minor decrease in size; another patient had a mixed response. The CBR was 19%. Median PFS as for Choi was 5.5 (range = 2-12+) months, with 1 patient being progression-free at 18 months. Toxicity was as expected. In one case treatment was interrupted due to side effects. No correlation was observed between EGFR expression/activation and response. Conclusions: This Phase II study showed a modest activity of lapatinib in chordoma. EGFR expression was not predictive of response. The clinical relevance of EGFR targeting in chordoma needs to be further investigated.
Clinical characteristics and survival outcomes in <i>BRCA1</i>-methylated epithelial ovarian cancer (Bmeth-OC): A pooled analysis of data for 1,278 patients across five studies.
Authors: Roshni Deepa Kalachand, Ilary Ruscito, Desislava Dimitrova, Pierluigi Benedetti Panici, Jalid Sehouli, Sven Olek, Elena Ioana Braicu, Lingeng Lu, Dionyssios Katsaros, Herbert Yu, Mark S Carey, Russell Broaddus, Karen H. Lu, Gordon B. Mills, Maria I Harrell, Kathy J Agnew, Elizabeth M. Swisher, William Grogan, Britta Stordal, Bryan Hennessy
Journal: Journal of Clinical Oncology (2015)

5526 Background: BRCA1/2 mutations render ovarian cancers (OC) homologous recombination deficient (HRD) and thus sensitive to platinum and PARP inhibitors. Data on BRCA1 promoter methylation in OC, another potential biomarker of HRD, are conflicting and limited. Methods: We searched PubMed and ASCO/ESMO abstracts for studies with survival outcomes in Bmeth-OC. Individual patient data were obtained from 5 studies. Associations between clinical characteristics and Bmeth-OC were determined using the Cochran-Mantel-Haenszel test. Progression-free (PFS) and overall survival (OS) differences between Bmeth-OC and non-Bmeth-OC (and between Bmeth-OC, BRCA1/2-mutated OC and BRCA1/2-wild type non-Bmeth-OC where data available) were estimated with Kaplan-Meier analysis, adjusting for cohort. Results: We obtained data for 164 patients (pts) with Bmeth-OC and 1114 pts with non-Bmeth-OC (Bmeth-OC frequency = 12.8%). Median age was 59 (range 26-93) and median follow-up was 31 months (range 0-203). 72.7% of OCs were high grade serous. 91.3% of pts received adjuvant platinum-based chemotherapy. Bmeth-OC was associated with high grade (85.4% vs 80.7% of non-BmethOC, p = 0.016) and younger age ( < 59: 58.5% vs 47.1% of non-BmethOC, p = 0.012), but not stage, histology, cytoreduction or platinum sensitivity. There was no difference in median PFS (18.7 vs 19.1 months, p = 0.42) or OS (44.3 vs 46 months, p = 0.62) between Bmeth-OC and non-Bmeth-OC. BRCA1/2 mutation status was assessed in 3 cohorts (639 pts). BRCA2-mutated OC had a better median PFS and OS compared to BRCA1-mutated OC, Bmeth-OC, and BRCA1/2-wild type non-Bmeth-OC (PFS: 26 vs 17.6, 15.6, 15.8 months, p = 0.025; OS: 74.3 vs 49.3, 41.9, 44mths, p = 0.003).On multivariate Cox analysis including clinical variables, BRCA2 mutation but not BRCA1 mutation/methylation had a significant effect on OS/PFS (p = 0.001, HR = 0.44 95%CI [0.27-0.70]/p = 0.001, HR = 0.5 95%CI [0.33-0.77]). Conclusions: BRCA1 methylation occurs in OC in younger pts, but has no impact on survival. BRCA2 mutation, in contrast to BRCA1 mutation/methylation, is an independent prognostic factor for improved survival in OC.
Efficacy of chemotherapy in patients with recurrent pancreatic cancer.
Authors: Akihiro Ohba, Hideki Ueno, Yuji Inagaki, Yasunari Sakamoto, Shunsuke Kondo, Chigusa Morizane, Takuji Okusaka
Journal: Journal of Clinical Oncology (2017)

466 Background: Gemcitabine (GEM) plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) are standard first-line chemotherapy regimens for metastatic pancreatic cancer (MPC) patients. GEM and S-1 are also used for these patients in Japan. However, the phase 3 trials included a small proportion of recurrent pancreatic cancer (RPC) patients, and patients who had received adjuvant chemotherapy were excluded. In clinical practice, RPC is treated in the same way as MPC. The aim of this study is to compare the efficacy of chemotherapy between RPC and MPC. Methods: We retrospectively analyzed the patients with RPC or MPC who received GnP, FFX, GEM, or S-1 as first-line chemotherapy between January 2014 and March 2016 in our institution. RPC was defined as pancreatic cancer with recurrence after R0 or R1 resection. Overall survival (OS), progression-free survival (PFS), response rate (RR), and disease control rate (DCR) were evaluated. Multivariate analyses of OS were performed with the use of a Cox proportional-hazard model. Results: A total of 181 patients, 40 RPC and 141 MPC, were selected in this study. RPC and MPC groups were similar with respect to age, sex, and performance status (PS). However, the RPC group had lower percentage of liver metastases (P &lt; 0.001). The regimens were GnP/FFX/GEM/S-1: 10/3/20/7 in the RPC group and 37/34/67/3 in the MPC group, respectively. In the RPC group, 31 of 40 patients had received adjuvant chemotherapy; S-1/GEM: 24/7. The median OS was 16.6 months in the RPC group as compared with 9.7 months in the MPC group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.37–1.10, P = 0.11). The median PFS was 4.8 months in the RPC group and 4.4 months in the MPC group (HR 0.86, 95% CI 0.57–1.30, P = 0.47). The RR was 10% versus 14% (P = 0.79), the DCR was 50% versus 52% (P = 0.86), in the two groups, respectively. Multivariate analysis showed PS (HR 2.19, 95% CI 1.38–3.49) and liver metastases (HR 2.34, 95% CI 1.47–2.34) were independent predictors of OS. On the other hand, RPC or MPC was not found to be an independent prognostic factor (HR 1.19, 95% CI 0.67–2.13). Conclusions: It is suggested that chemotherapy in RPC may have similar efficacy compared to MPC. The relatively longer OS in the RPC group seems to associate with the lower percentage of liver metastases.
MEK/ERK pathway characterization and its prognostic implication in gastric cancer (GC).
Authors: Marta Martin-Richard, Ariadna Tibau, Malena Ferre, Mireia Castillo-Martin, Anna Colomer, Nadine Erill, Francesc Sancho, Ignasi Gich, Agust Barnadas
Journal: Journal of Clinical Oncology (2012)

e14552 Background: MEK/ERK pathway is considered one of the main controllers of cell proliferation and survival and its deregulation has been involved in several tumors. Different mechanisms have been described leading to ERK activation and nuclear translocation including mutations on genes encoding pathway constituents', or upstream factors overexpression. Little is known about the status of this pathway in GC. The aim of our study was to evaluate the expression of different factors of this pathway in GC and their correlation with patient outcome. Methods: Fifty-eight patients with localized stage Ib-III GC who underwent radical surgery followed by adjuvant chemoradiotherapy were selected. ERK and its activated form (pERK) expression were analyzed by IHC, and KRAS and BRAF mutations were determined by PCR. Additionally, expression of upstream factors such as EGFR, HER2, VEGFR and downstream factor such as MST2 was evaluated by IHC. Finally, EGFR and HER2 copy number alterations were analyzed by FISH. Association of these markers to overall survival was assessed using the log rank test, and survival curves were plotted with Kaplan-Meier methodology. Results: Among the 58 tumors analyzed, 7% arose from the cardias and 33% corresponded to signet ring cell carcinomas. ERK and pERK expression was observed in the majority of tumors (86 and 64%, respectively, p=0.002). Cytoplasmic pERK expression did not show any association with the clinico-pathological characteristics. Notably, nuclear pERK (pERKnc) expression was observed in 12% of the cases and it showed a significant correlation with patient survival (p=0.05), conferring a worse prognosis. Moreover, EGFR overexpression (p=0.03) correlated with pERKnc. Finally, multivariate Cox analysis for survival confirmed that stage (HR 0.31, p=0.01) and pERKnc (HR 2.7, p=0.04) are unique independent prognostic factors. Conclusions: MEK/ERK pathway is commonly activated in localized GC, backed up by ERK and pERK being highly expressed in these tumors. Moreover, EGFR expression correlates with nuclear ERK expression, suggesting that ERK translocation to the nucleus could be mediated by this factor. More importantly, nuclear ERK has appeared as an independent marker of poor prognosis.