tbuckley/cabot-search huggingface dataset:
Next-generation sequencing of advanced, relapsed colorectal adenocarcinoma (CRC) to reveal mutations affecting Wnt, MAPK and PI3K pathway signaling: Emergence of novel combinatorial strategies.
Authors: Ishwaria Mohan Subbiah, Filip Janku, Apostolia Maria Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, Gary A. Palmer, David S. Hong
Journal: Journal of Clinical Oncology (2015)

605 Background: Advanced relapsed colorectal adenocarcinoma (CRC) is emerging as a cancer not with a singular phenotype but rather as a multitude of ‘diseases’ subdivided based on its molecular genotype. Given the heterogeneity in outcomes of CRC patients on targeted therapy clinical trials, we sought to identify a unique molecular subset within this disease. Methods: To that end, we identified advanced CRC patients in our Phase I clinic on whom adequate tissue was available for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: We identified 51 patients with advanced relapsed CRC (26 male, 25 female; median age 54 years; 49 colonic primary lesion, 4 rectum primary). Overall, 44 (86%) harbored a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 40 pts, 78%). Of these 44 patients, half (n=22, 50%) had ≥1 concurrent mutation affecting the PI3K/AKT/MTOR pathway, most commonly PIK3CA in 11 patients (4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K). Furthermore, 20 of these 22 pts with both Wnt and PI3K pathway mutations also demonstrated a concomitant MAPK pathway abnormality, most commonly KRAS (n=16) and 3 BRAF (V600E, G466R, D594G). Overall 20 of 51 (39%) patients had coexisting mutations implicated in all three signaling pathways (Wnt, PI3K, and MAPK). Conclusions: Three prominent pathways linked to the continuum of development and progression of cancer (Wnt, MAPK, PI3K) occur frequently in concurrence in patients with advanced CRC, thereby highlighting the role for an innovative therapeutic combination targeting all three pathways.
Doxorubicin and concurrent radiotherapy for anaplastic thyroid cancer: We need to do better
Authors: S. Lim, N. Y. Lee, M. G. Fury, R. A. Ghossein, A. R. Shaha, S. L. Wolden, D. G. Pfister
Journal: Journal of Clinical Oncology (2007)

16506 Background: Anaplastic thyroid cancer (ATC) is a rare, aggressive malignancy. The potential for pathologic misclassification complicates the interpretation of published data. One treatment option for locoregionally (LR) advanced disease is weekly low-dose doxorubicin (D) with concurrent radiation therapy (RT), based on reported 2-year local control rates of 68% (ATC)/77% (other TC histologic subtypes) (Cancer 1987;60:2372). We looked to evaluate our experience with this general approach, but in a larger series which included pathologic confirmation of all ATC cases. Methods: Patients (pts) were identified through the Memorial Sloan-Kettering Cancer Center (MSKCC) Radiation Oncology and Pathology Databases. Inclusion criteria: diagnosis of ATC between 1984–2006, with pathology review at MSKCC; LR disease only, able to be encompassed within a RT portal; treatment at MSKCC with planned weekly D (10 mg/m 2 ) and concurrent radiation. Prior surgery was allowed. Documentation of failure was based on clinical/radiographic assessment. Principal outcomes assessed: LR control (LRC: no failure at the primary site, in the neck, or the mediastinum), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was applied. Results: Thirty-seven patients were included in our analysis (median age 64; 54% female, 46% male). Median RT dose 5760 cGy, &gt;4500 cGy in 32 (87%), administered through hyperfractionated or once-daily schedules. Median number of D treatments received 5.5, &gt;4 in 24 (65%). 2-year outcomes: LRC 25%; PFS 8%; OS 18%. 6 patients remain alive at the time of last follow-up with survival durations of 4.1, 11.4, 11.7, 57.3, 58.5, and 140.7 months, respectively. A subset analysis was performed limited to the 24 patients (65%) who completed &gt;4,500 cGy of radiation and &gt;4 doses of D. 2-year outcomes were improved in this latter group, but remained disappointing, even among these more highly selected pts (LRC 30%; PFS 11%; OS 27%). Conclusions: Better therapy is needed for this poor prognostic disease. Future analyses will evaluate the impact of histologic subtype of ATC, radiation technique/dose, and surgical resection on outcome. No significant financial relationships to disclose.
Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study.
Authors: A C Wolff, D S Ettinger, D Neuberg, R L Comis, J C Ruckdeschel, P D Bonomi, D H Johnson
Journal: Journal of Clinical Oncology (1995)

PURPOSE A phase II study of ifosfamide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive-disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxicities, response, and median survival. PATIENTS AND METHODS Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosfamide 5 g/m2 by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m2 intravenously (IV) on day 1, and etoposide 50 mg/m2 orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients received ifosfamide 3.75 mg/m2 IV on day 1, carboplatin 300 mg/m2 IV on day 1, and etoposide 50 mg orally on days 1 to 14 (schedule II). RESULTS Nine of 18 patients (50%) on schedule I had 13 episodes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full doses on cycle 2. Objective responses were observed in 29 of 35 patients (83%) (schedule 1, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There were eight (23%) complete responses (CRs) and 21 (60%) partial responses (PRs). The median survival duration was 8.3 months, and 1- and 2-year survival rates were 37% and 14%, respectively. CONCLUSION ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two-drug regimens are warranted.
Abstract 18193: Stress Myocardial Perfusion Positron Emission Tomography Provides Incremental Risk Prediction in Subjects With and Without Diabetes
Authors: Hicham Skali, Marcelo F Di Carli, Ron Blankstein, Benjamin J Chow, Rob S Beanlands, Daniel S Berman, James K Min, Michael Merhige, Brent Williams, Emir Veledar, Leslee J Shaw, Sharmila Dorbala
Journal: Circulation (2014)

Introduction: The prognostic value of Positron Emission Tomography (PET) Myocardial Perfusion Imaging (MPI) is well established; however, it has not been extensively studied in subjects with diabetes mellitus (DM). We aimed to assess the prognostic value of PET MPI in subjects with and without DM. Methods: We studied 6037subjects (mean age 63±13 years, 47% women, 27% with DM, mean ejection fraction 60±16%, 33% with known coronary disease) who underwent a clinically indicated rest/stress Rubidium-82 PET MPI at 4 centers. Cardiac death (n=169) was evaluated at a mean follow-up of 2.5 ± 1.5 years. We used Cox proportional hazards models and risk reclassification measures stratified according to reported DM status. Bracco and Astellas provided initial funding for the PET registry. The current analysis is independently performed by the PET registry investigators. Results: Subjects with DM had a higher risk of cardiac death [hazard ratio (HR) (95% CI): 2.6 (1.9-3.5)] compared to those without DM. In multivariab...
Molecular characteristics of non-small cell lung cancer (NSCLC) patients sensitive to gefitinib
Authors: W. Pao, M. Zakowski, C. Cordon-Cardo, L. Ben-Porat, M. G. Kris, V. A. Miller
Journal: Journal of Clinical Oncology (2004)

7025 Background: Gefitinib (Iressa), a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFR-TK), induces objective regressions in 9–18% of NSCLC patients. Bronchioloalveolar histology and smoking history may predict response to gefitinib (Shah, NT, Proc ASCO 2003). Molecular studies to date have not shown any correlation between EGFR status and sensitivity to gefitinib (Bailey LR, Proc AACR 2003). To determine molecular characteristics predictive of sensitivity, we undertook selected analyses in gefitinib-sensitive and –refractory patients. Methods: Unstained slides or pathology blocks were collected on an IRB-approved protocol from 54 of 139 consecutive NSCLC patients treated at MSKCC with single agent gefitinib from 09/98 –11/02. Immunohistochemistry was performed on anonymized samples for total EGFR, the putative target of gefitinib; HER2/NEU, an EGFR family member whose co-expression may predict poorer outcome in NSCLC; phospho-AKT, an activated downstream signaling molecule that may confer resistance to gefitinib; and p53, a tumor suppressor gene frequently altered in NSCLC. Staining was graded by 2 pathologists blinded to clinical variables and outcomes. Results: The status of EGFR, HER2, p-AKT, and p53 are given in the table below. Among 20 patients whose tumors were EGFR(+) and HER2(+), 9 were gefitinib-sensitive; by contrast, only 1 of 8 patients whose tumors were negative for both markers was sensitive (p=0.19). Conclusions: We found no relationship between total EGFR, p-AKT or p53 and sensitivity to gefitinib. HER2 expression (63%) was higher than that usually reported in NSCLC. The high percentage (80%) of HER2-positive tumors among gefitinib-sensitive patients warrants confirmation in a larger series, and strategies to block concurrently both EGFR and HER2 may be clinically useful. Studies on p-EGFR, p-MAPK, and PTEN are in progress. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca Telek AstraZeneca
A comparison between surgery plus radiotherapy and exclusive chemoradiation therapy regimes in oral and oropharyngeal cancer: Long-term functional and psychological impact.
Authors: M. Airoldi, M. Garzaro, L. Raimondo, G. Pecorari, C. Giordano
Journal: Journal of Clinical Oncology (2010)

5575 Background: Treatment of head and neck tumors negatively affects speech, swallowing, and quality of Life (QoL). Our aim was the evaluation of QoL and psychological functioning comparing surgery + radiotherapy (S+RT) and exclusive chemo-radiation therapy (CH-RT) regimes. Methods: Seventy-two patients, homogeneous for demographic and TNM characteristics were affected by a tumor of oral cavity and oropharynx; 36 underwent S+RT and 36 received exclusive CH-RT. Late effects of treatment and psycho-oncological assessment included: Radiation Therapy Oncology Group (RTOG)-European Organisation for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring system, DISCHE morbidity recording scheme, Hospital Anxiety and Depression Scale (HADS), Montgomery Asberg Depression Rating Scale (MADRS), Mini Mental Adjustment to Cancer (MINI MAC), EORTC QoL Head and Neck35, Karnofky performance status, Visual Analogue Scales for dysphonia, dysphagia, dysmorphism and pain and Goodenough-Harris Draw a Person Test (DAP). Results: After median follow-up of 63 months, moderate-severe DISCHE score in S+RT vs. CT+RT was: taste impairment (64% vs. 89%), salivary function (59% vs. 79%), subcutaneous fibrosis (97% vs. 75%). Long term dysphagia: some discomfort (22% vs. 39%), soft diet required (42% vs. 28%), fluids only and naso-gastric tube feeding (11% vs. 4%); patients with severe dysphagia and taste impairment showed higher levels of anxiety (p<0.05): dysphagia influences the QoL, fatigue and physical-social functioning. Severe salivary function impairment is related only with troubles in social eating and contacts, without effects on QoL. MADRS depression was 56% vs. 46%, HADS anxiety was 22% vs. 21%. Just fair concordance in rate of depression between self-reported and clinician-rated scales was observed, with higher rates relieved in MADRS scale compared to HADS depression subscale (using 8 or 10 cut-off, Cohen's k test=0.401). Conclusions: A different pattern of long term toxicity was observed in S+RTvsCT+RT. Anxiety rate is lower, depression is present in half of patients and is statistically related with dysphagia. No significant financial relationships to disclose.
1290 THE EFFECT OF EXERCISE ON THE METABOLIC AND HISTOLOGICAL FEATURES OF NON-ALCOHOLIC FATTY LIVER DISEASE
Authors: I.J. Hickman, N.M. Byrne, I. Croci, A. Clouston, V.S. Chachay, E. Bugianesi, A. Gastaldelli, T.M. O'Moore-Sullivan, J.B. Prins, G.A. Macdonald
Journal: Journal of Hepatology (2012)
Phasing Analysis Of TKI Resistance Mutations In The BCR-ABL1 Kinase Domain and Neighboring Domains Using Next-Generation Sequencing
Authors: Jin Li, Zhenyu Yan, Agus Darwanto, Peng Fang, Weihua Liu, Kristy Drafahl, Julie Toplin, Cindy Spittle, Chad Galderisi
Journal: Blood (2013)
ING3 as a novel regulator of pancreatic cancer growth and aggressiveness.
Authors: Marina Koutsioumpa, Maria Hatziapostolou, Christos Polytarchou, Swapna Joshi, Dimitrios Iliopoulos
Journal: Journal of Clinical Oncology (2015)

304 Background: Recent studies demonstrate that chromatin regulation by posttranslational means, such as histone methylation or acetylation, is an essential control mechanism in tumorigenesis and tumor progression. Accumulative findings support the notion that pancreatic cancer tumorigenesis is not only governed by genetic alterations but also aberrant epigenetic regulation. The aim of the present study was to identify and assess the role of chromatin regulators in pancreatic cancer. Methods: The gene expression profile of chromatin regulators was assessed using gene expression microarray analysis in pancreatic cancer and uninvolved human tissues. Validation of microarray findings was performed by qRT-PCR in two extended cohorts of patients and by immunohistochemistry in pancreas tumor tissue microarrays. PANC-1, MIA Paca-2, Capan-2, HPAF-II and AsPC-1 cell lines were used for in vitro assays. Efficiency of knockdown experiments, performed by RNAi interference assays and shRNA-expressing lentiviral vectors, was evidenced by qRT-PCR and Western Blot Analysis. Cell proliferation, invasion and colony formation assays were conducted in genetically modified cells. The significance of variability between the results from each group and corresponding control was determined by unpaired t-test. Results: Differential expression analysis of chromatin regulators in pancreatic cancer versus uninvolved tissues demonstrates that 27 epigenetic molecules are significantly de-regulated (&gt;1.5 fold, P&lt;0.05). By hierarchical clustering, the samples are classified into two major groups that reflect the normal and cancer state. The decreased expression of inhibitor of growth family member 3 (ING3), a component of the NuA4 histone acetyl-transferase complex, was further validated by qRT-PCR and immunohistochemistry analysis in tumor tissues. Transient or stable silencing of ING3 caused significant increase of viability, proliferation, colony formation and invasion in several pancreatic cell lines. Conclusions: Our data show that human pancreatic cancer is characterized by loss of ING3 expression and we defined a potential role of the latter in pancreatic cancer cell growth and invasion.
A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors
Authors: M. J. Pishvaian, K. Firozvi, J. J. Hwang, J. L. Marshall, P. Ramzi, S. Malik
Journal: Journal of Clinical Oncology (2006)

13085 Background: Retinoids have been used to treat a wide variety of malignancies. Bexarotene is a synthetic retinoid that binds preferentially to the RXR subclass of retinoid receptors. In the initial phase I trial of bexarotene, a subset of patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. In vitro evidence suggests that the effects of retinoids may be enhanced when used in conjunction with taxanes. This is a phase I trial designed to determine the maximum tolerated dose of docetaxel in combination with a fixed dose of bexarotene. Methods: Patients with pathologically confirmed solid tumors for whom no standard therapies exist, who have an ECOG performance status ≤2, adequate organ function and normal serum triglycerides were eligible. Each cycle was 4 weeks long. Oral bexarotene was given at 400 mg/m 2 daily. Docetaxel was given weekly for 3 out of 4 weeks at two dose levels, 25 or 30 mg/m 2 , for up to 6 cycles. For patients exhibiting disease stabilization or response, treatment with bexarotene was continued until disease progression. Restaging studies were performed after every 2 cycles. Results: To date 10 patients have been enrolled, half of whom had NSCLC - 7 male, mean age = 61 (range 37–73), 100% PS = 0 or 1. 29 cycles were completed (range 1 to 8). 7 patients have been treated at 25 mg/m 2 and 3 at 30 mg/m 2 of docetaxel. Hypothyroidism, hypertriglyceridemia, and fatigue were common but generally mild. Two patients experienced grade III fatigue, and 1 each experienced grade III hypertriglyceridemia, neutropenia, and cough. There were no grade IV toxicities. Two patients were taken off study because of non-fatal radiation recall pneumonitis that was controlled with steroids. In this heavily pretreated population, of 8 patients assessable for response, 5 had stable disease for at least 2 cycles. One patient with NSCLC had a partial response that persisted for 6 cycles. Conclusions: Bexarotene and docetaxel (at a minimum of 25 mg/m 2 ) can be safely coadministered. Care should be taken in patients who have been previously irradiated. Enrolment and dose escalation for the phase I trial is still ongoing. A phase II trial of the combination as second line therapy in NSCLC is planned. [Table: see text]
ASCEND-2: A single-arm, open-label, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ).
Authors: Tony Mok, David Spigel, Enriqueta Felip, Filippo deMarinis, Myung-Ju Ahn, Harry J.M. Groen, Heather A. Wakelee, Toyoaki Hida, Lucio Crino, Makoto Nishio, Giorgio V. Scagliotti, Fabrice Branle, Chetachi Emeremni, Massimiliano Quadrigli, Jie Zhang, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2015)

8059 Background: In the ASCEND-1 study ceritinib showed clinical activity in pts with ALK+ NSCLC, including in brain metastases (BM). ASCEND-2 (NCT01685060) evaluated efficacy and safety of ceritinib in ALK+ NSCLC pts pre-treated with chemotherapy (≥ 1 platinum doublet) who progressed ≤30 days from last treatment with CRZ. Methods: At August 2014 data cut-off, 140 pts receiving oral ceritinib 750 mg daily had enrolled worldwide. Whole body (WB) and intracranial (I) responses were assessed by investigator; Lung Cancer Symptom Scale (LCSS) and EORTC (QLQ-C30) surveys assessed patient reported outcomes. Results: Of 140 pts: median age (range) 51 (29–80) years; 50.0% male; 60.0% Caucasian; 37.9% Asian; 71.4% with BM, of which 28.0% had no prior brain radiation (BRT). Median duration of exposure and follow-up time were 8.8 (0.1–19.4) and 11.3 (0.1–18.9) mos, respectively. At baseline, 20 pts had investigator-assessed measurable brain lesions (MBL); IDCR was 80.0% (95% CI: 56.3, 94.3); in 5 of 6 pts with MBL and no prior brain radiation, brain responses (2 CR, 3 PR) matched or exceeded WB response. Most common AEs (mostly Grade 1/2) were nausea (81.4%), diarrhea (80.0%), vomiting (62.9%). Eleven (7.9%) pts discontinued due to AEs, with no one AE predominating. LCSS showed improvement in symptom burden (-1.4 to -6.2). Global quality of life score (QLQ-C30) was maintained on treatment, with no substantial change from baseline (-1.5 to +4.6). Conclusions: Ceritinib provided durable responses and safety outcomes in CRZ-pretreated patients with or without BM consistent with those seen in ASCEND-1. Clinical trial information: NCT01685060.Investigator-assessed efficacy outcomes. BM N=100 No BM N=40 All N=140 WB ORR (CR+PR), n (%) [95% CI] 33 (33.0) [23.9, 43.1] 21 (52.5) [36.1, 68.5] 54 (38.6) [30.5, 47.2] WB DCR (CR+PR+SD), n (%) [95% CI] 74 (74.0) [64.3, 82.3] 34 (85.0) [70.2, 94.3] 108 (77.1) [69.3, 83.8] Median Duration of Response, Mos [95% CI] 9.2 [5.5, 11.1] 10.3 [7.4, 16.6] 9.7 [7.1, 11.1] Median Progression Free Survival (PFS) Mos [95% CI] 5.4 [4.7,7.2] 11.3 [5.7,15.6] 5.7 [5.4, 7.6]
Palliative Care Version 1.2016
Authors: Michael Levy, Thomas Smith, Amy Alvarez-Perez, Anthony Back, Justin N. Baker, Anna C. Beck, Susan Block, Shalini Dalal, Maria Dans, Thomas R. Fitch, Jennifer Kapo, Jean S. Kutner, Elizabeth Kvale, Sumathi Misra, William Mitchell, Diane G. Portman, Todd M. Sauer, David Spiegel, Linda Sutton, Eytan Szmuilowicz, Robert M. Taylor, Jennifer Temel, Roma Tickoo, Susan G. Urba, Elizabeth Weinstein, Finly Zachariah, Mary Anne Bergman, Jillian L. Scavone
Journal: Journal of the National Comprehensive Cancer Network (2016)

The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. The NCCN Guidelines are intended to provide guidance to the primary oncology team on the integration of palliative care into oncology. The NCCN Palliative Care Panel's recommendations seek to ensure that each patient experiences the best quality of life possible throughout the illness trajectory. Accordingly, the NCCN Guidelines outline best practices for screening, assessment, palliative care interventions, reassessment, and after-death care.