tbuckley/cabot-search huggingface dataset:
Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non–Small Cell Lung Cancers
Authors: Dhruba Deb, Satwik Rajaram, Jill E. Larsen, Patrick D. Dospoy, Rossella Marullo, Long Shan Li, Kimberley Avila, Fengtian Xue, Leandro Cerchietti, John D. Minna, Steven J. Altschuler, Lani F. Wu
Journal: Cancer Research (2017)

Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC-oncogenic alterations commonly found in non-small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070-81. ©2017 AACR.
L-asparaginase loaded red blood cells (RBC) in pancreatic cancer: A phase I clinical study.
Authors: Yann Godfrin, David Liens, Thierry Andre, Antoine Adenis, Florence Joly
Journal: Journal of Clinical Oncology (2012)

e14650 Background: L-asparaginase (L-asp) efficacy is based on sensitivity of tumoral cells to asparagine deprivation due to a lack of asparagine synthethase (ASNS). However its use is hampered by significant toxicities of which allergic reaction, coagulation disorders and pancreatic impairment take a prominent place. Deficiency in ASNS and therefore potential sensitivity to L-asp treatment has been reported in multiple tumor cell lines including pancreatic cancer, however tentative to use L-asp in solid tumor, and especially in pancreatic cancer is reported in the literature but all attempts so far have failed due to toxicity. Recently, a new formulation of L-asp loaded inside RBC (GRASPA) has shown a very promising safety profile in leukemic patients. Methods: GRASPANC is the first phase I clinical study with GRASPA in patients with pancreatic carcinoma. Primary objective was to find the Dose Limiting Toxicity (DLT) of this cell-based formulation in this setting. Secondary objectives were to assess overall safety profile and activity (defined as serum asparagine depletion) of GRASPA. Patients with non resectable, relapsed pancreatic cancer were included by cohort of 3 and treated with one injection of increasing dose (25, 50, 100 or 150 IU/kg) of GRASPA. An independent Safety Monitoring Board assessed toxicities at the end of follow-up of each cohort to decide for next dose. Results: Twelve patients were included between Dec 2009 and Feb 2011 by 3 centres in France. Mean age was 60.4 years (min: 42.6; max: 71.9) with 9 Male and 3 female. No limiting toxicity has been found up to the GRASPA highest dose (150 IU/kg) planned in the study and the DLT was not reached. No specific other unexpected non limiting toxicity was evidenced. In addition, at all doses GRASPA was shown to be effective at depleting serum asparagine with a trend toward longer activity with increasing dose. Conclusions: Preliminary conclusion is that the dose of 150 IU/kg of GRASPA is safe and appears suitable for further clinical development in patients with pancreatic carcinoma. In order to maximise potential efficacy of this new therapy, selection of patients should be made according to their screening for a none or low expression of ASNS in their tumour cells.
Association between human papillomavirus (HPV) status with serum cytokine and angiogenic factor (CAF) profile after induction chemotherapy in head and neck squamous cell carcinoma (HNSCC)
Authors: L. A. Byers, J. V. Heymach, J. J. Lee, H. Lin, A. K. El-Naggar, V. Papadimitrakopoulou, S. M. Lippman, W. K. Hong, F. C. Holsinger, M. S. Kies
Journal: Journal of Clinical Oncology (2009)

6081 Background: Human papillomavirus has been implicated in the development of head and neck squamous cell carcinoma and is associated with a more favorable clinical outcome. Previously, we identified a serum hypoxia signature associated with HNSCC progression (Byers et al, Proc ASCO. 2008). We investigated the association between HPV status, serum biomarkers, and clinical outcome in patients treated with induction chemotherapy. Methods: 47 previously untreated patients with locally advanced nodal disease (T0–4, N2b/c/3, M0) received 6 weekly cycles of paclitaxel (135 mg/m2), carboplatin (AUC 2), and cetuximab (400 mg/m2 week 1; 250 mg/m2 weeks 2–6) followed by definitive local therapy. 46 (98%) patients had a complete or partial response to induction chemotherapy (Kies et al, Proc ASCO. 2006), and 6 have had tumor progression (PD) after a minimum follow-up of two years. Formalin fixed biopsies were available for HPV testing by in situ hybridization with non-radioisotopic chromogen for 25 patients (including 5/6 with PD). 38 CAFs were measured by multiplex bead assay before and during treatment. Results: 12/25 patients were HPV-positive, all male and six were never smokers; of the 13 HPV-negative patients, four were male and three were never smokers. Among those with available data, all 5 patients with PD were HPV-negative (p = 0.02). There were four study deaths, all in the HPV-negative group. Overall survival was superior in HPV-positive patients (p = 0.04). There was no significant association between HPV status and serum CAF markers. However, among HPV-negative patients, PD was associated with the CAF hypoxia signature (5/8 patients with the hypoxia signature progressed versus 0/5 signature-negative). Of the individual CAFs, osteopontin was significantly elevated in all HPV-negative patients with PD. Conclusions: HPV positivity was associated with a longer progression-free survival and overall survival. Among HPV-negative patients, only those with a serum hypoxia signature had disease progression. These data suggest that the combination of HPV status and CAF profiling may identify patients at risk for relapse after sequential therapy. No significant financial relationships to disclose.
Patient-reported symptom burdens in NSCLC patients undergoing proton, 3DCRT, or IMRT.
Authors: Xin Shelley Wang, Zhongxing X. Liao, Ritsuko Komaki, James D. Cox, Daniel Richard Gomez, Raza H Bokhari, Mary L Sailors, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2013)

7574 Background: Concurrent chemoradiation (CXRT) for stage III non-small-cell lung cancer (NSCLC) patients is associated with the development of systemic self-reported symptom burden as well as radiation esophagitis (RE). This longitudinal study aims to provide a profile of the symptom burden among 3 radiation techniques concurrently used with chemotherapy: 3-dimensional conformal radiation therapy (3DCRT), intensity- modulated radiation therapy (IMRT) and proton beam therapy (PBT). Methods: NSCLC patients (N=164) treated at MD Anderson Cancer Center rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) weekly from pre-therapy up to 20 weeks post-therapy. Descriptive analysis identified major symptom burden, and mixed effect modeling examined change over time in symptom outcomes among the 3 types of CXRT. Results: Average total radiation dose was higher (p=.0003) for PBT (N=30, 71.6 Gy) and IMRT (N=67, 66.3 Gy) than for 3DCRT (N=24, 62.1 Gy). Over time, all patients reported a cluster of symptoms that increased as the dose accumulated, including fatigue, drowsiness, pain, difficulty swallowing, poor appetite and sore throat; symptoms generally peaked at week 7-9 and returned to pre-therapy levels at week 13. The IMRT group had significant less-severe sore throat (p=.03), while there were no significant differences in symptom severity among the 3 types of CXRT for the other major symptoms before, during and after CXRT. However, there was a trend of more patients reporting moderate to severe sickness symptoms as a component score (fatigue, pain, sore throat, poor appetite and drowsiness) in the 3DCRT group than in the IMRT or PBT groups at end of CXRT (50% vs. 44%, 31%) and at 13 weeks (53% vs. 23%, 25%). Also, there was a trend of more patients under 3DCRT than IMRT or PBT had moderate to severe sore throat (RE symptom) by end of CXRT (60% vs. 44%, 46%) and no different by 13 weeks (27% vs. 25%, 31%). Conclusions: Although clinical studies have reported the toxicities of CXRT, this is the first longitudinal study that compared symptom profiles for NSCLC patients receiving PBT, IMRT and 3DCRT. There is an impression of more severe treatment-related symptoms for 3DCRT (although in lower radiation dose) than IMRT or PBT.
Significance of systematic pelvic and para-aortic lymphadenectomy in epithelial ovarian carcinoma (EOC)
Authors: Y. Shimizu, K. Katase, Y. Kobayashi, K. Shimizu, S. Umezawa, K. Utsugi, T. Kato, K. Hasumi, S. Sakurai
Journal: Journal of Clinical Oncology (2004)

5009 Background: To assess the significance of systematic pelvic and paraaortic lymphadenectomy (SLA) up to the upper level of renal vein in EOC. Methods: Between 1/89 and 12/98, 359 consecutive patients (pts) with apparent stage I to IIIC EOC received SLA at the initial surgical attempt in addition to hysterectomy, bilateral adnectomy, omentectomy with or without more extensive surgery including intestinal resections. Six cycles of platinum-based regimens (CAP/TP) were given in pts with stage IC to IIIC EOC and at least 3 cycles of the platinum-based regimens were administered in pts with stage IB or grade 2 or 3 stage IA EOC. Survival distributions were estimated using the Kaplan-Meier method. Results: Significant complications associated with SLA were observed in less than 10% of pts. Lymph node (LN) involvement was observed in 17% (25/148) in pT1, 42% (14/33) in pT2, and 55% (97/178) in pT3 EOC. Five-year survival of pts by pT category was 98% for pT1N0M0 vs 74% for pT1N1M0 (p=0.0000), 79% for pT2N0M0 vs 75% for pT2N1M0 (p=0.897), and 36% for pT3N0M0 vs 31% for pT3N1M0 (p=0.816), respectively. Thus, LN involvement worked as a significant prognostic factor in apparent stage I (pT1) EOC, but it did not function in stage II or III EOC. Five-year survival was 92% for 148 pts with apparent stage I (pT1) EOC receiving SLA and 81% for 69 pts with pT1 without SLA but receiving the same platinum-based regimens who were treated before 1989 (p=0.0064). Pts with pT1N1M0 EOC, who were upstaged to stage IIIC according to the FIGO staging system, had a significantly better 5-year survival (74%) than those with pT3NanyM0 (32%) EOC. Conclusions: SLA is valid in apparent stage I EOC to find pts with worse prognosis, but it may be unnecessary at the initial surgical attempt for apparent stage II or III EOC pts in terms of both diagnosis and treatment. Regarding the FIGO staging system, retroperitoneal stage IIIC (pT1N1M0) should be separately defined from abdominal stage IIIC (pT3NanyM0) EOC which brings worse prognosis. No significant financial relationships to disclose.
A validation study of graded prognostic assessment index for lung cancer patients with brain metastases.
Authors: Lingling Du, Vyshak Alva Venur, Saurabh Dahiya, Rohan Garje, Kwabena Osei-Boateng, Paul Elson, John H. Suh, Samuel T. Chao, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2013)

2070 Background: The Graded Prognostic Assessment (GPA) is a commonly used index based on 5 prior randomized trials performed by the RTOG (Protocols 7916, 8528, 8905, 9104, and 9508). The purpose of this study was to validate GPA index in a recent cohort of lung cancer patients with brain metastases (LBM) at a larger tertiary care center. Methods: Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database was used to identify LBM treated in the recent era (2000-12). A proportional hazards model was used to assess overall survival (OS), measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 490 LBM (250 males) median age 61 years (range 35-86) were included. Histology included small cell (64, 13%) adenocarcinoma (289, 59%), squamous (53, 11%), large cell (26, 5%) and unknown (55, 11%). The median number of brain metastases was 1 (range, 1-47). Karnofsky Performance Scale (KPS) was 90-100 in 187 (41%), 70-80 in 238 (52%) and &lt;70 in 33 (7%). Extracranial Metastases was present in 327 patients (67%). OS was 14.1 months (95% C.I. 12.3-15.7). GPA for lung cancer is derived from KPS, the number of brain mets, the presence/absence of extracranial metastases, and age. GPA was 0-1.0 in 83 patients, 1.5-2 in 211, 2.5-3 in 135 and 3.5-4 in 18 patients. Although overall GPA was prognostic for survival (p&lt;.0001), not all of the factors used to derive it were significant (Table). Factors noted to be prognostic for survival included primary controlled (p=&lt;.0001), squamous cell histology (p=.0001), age (p=.0002), KPS (p=.0002). The new index divided the patients into unfavorable, intermediate, favorable that was prognostic for survival in this cohort (p&lt;.0001). Conclusions: New index developed based on a revised set of independent prognostic factors (primary controlled, squamous cell histology, age and performance status) is proposed. [Table: see text]
One evidence base; three stories: do opioids relieve chronic breathlessness?
Authors: Magnus Ekström, Sabrina Bajwah, J Martin Bland, David C Currow, Jamilla Hussain, Miriam J Johnson
Journal: Thorax (2017)

The efficacy of low-dose systemic opioids for chronic breathlessness was questioned by the recent Cochrane review by Barnes et al . We examined the reasons for this conflicting finding and re-evaluated the efficacy of systemic opioids. Compared with previous meta-analyses, Barnes et al reported a smaller effect and lower precision, but did not account for matched data of crossover trials (11/12 included trials) and added a risk-of-bias criterion (sample size). When re-analysed to account for crossover data, opioids decreased breathlessness (standardised mean differences −0.32; −0.18 to −0.47; I 2 =44.8%) representing a clinically meaningful reduction of 0.8 points (0–10 numerical rating scale), consistent across meta-analyses.
Clinical value of FDG PET/CT in predicting local failure in patients with esophageal cancer.
Authors: Bingjie Fan, Man Hu, Li Kong, Xiaoli Zhang, Zheng Fu, Jinming Yu
Journal: Journal of Clinical Oncology (2013)

e15197 Background: Local failure, including local residual tumor and local recurrence, is the most common failure patterns for patients with esophageal cancer (EC) treated with radiotherapy. The purpose of this study was to evaluate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for predicting local failure in patients with EC. Methods: Twenty-two patients with biopsy-proven EC treated definitively with RT with or without chemotherapy were enrolled from June 2010 to August 2012. Dose of 60.4 - 70.2 Gy with 1.8 - 2.0Gy /fraction were delivered with three-dimensional conformal radiation therapy (CRT). All patients underwent FDG PET/CT scan prior to therapy. The patients were followed up every 3 months after treatment completion. Patients who developed local failure were confirmed with histological evidence or follow-up. Results: The follow up time was in the range of 5-30 months. Of 22 patients, 3 patients had local residual tumor, 2 patients experienced local recurrence. The mean SUVmax for patients with local failure was higher than that for patients without local failure (15.688±3.115 vs. 14.137± 4.397, p = 0.54). The local failure regions were mostly the regions with higher metabolic activity before radiotherapy. Conclusions: Patients with higher FDG-uptake may have higher risk to experienced local failure. The local failure regions were localized mostly in the higher FDG uptake regions of pre-therapeutically FGD PET/CT scans of the patients with EC.
Prognostic factors in patients enrolled in clinical trials of second-line chemotherapy for advanced non-small cell lung cancer (aNSCLC): A pooled analysis of 11 randomized trials
Authors: M. Di Maio, C. Camps, E. F. Smit, W. Schuette, V. Georgoulias, K. Takeda, E. Quoix, F. M. Wachters, V. Gebbia, C. Gridelli
Journal: Journal of Clinical Oncology (2009)

8082 Background: Prognostic factors for newly diagnosed aNSCLC have been extensively studied, but less information is available on factors associated with outcome of 2nd-line treatment. Better knowledge of prognostic factors could be helpful to better select patients for further chemotherapy after failure of 1st-line treatment. Methods: The analysis is based on individual patient data collected for 2 meta-analyses on 2nd-line treatment of aNSCLC, one comparing weekly vs every 3 week docetaxel (Di Maio, J Clin Oncol 2007; 25:1377), and one comparing single-agent vs doublet chemotherapy (Di Maio, J Clin Oncol in press). Primary endpoint was overall survival (OS). All analyses were stratified by trial. Results: Out of 11 trials, 2 trials were excluded due to missing information on baseline characteristics considered in multivariate analysis. Of the other 9 trials (1239 pts), 1197 pts (97%) had complete information: 78%/22% males / females, 83%/17% younger / older than 70, 28%/59%/13% Performance Status (PS) 0 / 1 / 2, 18%/82% stage IIIB / IV, 32%/47%/21% squamous / adenocarcinoma / other histology. 84% were pretreated with platin and 44% had obtained objective response (OR) to 1 st line treatment. With 956 deaths, median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males vs females, Hazard Ratio [HR] 1.23 [95%CI 1.04–1.45], p=0.01), by PS (worse in PS1 vs PS0, HR 1.36 [1.16–1.59], p=0.0001 and in PS2 vs PS0, HR 3.01 [2.41–3.76], p&lt;0.00001), by tumor histology (better in adenocarcinoma vs squamous, HR 0.85 [0.73–0.99], p=0.04 and worse in other histology vs squamous, HR 1.27 [1.05–1.52], p=0.01), by stage (worse in stage IV vs IIIB, HR 1.28 [1.07–1.53], p=0.007), by type of previous treatment (worse for pts pretreated with platin vs pts not pretreated with platin, HR 1.49 [1.14–1.93], p=0.003), and worse for pts not obtaining OR vs pts obtaining OR during 1 st line (HR 1.25 [1.10–1.44], p=0.001). Conclusions: In addition to patient-related (gender, PS) or tumor-related factors (histology, stage), prognosis of pts eligible for 2 nd line treatment of aNSCLC is significantly conditioned by previous use of platin and response to 1 st line treatment. No significant financial relationships to disclose.
A phase II trial of weekly paclitaxel (P) and gefitinib (G) in patients (pts) with gefitinib-refractory or -resistant non-small cell lung cancer (NSCLC)
Authors: K. Kasahara, T. Sone, H. Kimura, A. Yoshimoto, T. Araya, K.-I. Iwasa, H. Shirasaki, H. Shintani, M. Fujimura, S. Nakao
Journal: Journal of Clinical Oncology (2004)

7091 Background: Gefitinib (G) is an EGFR-TK inhibitors and G and paclitaxel (P) have synergistic antitumor effect in G-resistant non-small cell lung cancer cell lines in vitro. The purpose of this phase II trial was to evaluate the activity and the toxicity in pts with G-refractory or G-resistant NSCLC of co-administration of G and weekly P. Methods: Eligibilities were histologically or cytologically proven NSCLC resistant or refractory to G and cytotoxic chemotherapy, measurable lesion, ECOG PS0–2, adequate organ functions, life expectancy longer than 12 weeks and written informed consent. G (250 mg/day) was orally administered daily and P (60 mg/m2)was administered intravenously on day 1, 8, 15. This combination treatment was repeated every 4weeks. Primary endpoint was response rate and secondary endpoints were toxicities, time to progression (TTP), and overall survival (OS). Results:From October 2002 to November 2003, 20 pts were enrolled and eligible for activity and toxicities: males/females 13/7; median age 64 (range 41–77); PS 0/1/2 4/12/4; stage IIIB/IV 4/16; adeno/squamous/large/not specified 12/5/2/1. Median prior chemotherapy regimen was 2 (range 1–6) and 18 pts were received platinum agents and 16 pts were received taxan. A total of 55 cycles (median 2/pt, range 1–8) were given. 6(30%) had partial response and 6(30%) had stable disease. At this writing, median TTP is 97 days and median OS is 157 days, and 11 pts (55%) are still alive. Grade 3/4 toxicities were neutropenia in 10% of pts, leukopenia in 10%, and anemia in 20%. Grade 3 pulmonary toxicity was observed in 2 pts (10%). There was no treatment-related death. Conclusions: This G and weekly P combination treatment shows an moderate activity in pts with G-refractory or -resistant NSCLC. Phase I trial is warranted for chemotherapy-naïve NSCLC. No significant financial relationships to disclose.
Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis
Authors: Guo-hua Zhao, Xiao-min Liu
Journal: Translational Neurodegeneration (2017)

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.Most HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.