tbuckley/cabot-search huggingface dataset:
Skin-directed electrochemotherapy: A prospective multi-institutional study on 394 patients with superficial tumors.
Authors: Luca Giovanni Campana, Pietro Quaglino, Antonio Bonadies, Pietro Curatolo, Alessandro Testori, Massimo Framarini, Ermenegildo Cubicciotti, Gianni Gerlini, Paolo Antonio Ascierto, Michele Guida, Roberta Rotunno, Federica Marenco, Angela De Paoli, Gian Luca De Salvo, Carlo Riccardo Rossi
Journal: Journal of Clinical Oncology (2015)

e20001 Background: Despite the availability of several skin-directed therapies, cutaneous metastases afflict 1-10% of cancer patients and 45% of those with metastatic melanoma. The basic principle of electrochemotherapy (ECT) relies in administering a poorly permeant cytotoxic agent together with local electric pulses that permeabilize the cell membrane and propel drug molecules into tumors. The goal of this study was to confirm the activity and safety of ECT in a large series; moreover, we evaluated local control, the feasibility of the European Standard Operating Procedures of ECT (ESOPE) and patient quality of life (QoL). Methods: Aprospective, non-randomized, multi-institutional study enrolling patients with unresectable superficial tumors of any histotype who underwent ECT at 10 Italian centers between 2009 and 2013. Treatment outcome included: tumor response, local progression-free survival (LPFS), toxicity (CTC 3.0) and QoL (EORTC QLQ-C30 plus a dedicated questionnaire). Results: A total of 394 patients were enrolled (median age 71 years, 77% with a 0-1 performance status). Distribution according to histotype was as follows: melanoma 55%, squamous cell carcinoma 12%, Kaposi sarcoma 10%, breast cancer 8%, basal cell carcinoma 6%, soft tissue sarcomas 3%, other 6%. ECT was administered under local anaesthetics (14%), sedation (62%) or general anaesthesia (21%). Ninety-one percent of patient received intravenous bleomycin. One-month tumor response, assessed on 1296 target lesions (median size 1 cm, range 0.5-60) was complete in 39%, partial in 31%. Toxicity was mainly dermatological, G3 in 7% of patients. One-year LPFS was 76.5% (95% CI 68.4-78.3). Small tumor size ( < 2 cm) predicted complete response achievement (OR 2.24, 95% CI 1.32-3.80 P= .002) and longer LPFS (HR 1.47 95% CI 1.05-2.07 P= .003). Patient benefits included an improvement of Global Health Status (P< .001), local bleeding (P< .001), wound healing (P= .002) and aesthetics (P< .001). Conclusions: ECT was an effective skin-directed therapy in a real-world context. General sedation plus intravenous BLM were the most suitable treatment modality. Patient-reported outcomes were encouraging.
Next-generation sequencing in pancreatic cancer: Novel mutations and potential targets for therapy.
Authors: Andrea S. Teague, Benjamin R. Tan, Joel Picus, Albert C. Lockhart, Steven Sorscher, Rama Suresh, Steven M. Strasberg, William G. Hawkins, Ryan C. Fields, David Linehan, Andrew Bredemeyer, Catherine E Cottrell, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2014)

e15228 Background: Pancreatic adenocarcinoma (PA) has one of the worst prognoses of all malignancies prompting the search for oncogenic mutations that might be targets for therapy. Methods: We conducted a retrospective analysis of patients with PA who had next-generation sequencing (NGS). Key genes included were APC, ATM, BRAF, BRCA1, BRCA2, FLT3, NOTCH1, MET, FGFR4, MAPK1, MAP2K2, IDH1, IDH2, RET, JAK2, KRAS, NRAS, PTEN, EGFR, PIK3CA, PDGFRA, RUNX1, KIT, ALK, and TP53. Fluorescence in-situ hybridization (FISH) for EGFR gene amplification and MLL and ALK gene rearrangement was performed in a subset of patients. Variants were annotated with data incorporated from dbSNP, ClinVar and COSMIC. In-silico predictions were performed where applicable using PROVEAN (Protein Variation Effect Analyzer) and SIFT, and/or Polyphen (Polymorphism Phenotyping v2). Results: Among 45 patients with NGS, 31 patients (68.9%) had KRAS mutations and 14 patients (31.1%) were wild-type for KRAS. Of 29 patients whose tumors underwent FISH, 3 patients had EGFR gene amplification, 1 patient had both EGFR gene amplification and ALK gene rearrangement, and 1 patient was positive for the MLL gene rearrangement. There were novel mutations not previously described in the COSMIC database, and at least 8 were predicted to be deleterious or damaging. There was a novel missense variant observed in BRCA1 and several missense variants of unknown significance in BRCA2. A novel variant was found in RET, predicted by Polyphen as probably damaging and by Provean as neutral. A novel variant in PIK3CA was predicted to be deleterious by Provean/SIFT. Possible targetable alterations include mutations in NOTCH1, JAK2, ATM, FLT3, PTEN and EGFR, among others Of the 31 patients with mutant KRAS, 21 had resectable PA with known follow-up, with a median overall survival of 21.5 months (8.4-58.9). In the wild-type KRAS patients, 9 of the 14 patients had resectable PA with known follow-up, with a median overall survival of 17.3 months (6.2-91.6). Conclusions: NGS of PA confirmed common mutations and also revealed genomic alterations that may be potentially responsive to available targeted agents. The discovery of novel mutations PA warrants further investigation.
The dynamics of circulating nucleosomes following chemotherapy for breast cancer.
Authors: Sudeep Gupta, Nishitha Shetty, Indraneel Mittra, Naveen Kumar Khare, Vani Parmar, Nita S. Nair, Rajendra A. Badwe
Journal: Journal of Clinical Oncology (2014)

e22028 Background: There is sparse data on the dynamics of circulating nucleosomes following cytotoxic chemotherapy. We have studied the levels of circulating nucleosomes after first cycle of anthracycline based chemotherapy in women with breast cancer and their correlation with white blood cell (WBC) counts. Methods: This was a prospective observational single centre study which included 17 women with either locally advanced/metastatic breast cancer planned for neoadjuvant/palliative chemotherapy (LABC/MBC, N=9) or early breast cancer planned for adjuvant chemotherapy (EBC, N=8). All patients received an anthracycline chemotherapy regimen. The serum nucleosome levels were measured using Cell Death Detection ELISA plus kit (Roche) based on the quantitative sandwich-enzyme-immunoassay principle. Nucleosome levels and WBC counts were measured at baseline (immediately prior to 1st cycle of chemotherapy) and at 6 hours (H), 24 H , 48 H (3rd day), 72 H (4th day), 96 H (5th day), 144 H (7th day) and 312 H (14th day) thereafter. Time curves of the mean nucleosome level and WBC count were derived and assessed for correlation. Results: The mean baseline nucleosome level was 1.839 AU (arbitrary units). Following a small initial increase to 2.015 AU at 6 H, there was a gradual progressive decline to a mean value of 0.323 AU at 312 H (14th day). The mean WBC counts also showed a gradually declining trend over the same observation time points. On linear regression analysis there was a positive correlation between serum nucleosome levels and WBC counts (r2=0.265). Conclusions: After chemotherapy there is gradual decline in circulating nucleosome levels over an observation period of 14 days. Our results suggest that nucleosome levels are likely to be in dynamic equilibrium with circulating nucleated hematopoietic cells. Detailed results including concentration curves will be presented at the Meeting.
Contemporary Approaches to Modulating the Nitric Oxide–cGMP Pathway in Cardiovascular Disease
Authors: Jan R. Kraehling, William C. Sessa
Journal: Circulation Research (2017)

Endothelial cells lining the vessel wall control important aspects of vascular homeostasis. In particular, the production of endothelium-derived nitric oxide and activation of soluble guanylate cyclase promotes endothelial quiescence and governs vasomotor function and proportional remodeling of blood vessels. Here, we discuss novel approaches to improve endothelial nitric oxide generation and preserve its bioavailability. We also discuss therapeutic opportunities aimed at activation of soluble guanylate cyclase for multiple cardiovascular indications.
ST2 and Endothelial Injury as a Link between GVHD and Microangiopathy
Authors: Seth J Rotz, Christopher E Dandoy, Stella M Davies
Journal: New England Journal of Medicine (2017)

Some patients with high ST2 levels, a marker for endothelial injury that is seen in graft-versus-host disease (GVHD), may have a response to treatment aimed at thrombotic microangiopathy.
Neoadjuvant therapy versus upfront surgery for pancreatic adenocarcinoma: A propensity score matched analysis of short-term outcomes.
Authors: Gyulnara G. Kasumova, Susanna W.L. de Geus, Omidreza Tabatabaie, Ayotunde B. Fadayomi, Rebecca A. Miksad, Sing Chau Ng, Arthur J. Moser, Manuel M. Hidalgo, Jennifer F. Tseng
Journal: Journal of Clinical Oncology (2017)

361 Background: Neoadjuvant therapy is increasingly utilized and has demonstrated a survival advantage in borderline and locally advanced pancreatic cancer. However, many have feared that preoperative chemotherapy and radiation result in a more challenging operative field and consequently increased morbidity. Methods: ACS-NSQIP targeted pancreas database was queried for patients with adenocarcinoma who underwent PD in 2014. Propensity score matching was used to account for potential selection bias in pre-operative and intra-operative characteristics. Sensitivity analysis assessed the impact of neoadjuvant radiation. Results: 1,313 patients were identified, of whom 338 (25.7%) received neoadjuvant therapy. Patients who received neoadjuvant therapy vs upfront surgery were more likely to be: female (53.6% vs 47.2%; p=0.04), &lt; 65 years of age (53.0% vs 39.2%; p &lt; 0.0001), have BMI &lt;25.0 (43.5% vs 36.6%; p = 0.03), and require vascular resection (37.6% vs 19.6%; p &lt; 0.0001). Patients receiving neoadjuvant therapy were less likely to develop pancreatic fistulae (9.2% vs 14.0%; p = 0.02), more likely to require transfusion (27.8% vs 22.4%; p = 0.04), and had longer operative time (median: 405 vs 371 mins; p &lt; 0.0001). After matching, there were no differences in baseline characteristics, approach, biliary stenting, and vascular resection. The only significant difference in outcomes between the two groups was longer operative time (median 405 vs 377, p = 0.006; Table). These results were robust on sensitivity analysis for use of radiation. Conclusions: Neoadjuvant therapy is safe and, despite prolonging operative time, does not affect 30-day outcomes. Concern for increased morbidity should no longer preclude treatment with neoadjuvant chemotherapy and/or radiation in borderline, locally advanced, and resectable pancreatic tumors. [Table: see text]
Safety and efficacy of eribulin mesylate (EM) in patients with advanced breast cancer: The Royal Marsden experience.
Authors: Eirini Thanopoulou, Claudia Omarini, Belinda Yeo, Mark Allen, Marina Parton, Nicholas C. Turner, Mary E.R. O'Brien, Stephen R. D. Johnston, Ian E. Smith
Journal: Journal of Clinical Oncology (2014)

e12004 Background: Eribulin mesylate (EM) is a non-taxane, microtubule dynamic inhibitor that has been approved for the treatment of patients with metastatic breast cancer (MBC) after the pivotal phase III trial (EMBRACE study). Our aim was to audit the real life experience of treating MBC with EM. Methods: All patients (pts) receiving EM at the Breast Unit, Royal Marsden NHS Foundation Trust were treated according to the approved indication for their MBC and prospectively registered in a database (Nov 2011 –Dec 2013). All pts registered at the time of analysis were evaluated for safety and efficacy. Treatment toxicities were graded according to CTCAE v4.0. Efficacy was assessed using routinely performed imaging. Results: To date, 108 pts have been treated with EM. All were heavily pretreated with a median of 3 (range 1-7) previous chemotherapy lines for MBC. The median age of the pts was 54 years (range 33-80). With regards to receptor status, 68% of pts were ER positive (+ve), 17% were Her2 (+ve), 23% were triple negative and 9% ER negative, Her2 (+ve). 56 pts are alive and 18 are still undergoing treatment with EM. Fatigue was the most common side effect observed in 65% of the pts (grade 3 7%), followed by neutropenia in 45% of pts (grade 3-4 32%), alopecia in 35% and neurotoxicity in 28% (grade 3 2%). No toxic deaths were observed. The median number of Eribulin cycles was 5 (range 1-14), with 62% of pts receiving more than 5 cycles. All pts were assessed for efficacy with 27% of them exhibiting ORR (CR+PR), 39% SD and 34% PD as best response. The clinical benefit rate (CR+PR+SD>6months) was 34%. The median PFS was 4.2 months (95% CI: 3.5 – 4.8) and the median OS was 10.4 months (95% CI: 8.1 – 12.7). Conclusions: EM administered outside the context of a clinical trial was safe, well tolerated, and with significant efficacy in this heavily pretreated population. Our results were consistent with those published in the EMBRACE study.
Outcomes of rural patients with metastatic colorectal cancer treated in a centralized system compared with their metropolitan counterparts.
Authors: Timothy Jay Price, Vy Broadbridge, Carol Beeke, Robert Padbury, Guy Maddern, David Roder, Christos Stelios Karapetis
Journal: Journal of Clinical Oncology (2013)

6598 Background: Significant geographical variation in survival after diagnosis of colorectal cancer (CRC) has been reported in Australia. Patients residing in rural locations have inferior survival time compared to metropolitan patients. Factors which have an impact on survival include local access to services (investigations, surgery and chemotherapy). Rural patients tend to present with more advanced disease. We analysed data from South Australia (SA) where cancer care has tended to be centralised to determine if rural patients in this setting have inferior outcomes to metropolitan patients. We examined survival of patients with stage 4 CRC. Methods: An analysis of the SA mCRC registry was performed to compare the oncological and surgical management and survival of city (metropolitan postcode) v rural (rest of state) patients. Overall Survival (OS) was calculated using the Kaplan-meier method. Results: Data from 2289 patient with mCRC since February 2006 were analysed. 27% of patients were rural. Patient characteristics did not differ between the 2 groups. There was no difference in chemotherapy use; City v rural, 1 st , 2 nd and 3 rd line respectively-56%v58%, 23%v23%, 10%v9%. Choice of chemotherapy did not differ between city and rural; FU/Oxaliplatin 61%v60%, irinotecan+/-FU 9%v6%, FU alone 28%v31%. When an oxaliplatin doublet was chosen, oral capecitabine was used more frequently 32% in rural v 13% in city (P&lt;0.001) Addition of bevacizumab/anti-EGFR to first line chemotherapy was equivalent: 19.7% v 14.3%/1.6% v 1.4%. Hepatic resection was also similar in 2 groups 14%v12%. Median OS did not differ; 23.4 months city v 23.5 months rural. These outcomes were similar for men and women. Conclusions: The patient characteristics, choice of chemotherapy (drug and single v doublet), hepatic resection rates and importantly, overall survival did not differ between city v rural patients. Oral chemotherapy used was higher in rural patients without affecting outcome.
Does the timing of adjuvant chemotherapy for gastric cancer influence patient outcome?
Authors: Mi Sun Ahn, Seok Yun Kang, Hyun Woo Lee, Jin-Hyuk Choi, Sang Uk Han, Yong Kwan Cho
Journal: Journal of Clinical Oncology (2014)

e15056 Background: Although adjuvant chemotherapy is currently established as standard treatment in stage II/III gastric cancer, there is no report about the optimal timing of the initiation of chemotherapy. We investigated the effect of the interval between surgery and the start of chemotherapy on patient outcome. Methods: A retrospective review was conducted of 410 patients who underwent 5-fluorouracil/mitomycin-C/polysaccharide-K adjuvant chemotherapy for stage IIA-IIIC gastric cancer after curative resection. Overall survival (OS) was compared among patients grouped by time from surgery to start of adjuvant chemotherapy. Results: The median time from surgery to chemotherapy was 21 days (7-80 days). Seventy-seven patients (18.8%) began adjuvant chemotherapy ≥28 days after surgery. The median follow-up duration was 150 months (97-195 months) for the survivors. There was no significant difference in 10-year OS between the patients who started chemotherapy <21 days after surgery and those who initiated it later (57.3% vs. 51.4%; p=0.409). However, commencing chemotherapy ≥28 days after surgery was associated with inferior 10-year OS compared with earlier initiation (38.8% vs. 57.5%; p=0.003), with a significant correlation in stage III (p<0.0001) but not in stage II (p=0.326). Furthermore, initiation of adjuvant chemotherapy ≥28 days after surgery was an independent prognostic factor of poor OS (p=0.008), along with old age, large tumor size, Borrmann type IV, and advanced stages. Conclusions: It does not seem to be necessary to initiate adjuvant chemotherapy too early after gastric cancer surgery. However, it is desirable to start treatment within 4 weeks after surgery if patients have fully recovered, especially in those with stage III.
The landscape for genetic eligibility to basket clinical trials.
Authors: Todd Cory Knepper, Christine Marie Walko, Gillian Casey Bell, Eric Padron, Jamie K. Teer, Howard L. McLeod
Journal: Journal of Clinical Oncology (2015)

1530 Background: There is a movement toward basket trials, where eligibility is based on molecular aberrations rather than anatomical origin of a cancer. There is a paucity of information on how many cancer patients (pts) meet eligibility for basket trials. This study assessed the genetic eligibility of cancer pts seen at a large cancer center for the currently open basket trials. Methods: Moffitt’s Clinical Genomic Action Committee (CGAC) database was used to assess 236 pts across 30 cancer types with targeted deep sequencing as part of clinical care between 1/1/2013 and 12/31/2014. Pts were screened for basic histologic and genetic eligibility on all basket trials open in North America in January, 2015 (Novartis Signature, NCI-MATCH, NCI-M-PACT). The trials included 23 different arms utilizing different agents based on 44 different molecular alterations; 11 of these alterations allowed eligibility into multiple trials. Results: Among the 236 evaluable pts, 83.5% met genetic eligibility for at least 1 of the arms examined with an average of 2.89 eligible arms per patient and a range of 0 to 15. The percentage of histologically eligible pts meeting genetic eligibility ranged from 0% (non-melanoma or colorectal BRAF V600 mutated solid or hematologic malignancy) to 50.0% (PARP1/2 or TP53 mutated solid tumor) across all treatment arms. Of 188 pts with solid malignancies, 93.6% met genetic eligibility for at least 1 of the trials vs. 45.8% of 48 pts with hematologic malignancies. Conclusions: The vast majority of pts within a clinical genetic database who received somatic tumor sequencing met genetic eligibility for at least one aberration-specific clinical trial; however 16.5% of pts overall and the majority of those with hematologic malignancies remained without basket trial options. These results highlight opportunities for enrollment in clinical trials given access to both tumor sequencing and next-generation clinical trials. All Pts (n = 236) Solid Malignancies (n = 188) Heme Malignancies (n=48) Any Trial 197 (83.5%) 176 (93.6%) 22 (43.8%) SIGNATURE 160 (67.8%) 139 (73.9%) 22 (43.8%) NCI-MATCH 22 (41.9%) 97 (51.6%) Only lymphomas eligible (n = 6) 2 (33.3%) NCI-M-PACT 156 (66.1%) 156 (83.0%) n/a
Tolerance and feasibility of chemotherapy by procarbazine, lomustine, and vincristine (PCV) for oligodendroglial anaplastic gliomas (OAG).
Authors: Marine Daros, Emeline Tabouret, Maryline Barrie, Mona Matta, Didier Autran, Celine Boucard, Marie Wertz, Dominique Figarella, Stéphane Honoré, Oliver L. Chinot
Journal: Journal of Clinical Oncology (2012)

2060 Background: Chemosensitivity of OAG has been documented although their role as part of adjuvant treatment combined to radiotherapy is debated. Beside temozolomide still under investigation, several studies have underlined activity of PCV regimen in this setting. However, significant toxicity has been described and dose intensity and schedule duration are not clearly reported. Methods: This monocentric retrospective analysis included all pts with OAG treated with at least 1 cycle of PVC (lomustine 110mg/m2 every 6 weeks) at our institution from August 2007 to August 2011 (pharmacy charter). Toxicities data were collected from clinical observations and blood investigations. Results: 40 pts were identified (M/F: 23/17). Median age was 45y (20 – 72). At the time of analyses, 32 pts were still alive. Histologies were oligodendroglioma (73%) or oligoastrocytoma (27%). Codeletion 1p19q was observed in 30 % of pts. PCV was administered in first or second line of chemotherapy for 60 % and 40 % of pts respectively. Seventy five percent and 52.5% of pts completed at least of 4 and 6 cycles respectively. Discontinuation of PCV occurred in 45% of pts for toxicity (10%), progression (30%), or other reason (5%). Because of toxicity 38/196 (19%) PCV cycles were delayed. Dose was adapted for 73% of pts and decreased under 60% of theoretical dose in 30% of pts at cycle 4 and in 57% of pts at cycle 6 (table1). Grade III or IV toxicity occurred in 28% of pts and only grade I-II in 50%. Neuropathies occurred in 43 % of pts. Conclusions: Despite activity of PCV regimen, significant toxicity is associated to this schedule, that impact feasibility and compliance. PVC schedule should be redefined taking into account dose intensity applied in toxicity observed. [Table: see text]
Signaling pathway differences between EGFR TKI-sensitive and -resistant non-small cell lung cancer cells.
Authors: Shi-Jiang Fei, Xu-Chao Zhang, Song Dong, Hua Cheng, Yi-Fang Zhang, Zhihong Chen, Zhi Xie, Yi Long Wu
Journal: Journal of Clinical Oncology (2012)

e13510 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have showed dramatic clinical benefits in advanced non-small cell lung cancer (NSCLC), but the biggest problem is resistance. How to overcome resistance is still a serious problem to clinical practice. The aims of this studies was to analyse the signaling pathway differences between the EGFR TKI-sensitive and resistant NSCLC cell lines and to seek potential molecular targets for tumor treatment after resistance. Methods: We selected four types of NSCLC cell lines: PC-9(exon19 del), PC9GR (gefitinib-acquired resistant cell), H1650(exon19 del), H1975 (L858R+T790M), signaling pathway differences between PI3K/Akt/mTOR,MAPK and STAT3 were analysed through western blot, immunoprecipitation and confocal microscope. Results: Activation status of EGFR super signaling pathways: PI3K-Akt, Erk and STAT3 between EGFR TKI- sensitive and resistant NSCLC cells was different under basic state. The phosphorylation levels of Akt ser473, FOXO1 and Erk in EGFR TKI-resistant cells, especially in H1650 cell, were more higher than that in PC9 cell except for p-STAT3. p-STAT3 expression in PC9 was higher than that in resistant NSCLC cells. The further analysis showed that cellular localizations of p-STAT3 between sensitive and resistant cells were different through confocal microscope, p-STAT3 in PC9 and H1975 cells was almost in nucleus, while in PC9GR and H1650 cells was almost in cytoplasm. The assay of mTORC2 kinase activities in vitro showed that mTORC2 kinase activities in the resistant cells were obviously higher than that in sensitive cells. Conclusions: we found that EGFR TKI-sensitive and resistant NSCLC cells had different activation status of signaling pathways especially mTOR associated signaling pathways and different mTORC2 kinase activities. These results indicated that targeting mTOR with specific mTOR inhibitors would be a good strategy for NSCLC treatment after EGFR TKI resistance.