tbuckley/cabot-search huggingface dataset:
Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC).
Authors: Paul Joseph Hesketh, Giorgia Rossi, Giada Rizzi, Marco Palmas, Anna Alyasova, Igor Drobner, Richard J. Gralla
Journal: Journal of Clinical Oncology (2013)

9512 Background: Further progress in preventing CINV will require the introduction of novel agents providing maximal convenience and with efficacy for nausea as well as vomiting. NEPA is a single dose combination of NETU, a novel NK 1 receptor antagonist (RA) and PALO, a pharmacologically distinct 5-HT 3 RA. This study was designed to determine the proper dose of NETU to combine with PALO. Methods: This was a randomized, double-blind, parallel group study in chemotherapy-naïve patients (pts) undergoing cisplatin-based HEC. Four study arms compared 3 oral doses of NEPA (NETU 100, 200, 300mg + PALO 0.50 mg) with oral PALO 0.50 mg, all given on day 1. All pts received oral dexamethasone (DEX) days 1-4. An exploratory aprepitant (APREP) + ondansetron/DEX arm was included. The primary endpoint was complete response (CR: no emesis, no rescue) in the overall (0-120h) phase. Results: 694 pts were enrolled with comparable characteristics across groups: males (57%), median age 55. Common cancers: lung (27%), head and neck (21%). Median cisplatin dose: 75 mg/m 2 . All NEPA groups showed superior CR rates compared with PALO during the overall and delayed phases, with NEPA 300 also superior to PALO during the acute phase. NEPA 300 was also superior to PALO during all phases for no emesis, no significant nausea and complete protection with incremental benefits over lower NEPA doses. AEs were comparable across groups with no dose-response. The % of pts developing ECG changes was comparable across groups. Conclusions: Each NEPA dose resulted in superior CR rates compared with PALO. NEPA 300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints (including nausea). NEPA doses were well tolerated with similar safety profiles to PALO and APREP. NEPA combined with DEX is superior to PALO plus DEX in prevention of CINV following HEC. [Table: see text]
A national study on conditional survival and excess mortality after high dose therapy with autologous stem cell transplantation for non-Hodgkin lymphoma.
Authors: Knut BjÃ¸ro Smeland, Cecilie E Kiserud, Grete F Lauritzsen, Anne Kirsti Blystad, Unn-Merete Fagerli, Ragnhild Sorum Falk, Oystein Fluge, Alexander Fossa, Arne Kolstad, Jon Havard Loge, Martin Maisenholder, Stein Kvaløy, Harald Holte
Journal: Journal of Clinical Oncology (2015)

8598 Background: The aim of this study was to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT) for non-Hodgkin lymphoma (NHL) in a national population-based cohort, and to analyse cause of death and incidence of second malignancies. Methods: All patients ≥ 18 years treated with HDT for NHL in Norway 1987-2008 were included (n =578). Information about cause of death from Statistics Norway and second malignancies from Cancer Registry of Norway were linked with clinical data. Treatment related mortality (TRM) was defined as death from a complication to HDT in tumour free patients. Observation time was estimated from HDT to death or cut-off at June 30th 2014 (median 6.7 years, range 0-27). Data on second cancer was available until end of 2012. Results: The 10- and 15-year overall survival (OS) was 52% (95%CI 48%-56%) and 49% (95%CI 44%-53%). Conditional 5-year OS are shown in the table. SMR was 12.3 (95% CI 11.0-13.9) for the entire cohort and 4.9 (95% CI 4.1-5.9), 2.4 (95% CI 1.8-3.2) and 1.0 (95% CI 0.6-1.8) for patients having survived 2, 5 and 10 years after HDT respectively. Among 281 deaths the underlying causes were NHL (n = 216, 77% of deaths), TRM (n = 21, 7%), second cancers (n = 20, 7%), cardiovascular disease (n = 8, 3%), infections (n = 6, 2%), pulmonary disease (n = 5, 2%) and others/missing (n = 5). Second malignancy after HDT was diagnosed in 38 (6.6%) (non-melanoma skin excluded), including 15 leukaemia/myelodysplastic syndrome. Conclusions: The conditional OS improved for each additional year survived after HDT. NHL-patients undergoing HDT had 12-fold increased mortality compared to the general population, but only 2-fold conditioned on having survived 5-years. After 10 years the mortality risk was no longer elevated. TRM and second cancers are the most common non-relapse related causes of death. 5 year OS (%) conditioned on having survived 0 y 2 y 5 y All (n = 578) 61 81 97 Diffuse large cell (n = 187) 52 77 88 T-cell (n = 93) 52 88 95 Transformed (n = 87) 57 72 80 Follicular (n = 74) 68 76 74 Mantle cell (n = 67) 81 82 72 Lymphoblastic (n = 45) 76 94 100 Burkitt (n = 17) 76 100 100 Other/unspecified (n = 8)
Therapeutic Interventional Mapping System (TIMS): A novel strategy for the selection of tri-targeted therapy combinations for non-small cell lung cancer (NSCLC).
Authors: John Mendelsohn, Vladimir Lazar, Eitan Rubin, Yudi Pawitan, Catherine Bresson, Jean-Charles Soria, Alexander Eggermont, Fanny Wunder, Jean-Yves Scoazec, Waun Ki Hong, Jean-Yves Blay, Richard L. Schilsky, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2015)

7524 Background: Combining three targeted therapies significantly improved outcomes in AIDS. A similar strategy could theoretically benefit patients with metastatic NSCLC, but a scientific method for rational selection of drug combinations is needed. Methods: We assessed genomics and the transcriptome (including miRNA), utilizing defined subsets of relevant genes/gene products, and scored information about the relationships between targeted drugs and genes, based in part on the biological hallmarks of cancer. Interventional points (genes/group of genes) that, when activated, could be blocked by a customized therapy combination, were identified. The underlying algorithm integrates and weighs the genomic (DNA sequencing) and transcriptomic data (mRNA and miRNA differential expression between tumor and normal -bronchial mucosa - tissues). Results: Key genes (N = 183) grouped in 24 interventional points forming the Therapeutic Interventional Mapping System (TIMS) were elucidated. Frequency and trends of co-activation derived from 121 NSCLC patients defined a list of candidate triple therapy combinations. The focus, in order to limit toxicity, was on the application of two small molecules (TKI) and an immune-modulator (anti-PD1L). Twenty-eight percent of NSCLC patients displayed the simultaneous activation of PD1L, Ras/Raf and mTor/PI3K interventional points. Overall, fifty two percent of NSCLC patients could be targeted by a triple combination that includes an anti-PD1L agent. Most individuals could benefit from two or even more triple combinations to overcome resistance. Conclusions: The TIMS’s strategy enables conversion of thousands of genomic and transcriptomic measurements into a simple and actionable result (a 1 to 10 score) that may be usable by physicians to select triple drug therapy. Comparing tumor and normal tissue biopsies has proven feasible in the ongoing WINTHER trial (NCT01856296). This novel strategy may allow deployment of personalized tri-targeted therapies that will be prospectively tested in a clinical trial with the objective to significantly impact survival in advanced NSCLC and other malignancies.
Predicting local recurrence using PAM50 in postmenopausal endocrine responsive breast cancer patients.
Authors: Florian Fitzal, Martin Filipits, Christian Fesl, Margaretha Rudas, Peter Christian Dubsky, Rupert Bartsch, Peter Regitnig, Thomas Bauernhofer, Richard Greil, Gerhard Leitner, Michael Knauer, Michael Hubalek, Michael A. Fridrik, Walter Herz, Otto Dietze, John W Cowens, Sean Ferree, Torsten O. Nielsen, Michael Gnant
Journal: Journal of Clinical Oncology (2014)

1008 Background: Breast conservation may lead to increased local recurrence rates compared with mastectomy. We investigated whether genetic expression profiling using PAM50 may predict local recurrence free survival (LRFS) independent of established factors Methods: Tumor blocks from patients randomized within the ABCSG 8 trial comparing tamoxifen with tamoxifen followed by anastrozole after surgery were analysed by the PAM50 assay (Prosigna, NanoString Technologies). Postmenopausal patients with endocrine responsive her2neu negative breast cancer were included. The risk of recurrence (ROR) score as well as biological subtypes (Luminal A and B) were correlated with LRFS. Results: 1,308 patients were analysed. 59% were <65 years, 79% had breast conservation (BCT) followed by radiotherapy and 32% were nodal positive. 72% had a low ROR score, 68% were luminal A while 28% had a luminal B cancer. After a median follow up of 11 years, 34 locoregional recurrences were observed, defined as ipsilateral in breast or axillary recurrences. Cox regression model showed that the ROR score significantly predicted LRFS independent from nodal status, tumor size and age (p<0.0081). Patients with high risk (ROR ≥ 57) had a LRFS of 94.4% while low risk patients (ROR < 57) showed a 98.4% 10-year LRFS (p=0.0005). Biological subtype analysis did also show a significant difference in LRFS comparing luminal A (98.1% 10-year LRFS) and luminal B cancer (95.9% 10-year LRFS, p=0.022). Multivariate analyses demonstrated that BCT did not significantly influence LRFS and was oncologically “safe” even in high risk patients (p=0.174). Conclusions: The PAM50 ROR score and intrinsic subtype are independent predictors for LRFS. Mastectomy seems unlikely to imporve LRFS in high risk patients. Clinical trial information: NCT00291759. Age category ≥65 years vs <65 years 0.873 (0.426 1.789) p=0.7101 Tumor stage T2/T3 vs T1 0.911 (0.419 1.980) p=0.8139 Node status N1 vs N0 1.325 (0.635 2.764) p=0.4540 Type of surgery Mastectomy vs BCT 0.468 (0.161 1.357) p=0.1620 Treatment Tam/Ana vs Tam alone 0.685 (0.346 1.358) p=0.2784 Risk group High vs low 3.621 (1.822 7.199) p=0.0002
Differential luminal breast cancer (LBC) reprogramming in response to BIBF1120 (BIBF) or bevacizumab (B).
Authors: Miguel Quintela-Fandino, Paloma Navarro, Tamara Mondejar, Jesus Sanchez, Elena Garcia, Gonzalo Gomez, David Gonzalez-Pisano, Ramon Colomer
Journal: Journal of Clinical Oncology (2013)

11033 Background: FVB MMTV PyMT is a great mouse model for studying LBC due to its stochastic nature, immune system preservation, natural growth kinetics and ER/HER2 status. We approached the transcriptomic (T), proteomic (P), phospho-proteomic (P-P) and metabonomic (M) layers of regulation of the tumor phenotype attempting to unravel mechanisms of resistance to antiangiogenic drugs (ADs) and find new targets. Methods: Treatments started when tumors measured 0,1cm 3 ; with the VEGFR/PDGFR inhibitor BIBF 85mg/kg/day; a murine analog of B 10mg/kg/biweekly; or vehicle (V). Tumors were harvested at time 0, week 1 (T1), or at sacrifice (Tend, 1cm 3 ). Cd31 and pimomidazole measured vascularization and O2. T; P/P-P; and M layers were interrogated with sure print 3G arrays; titanium separation - HPLC fractionation - orbitrap spectrometer run; and GC/MS and LC/MS. Gene ontology pathways were discovered with GSEAS; kinase networks by consensus domain analysis; metabolic pathways rearrangement with in-house built bioinformatic tools. Pairwise comparisons included &gt;15 mice/condition. All results: p or false-discovery ratio&lt;0,05. Results: Total mice in study:2,327. BIBF-treated showed: early (T1 vs. 0) ↓glycolysis (55%) and ↑pyruvate diversion to Krebs mediated by ↓800% phosphorylation of PDH, ↑ ketones uptake and degradation (220%), mediated by 2700% ↑AMPK activity; late (Tend) 900% ↑ lipid uptake and aerobic degradation mediated by &gt;800% ↑ ERK/B-adrenergic/PKA and PPARg (1600%) signaling. All changes supported by GSEAS. Adding blockade of AMPK, ERK, B-adrenergic or PPARg (ShRNAs or compounds) to BIBF yielded at least 50% growth delay (Anova). Tend B-treated tumors showed 210% ↑degradation of tryptophan to immunosuppressive (IS) kynurenine, and &gt;200% ↑ levels of IS/vasodilator prostaglandins. Celecoxib added to B delayed growth 90%. B and V induced similar ↑of hypoxic/necrotic areas (T0-1-end: 5%-15%-52%, Poisson), no change in CD31. BIBF avoided necrosis/hypoxia despite &gt;30% ↓ in CD31. Conclusions: Our strategy identified differential mechanisms of action of ADs in LBC. BIBF induces a switch from Warburg to aerobic metabolism; B reprograms the immune response. Regulators of these processes constitute targets.
Early stage mycosis fungoides treated with IFN a2b and PUVA: Molecular analysis of T cell monoclonahty by PCR in skin biopsies during and after therapy
Authors: Gaia Goteri, Serena Rupoli, Mirella Giangiacomi, Sara Barulli, Barbara Guiducci, Donatella Brancorsini, Renzo Ranaldi, Giuliano Brandozzi, Giorgio Filosa, Leonardo Bugatti, Sergio Lanari, Giorgio Mozzicafreddo, Ivana Cataldi, Alfredo Giacchetti, Stefano Serresi, Elio Grilli Cicilioni, Giuseppe Ricotti, Marco Simonacci, Italo Bearzi, Pietro Leoni
Journal: Blood (2000)
Association of adjuvant chemotherapy with improved overall survival for patients with locally advanced rectal cancer (LARC) who achieve a pathologic complete response (pCR) to neoadjuvant chemoradiation (nCRT).
Authors: Danish Shahab, Emmanuel M. Gabriel, Kristopher Attwood, Valerie Francescutti, Wen Wee Ma, Steven J. Nurkin, Patrick McKay Boland
Journal: Journal of Clinical Oncology (2017)

716 Background: 15-20% of patients with locally advanced rectal adenocarcinoma (LARC) achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation (nCRT). The role of adjuvant chemotherapy has been questioned. Methods: Patients with rectal cancer receiving nCRT in the National Cancer Data Base (NCDB) 2006-2013 data set were evaluated. The primary outcome was overall survival (OS). The association between OS and patient characteristics were examined using multivariable Cox regression models. Results: 2,903 patients were identified who achieved a pCR. The median follow up was 43.2 months. 2,102 received nCRT and 789 received nCRT + adjuvant chemotherapy. Factors significantly associated with OS included age (p&lt;0.001), gender (p=0.011), Charlson-Deyo comorbidity score (CDI) (p&lt;0.001), grade (p=0.029), clinical T stage (p=0.030), and CEA negativity (p=0.002), but not nodal status. The 3-year OS rate was 94% in the adjuvant therapy group as compared to 84% in the nCRT alone group (p&lt;0.001). In considering clinical N-stage, the benefit was comparable for both N+ and N- tumors. Adjuvant chemotherapy was more likely to be given for younger patients (age &lt; 60), lower comorbidity score, higher grade, positive CEA status, higher clinical T stage, and higher clinical N stage. When stratifying by these factors, similar benefits in OS were observed in the adjuvant cohort. Conclusions: Following nCRT and achievement of a pCR, the receipt of adjuvant chemotherapy is associated with improved OS. Patients receiving adjuvant therapy were more likely to be younger and have a low CDI, but have more advanced stage disease. Thus, a selection bias may be present. Nonetheless, in the setting of the already excellent outcome associated with pCR, the additional benefit of adjuvant chemotherapy should be weighed against toxicity.
A phase I study of ruxolitinib in children with relapsed/refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group Phase I Consortium study (ADVL1011).
Authors: Sarah K. Tasian, Mignon L. Loh, Karen R. Rabin, Patrick Andrew Brown, Charlotte H. Ahern, Brenda Weigel, Susan Blaney
Journal: Journal of Clinical Oncology (2014)

10019 Background: Ruxolitinib, an orally bioavailable inhibitor of the JAK family of kinases, may play a role in the treatment of childhood cancers with JAK1, JAK2, CRLF2, or other BCR-ABL1-like (Ph-like) alterations. We performed a phase 1 and pharmacokinetic (PK) study of ruxolitinib in children with relapsed/refractory solid tumors (STs) or hematologic malignancies (HMs; leukemias or myeloproliferative neoplasms). Methods: Ruxolitinib was administered orally twice daily (BID) continuously in 28 day cycles. The starting dose (15 mg/m2; dose level 1, DL1) was equivalent to the recommended adult dose of 25 mg/dose BID. Using the rolling six design, subsequent 20% dose escalations were 21 (DL2), 29 (DL3), 39 (DL4), and 50 (DL5) mg/m2/dose. Patients with HMs were enrolled at one dose level below ST patients. PK and pharmacodynamic analyses of phosphorylated (p) JAK2, STAT5, and S6 were performed in Cycle 1. Results: Twenty-eight ST and 21 HM patients were enrolled (median age 14.4 years; range 2.4 - 21.4). Twenty-seven ST and 10 HM patients were evaluable for toxicity. Ruxolitinib was generally well-tolerated, although there was 1 grade 5 event at DL2 in a ST patient (multi-system organ failure). During the dose escalation phase in STs, there was 1 dose-limiting toxicity at DL3 (neutropenia), DL4 (neutropenia), and DL5 (increased CPK). Grades 3 and 4 non-dose-limiting adverse events related to therapy in STs included cytopenias, nausea, and elevated transaminases and creatinine. PK parameters were similar to those in adults with marked inter-patient variability in the Cmax and AUC. Median peak plasma inhibitory activity of pJAK2 (44.8%), pSTAT5 (58.9%), and pS6 (62.3%) appeared generally dose-independent with the exception of greater pSTAT5 inhibition at DL5. Conclusions: The recommended phase 2 dose of ruxolitinib is 50 mg/m2 orally BID. A trial of ruxolitinib with chemotherapy for children with acute lymphoblastic leukemia harboring activating JAK mutations or fusions or other Ph-like alterations is in development. Clinical trial information: NCT01164163.
Clinicopathologic differences and survival of Hispanics (H) versus Non-Hispanic Whites (NHW) with gastric cancer (GC) at a Majority Minority Cancer Center in South Texas.
Authors: Cesar Ivan Barron, Brian Hernandez, Devalingam Mahalingam, Joel Michalek, Sukeshi R. Patel
Journal: Journal of Clinical Oncology (2017)

208 Background: Incidence rates for GC have shown to be increased in H vs NHW in studies. With a higher incidence of GC in South Texas compared to the rest of US, South Texas H have more than twice the incidence of GC than NHW with possibly worse survivals. However, these patients are not included in the SEER database, and the etiology of worse survival is unclear. To date, evaluation of a South Texas population with a more homogeneous H population has not been undertaken. Therefore, we chose to evaluate differences in clinical and histopathologic features in H vs NHW with GC at our South Texas NCI-designated cancer center where the homogenous H population is the majority. Methods: Retrospective analysis of GC patients from 2000-2016 at the Cancer Therapy and Research Center, San Antonio, TX. Median overall survival (mOS) was estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. Results: 168 patients with H 64% (n = 108), NHW 36% (n = 60). Median age 59 years (26-94): H 59.6 vs NHW 58.8 years. Females: H 48% vs NHW 37%. ECOG 0-1: H 48% vs NHW 53% (p = 0.46). Common Locations: H (Antrum 30%, Body 30%, GEJ 16%, Cardia 7%, Fundus 3%) vs NHW (Antrum 23%, Body 40%, GEJ 18%, Cardia 2%, Fundus 2%) (see table). Poorly differentiated: H 58.3% vs NHW 48.3% (P = 1). Stage IV at diagnosis: H 42% vs NHW 23% (P = 0.22). Diffuse-type: H 38% vs NHW 30% (P = 0.41); Intestinal-type: H 9% vs NHW 10% (P = 0.78). No significant difference in regards to Her2, H pylori, location of metastases. mOS: H 11 months (95% CI: 7-14) vs NHW 9.5 months (95% CI 6-n/a), p = 0.66. Conclusions: Despite historical worse prognosis of GC in H, at our majority minority cancer center in South Texas,H did not have a worse prognosis than NHW, and significant differences were not observed in clinicopathologic features. Prospective studies of H patients with GC should investigate differences in epidemiology, pathogenesis, and molecular signatures of GC between both groups to identify variables that correlate with survival and predict efficacy to cancer treatments. [Table: see text]
A phase II pilot trial of nivolumab + albumin bound paclitaxel + paricalcitol + cisplatin + gemcitabine (NAPPCG) in patients (pts) with previously untreated metastatic pancreatic ductal adenocarcinoma.
Authors: Erkut Hasan Borazanci, Gayle S. Jameson, Mitesh J. Borad, Ramesh K. Ramanathan, Ronald Lee Korn, Lana Caldwell, Karen Ansaldo, Kristin Hendrickson, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2017)

TPS511 Background: Despite decades of basic and clinical research, effective therapy for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest unmet clinical needs in oncology today. Albumin-bound paclitaxel (AP) and gemcitabine (G) reported on an improvement in overall survival in metastatic (m) PDAC [NEJM 2013; 369:1691-1703]. The addition of cisplatin (C) has shown promising clinical data in previously reported studies [Cancer Res 2015; 75(15 Suppl):Abstract nr LB-003]. Through further preclinical work, vitamin D analog therapy decreases myeloid derived suppressor cell (MDSC) and regulating T cells (Tregs) thus turning PDAC into a more immune friendly microenvironment. This trial combines AP/C/G with the vitamin D analog paricalcitol (P) and the antibody-PD-1 drug Nivolumab (N) as a combination therapy for individuals with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in patients in that population (NCT02754726). Methods: Key eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. Key exclusion criteria include prior PD-1 or PD-L1 therapy. Doses are AP 125 mg/m 2 undiluted, G 1000 mg/m 2 in 500 ml of normal saline (NS), each infused over 30 minutes with C 25mg/ m 2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42 day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV on days 1,4,8,12,15,22,26,29,32,36,and 39. Primary objective is to determine the efficacy of the combination NAPPCG for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate the safety of NAPPCG in patients with previously untreated metastatic PDAC. The study initiated accrual in April of 2016. If 4 of the first 10 patients are determined to have a PR the trial will expand to a total of 25 patients. Clinical trial information: NCT02754726.