bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of entinostat onresistance to cetuximab and EGFR TKIs in non-small cell lung cancer.
Authors: Witta Samir E. , Chan Dan , Girard Luc , Zheng Di , Franekova Veronica , Peyton Michael , Zhang Zhi-Yong , Kline Zoe , Minna John D. , Bunn Paul A. , Hirsch Fred R. 
Published: March 2020

e18077 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor (EGFR) is active in patients with NSCLC. Gate keeper mutations in EGFR, such as T790M and activation of alternative driven pathways such as Met amplification are known mechanisms of acquired resistance to EGFR TKI. Here we evaluated the effects of the class I histone deacetylase inhibitors (HDACi), entinostat with cetuximab or EGFR TKIs in NSCLC cell lines with 3 potential mechanisms of intrinsic and acquired EGFR inhibitor resistance: RAS mutation according to E-cadherin expression, T790M EGFR mutation, and amplified MET. Methods: In vivo efficacy of entinostat alone or in combination with cetuximab or gefitinib was tested in athymic nude mice bearing RAS mutant, E-cadherin positive (A549) and E-cadherin negative (NCI-H460) NSCLC xenograft tumors. NSCLC cell lines were treated with various dilutions of cetuximab, entinostat or erlotinib. The NCI-H1975 and NCI-H1993 cell lines harboring the EGFR-L858R/T790M mutation and MET amplification, respectively, were treated with the combination of entinostat and erlotinib. Cell growth was analyzed by the MTT assay. Expression of e-cadherin was evaluated using affymetix microarrays. Results: When entinostat (E; 5mg/kg) was combined with cetuximab (C; 25mg/kg) in nude mice bearing the E-cadherin positive A549 xenograft, tumor growth inhibition was higher than each drug alone in (C: 65%; E: 70%; E+C: 88%; p=0.001) or what is detected in the E-cadherin negative H460 xenografts (C: 3%, E: 64%, E+C: 75%). Synergistic effects were detected when entinostat was combined with erlotinib in the NCI-H1975 or NCI-H1993 cell lines (combination index, CI<1). Conclusions: Entinostat enhances the effect of Cetuximab in vivo in Ras mutant, E-cadherin positive NSCLC cell lines, or erlotinib in cell lines harboring the EGFR mutation T790M or amplified MET. The combination of entinostat and EGFR inhibitors could provide the rational for developing clinical trials in patients with NSCLC with tumors resistant to EGFR inhibitors.
EGFR status and daily dose: Effect on tumor growth inhibition in cancer patients treated with dacomitinib (PF-00299804).
Authors: Ruiz-Garcia Ana , Janne Pasi A. , Park Keunchil , Yamamoto Nobuyuki , Giri Nagdeep , Bello Carlo , O'Connell Joseph P. 
Published: March 2020

e18093 Background: Dacomitinib (D) is a highly selective, irreversible small molecule pan-human epidermal growth factor (EGFR/HER) inhibitor. The effect of mean D daily dose (exposure) on tumor growth dynamics was analyzed using a longitudinal exposure-response tumor growth inhibition model. Methods: Estimated parameters included tumor shrinkage rate (KD), which changes over time as resistance to therapy develops according to an exponential decay function where λ = slope of the dynamic shrinkage rate change; and tumor growth rate constant (KL). eDose, the effect of mean D daily dose changes on tumor shrinkage rate, was tested in the base model to establish the best relationship between tumor shrinkage and drug exposure. Model parameters were estimated using a population (pop) approach. Pop pharmacodynamic analyses included data from 4 clinical trials (3 phase I and 1 phase II) of D (15–45 mg QD) in patients (pts) with advanced solid tumors. Multiple tumor size (SLD) measurements were collected from each pt. Data analysis used nonlinear mixed effects modeling (NONMEM, v 7.1.2). After visual inspection of relationships between covariates (weight, age, creatinine clearance, bilirubin, ALT, baseline ECOG PS, race, sex, EGFR status) and individual parameter estimates of KD; subpopulation analysis was carried out in pts with confirmed EGFR status (mutation [mu] or wild type [WT]) to quantify the potential effect of EGFR status on KD. Results: SLD values over time were collected from 200 pts (47% male). For a typical pt, KL = 0.63 year-1; KD = 1.6 year-1; developed therapy resistance over time (λ) = 13.7 year-1; and eDose = 0.45. Drug-specific parameters affecting tumor shrinkage (KD, λ, eDose) and the disease-specific KL were well estimated with low relative standard errors. Visual inspection of relationships between covariates and individual parameter estimates showed a higher shrinkage rate (KD) for pts with EGFR mu vs those with WT EGFR. Conclusions: D mean daily dose affected tumor growth dynamics. Tumor shrinkage rate at an averaged daily dose below 45 mg QD was lower vs 45 mg QD. EGFR status was a significant covariate affecting tumor shrinkage rate (83% less shrinkage in pts with EGFR WT vs. pts with EGFR mut).
TGFb expression as predictor of outcome in EGFR wild type (WT) metastatic non-small cell lung cancer (NSCLC) patients (PTS) treated with EGFR tyrosine kinase inhibitors (TKIs).
Authors: Finocchiaro Giovanna , Toschi Luca , Gianoncelli Letizia , Canal Barbara , Rubino Luca , Lo Russo Chiara , Giordano Laura , Destro Anna , Garassino Isabella , Siracusano Licia , Cavina Raffaele , Roncalli Massimo , Carbone Antonino , Santoro Armando 
Published: March 2020

e18104 Background: Gefitinib and erlotinib have shown to be highly effective in pts harboring EGFR mutations, while the majority of EGFR wt pts does not respond to treatment.Preclinical data suggested that TGFb and HGF could affect response to TKIs. Aim of the present study is to investigate molecular predictors for primary resistance to TKIs in metastatic NSCLC pts. Methods: This retrospective study included 120 metastatic NSCLC patients treated with gefitinib (68/56.7%) or erlotinib (52/43.3%) in first line (20/16.7%) or after prior chemotherapy (100/83.4%) with at least one measurable lesion and availability of paraffin-embedded tumour tissue from primary cancer. Analyses included presence of mutations in EGFR and KRAS genes, assessment of ALK rearrangement by fluorescence in situ hybridization (FISH) and protein expression of HGF and TGFb by immunohistochemistry (IHC). Pts were grouped in IHC+ and IHC- according to staining intensity. Results: In the whole study cohort response rate (RR) was 9.2%, median progression free survival (PFS) 2.5 months, and overall survival (OS) 7.8 months. EGFR mutations were observed in 9.2% of pts and were significantly associated with better pts outcome. KRAS was mutated in 23.3% of pts without any correlation with clinical end points. ALK translocations were observed in 5 pts (4.2%), and none responded to treatment. IHC was successfully performed for HGF and TGFb in 95 and 75 pts respectively. No difference was seen in HGF+ (9/9.5%) vs HGF- pts in terms of RR, PFS and OS. TGFb+ pts (41/54.7%) had a significantly shorter OS than TGFb- pts (6.7 vs 10.3 months, p=0.020) although no difference in terms of RR and PFS was observed. When restricting survival analysis to EGFR wt/KRAS wt pts (n=80) TGFb+ subjects had a significantly worse PFS (1.9 vs 2.9 months, HR 2.16, CI 95% 1.18;3.95, p=0.013) and OS (5.3 vs 8.8 months, HR 2.07, CI 95% 1.10;3.91, p=0.025) when compared with the TGFb- group. Conclusions: Overexpression of TGFb is associated with a poor outcome in EGFR and KRAS wt pts treated with gefitinb or erlotinib. Prospective validation of the role of TGFb as a mediator of intrinsic resistance to EGFR TKIs in NSCLC is warranted.
Impact of local and systemic treatment on survival and on brain relapse of patients with localized or metastatic non-small cell lung cancer who develop brain metastasis.
Authors: Florescu Marie , Blais Normand , Tehfe Mustapha , Begin Marie Josee 
Published: March 2020

e18120 Background: Up to 20% of patients with localized NSCLC develop brain metastasis, and twice more with metastatic NSCLC. We analyze retrospectively 216 unselected consecutive patients diagnosed with stage I to IV NSCLC treated at Notre-Dame Hospital from 2006 to 2010. Methods: Patients who developed their brain metastasis within 6 months of the NSCLC diagnostic were considered to have synchronous brain metastasis although those who developed more than 6 months later were designated metachronous. We compared the survival Kaplan-Meyer plots with log-rank tests in between each group category: synchronous brain metastasis with localized NSCLC (Sync Loc), synchronous brain metastasis with metastatic NSCLC (Sync Meta), metachronous brain metastasis in patients with localized NSCLC (Mec Loc) and metachronous brain metastasis in patients with already metastatic extracranial NSCLC (Mec Meta). Results: Comparing the 38 patients of Sync Loc with the 95 patients of Sync Meta, we found a not statistical significant difference in median survival with 15.4 months (Sync Loc) vs 6.8 months (Sync Meta) (p=0.18), but a similar 2 years survival 20.4% (Sync Loc) vs 15.7% (Sync Meta). Despite, only 27% of patients of Sync Loc received systemic treatment compared with 43% of patients Sync Meta, the two groups had no statistically significant difference in the median brain-relapse free survival with 18.5 months vs 14.1 months (p=0.335). The metachronous brain metastasis group had a significant difference in the median overall survival with 32.1months for the 61 patients Mec Loc and 18.1months for the 24 patients Mec Meta. Interestingly, stage I NSCLC patients with metachronous metastasis have a 2 year overall survival of 81.6%, stage II of 64.2% and stage III of 49.2%, similar to patients with no brain metastasis. Conclusions: Patients with localized NSCLC diagnosed with synchronous brain metastasis have probably already a metastatic disseminated disease with the same outcome than patients with NSCLC with extracranial metastatic disease. However, patients with metachronous brain metastasis and treated localized NSCLC have a very good prognostic.
Improving outcomes in mantle cell lymphoma patients treated with R-CHOP using autologous transplant.
Authors: McQuade Jennifer , Ahmadi Tahamtan , Porter David L. , Frey Noelle V. , Goldstein Steven C. , Loren Alison W. , Svoboda Jakub , Stadtmauer Edward Allen , Schuster Stephen J. , Nasta Sunita 
Published: March 2020

e18540 Background: Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. There is no standard upfront therapy, although Phase II trials have shown a survival benefit to dose-intensified regimens in selected patients. However, many patients are not candidates for these regimens secondary to age or comorbidites. These patients are often treated with R-CHOP with consideration for consolidation with ASCT. Methods: We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-CHOP (N=32) with or without autologous stem cell transplant (ASCT). The primary study endpoint was PFS as assessed by chart review and confirmed by SSDI database. Results: Median follow up for all pts was 2.5 years. The median age was 62.5, and 80% (n=30) were stage IV at diagnosis. 16 patients underwent consolidative ASCT. Comparing patients treated with R-CHOP vs R-CHOP +ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. The response rate for all patients was 96.9% and 87.5% of patients achieved CR. Median PFS for all patients was 2.8 years: R-CHOP alone 1.9 years vs. R-CHOP+ ASCT 3.9 years (P=0.02, HR 3.44, 95%CI: 1.2-9.5). Conclusions: Outcomes are poor for MCL patients treated with R-CHOP with continuous recurrence despite excellent initial response. Our data suggest an improved PFS in patients with advanced MCL when R-CHOP is consolidated with ASCT in first remission as compared to R-CHOP alone. Prospective RCTs are needed to determine the optimum treatment for patients who are not candidates for dose-intensive therapy.
A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).
Authors: Yellin Ori , Berenson James R. , Boccia Ralph V. , Cohn Allen Lee , Berard Paul , Ghazal Hassan , Jamshed Saad , Kingsley Edwin , Harb Wael A. , Noga Stephen J. , Nassir Youram , Swift Regina A. , Vescio Robert A. 
Published: March 2020

e18558 Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.
Chemotherapy for patients with brain metastases from melanoma.
Authors: Naskhletashvili David R. , Gorbunova Vera A. , Bychkov Mark B. , Bekyashev Ali H. , Karahan Vladislav B. , Aloshin Vladimir A. , Michina Zoya P. , Moskvina Ekaterina A. 
Published: March 2020

e19012 Background: There have not been standards of chemo- and chemo-radiotherapy for treatment for patients with brain metastases. The patients (pts) with brain metastases (BM) from melanoma have poor prognoses. The main goal of this trial is to assess the efficacy of nitrosoureas (CCNU or FCNU), temozolomide (TMZ) as monotherapy, TMZ combined with whole brain irradiation (WBI), or combined chemotherapy of TMZ and cisplatin in pts with BM from melanoma. Methods: 78 pts were included in this study. 21 pts were treated with WBI (3Gy/30Gy) and concomitant TMZ therapy (75 mg/m2/day orally on days 1-14), 19 pts were treated with TMZ (150 mg/m2/day orally on days 1-5, every 4 weeks) as monotherapy, 17 pts pts were treated with nitrosoureas (CCNU or FCNU), 21 pts were treated with combined chemotherapy of TMZ (150/mg/m2/day orally on days 1-5, every 4 weeks) + cisplatin (20/mg/m2/day intravenous on days 1-5, every 4 weeks). The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (mOS), 1-year and 2-year survival. Results: Observations were as follows: in the TMZ + WBI treated pts, 4 OR (19,0%) in 21 pts group in the brain and 1 OR (6,7%) in 15 pts group in ES. The mOS was 6.0 months, 1-year survival was 23,8%. In the TMZ monotherapy treated pts there were 5 OR (26,3%) in 19 pts group in the brain and no OR in 13 pts group in ES. The mOS was 6 months, 1-year survival was 21,1%. In the nitrisoureas treated pts we achieved 2 OR (11,8%) in 17 pts group in the brain and 1 OR (9,1%) in 11 pts group in ES. The mOS was 5 months, 1-year survival was 17,6%. In the TMZ + cisplatin treated pts there were 7 OR (33.3%) in 21 pts group in the brain and 7 OR (35,0%) in 20 pts group in ES. The mOS was 8 months, 1-year survival was 33,3%. 2-year survival (19,0%) was achieved only in TMZ and cisplatin group. Conclusions: Previous results of our study showed promising higher efficacy of TMZ and cisplatin, especially in OR in ES (p<0.05) and in 2-year survival (p<0.05), in comparison with TMZ alone, nitrosoureas or TMZ with whole brain irradiation in patients with metastatic melanoma with BM. Control of extracranial lesions is important factor for patients with BM. Further investigation is to be expected.
Intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) combined with adoptive TIL transfer in patients with metastatic melanoma.
Authors: Khammari Amir , Limacher Jean-Marc , NGuyen Jean-Michel , Quereux Gaelle , Brocard Anabelle , Peuvrel Lucie , Knol Anne-Chantal , Saiagh Soraya , Bataille Vincent , Dreno Brigitte 
Published: March 2020

e19019 Background: Several tumour factors limit the efficacy of spontaneous immune responses. By changing the tumour environment through immune-stimulation, responses could be more efficient. Methods: This is a phase I/II open, monocentric study with a sample size of 12 patients. The main inclusion criteria were: age 18 to 75, melanoma stage IIIc/IV with cutaneous and visceral metastases except brain metastases. Patients received intra-lesional injections TG1042 combined with tumor infiltrating lymphocytes (TILs) infusions and interleukine-2 (IL2) sub-cutaneous injections. TILs were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every two weeks from day -15 to month 2 and then every month up to month 11 or progression. The main objectives were to evaluate the clinical response and safety. Results: Twelve patients stage IVa-c AJCC have been included. Three patients progressed rapidly before starting any treatment and for 2 others TILs were not obtained due to insufficient tumor tissue. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections was observed. No grade 3 or 4 treatment related adverse events were reported. Among the 7 patients evaluable for tumor response (RECIST rules), 2 partial and 2 complete responses were observed. Distant responses were also observed for 2 patients. Immunohistochemical analysis on biopsies from an injected lesion of 3 patients before and after 3 months of treatment showed an increase of CD8 T lymphocytes in 2 patients with clinical response associated with an increase of IFN-γ and STAT 1 expression. Conclusions: Results of this study demonstrate that TILs-based adoptive cell therapy combined with intra-lesional immunostimulation induced by TG1042 is feasible, safe and can induce a disease control in a majority of patients. Stimulation of innate immunity by adenovirus expressing interferon gamma seems able to reverse the tolerance state within the tumour environment, thus making TILs able to exercise their cytotoxic activity against melanoma.
Role of palliative care department in modifying ICU admissions for patients with advanced cancer: A study.
Authors: ROY Rakesh - 
Published: March 2020

e19517 Background: Admission of cancer patients are on the rise in the Intensive Care Unit due to advancement in healthcare facilities. But limited number of ICU beds, health resources and lack of structured Palliative Care services are a matter of concern. Methods: A retrospective study was conducted in an Indian tertiary cancer centre from Jan – Jun 2010 to find out total number and cause of ICU admission of advanced cancer patients when a Palliative Care Department did not exist. Information source were case files and interviews after appropriate consent. Exclusion criteria - age < 18 years, post operative care, complications arising from a major surgery, established oncological emergencies, patients with curative intent. With a 24 hr Palliative Care department under operation from Aug 2010 - another similar study was performed from Jan – Jun 2011. Results: Jan – Jun 2010: Total admissions 542. 297 patients matched the exclusion criteria. Of the remaining 245 patients (45.2%) considered for the study 35 patients (14.2%) died. 11 patients (4.4%) were put on ventilator. Average occupancy of bed 5 days. Commonest cause was respiratory distress. Review of the case notes revealed 54 patients (22%) were admitted due to lack of Palliative Care service. Study was repeated from Jan – Jun 2011 after the initiation of a Palliative care Department from Aug 2010. Out of 487 patients, 195 patients (40%) were considered for study. 18 (9.2%) died. 6 patients (3%) were put on ventilator. The average duration of stay was 4 days. Components of Palliative Care like good communication, early consent from patients as to where they wish to die, do not resuscitate policy for some patients in the background of ethical issues, 24 hour Palliative care service, emergency helpline, home based care, good psychological counselling etc were identified as the key reasons for reduced admissions. Conclusions: Effective round the clock Palliative care service can increase ICU bed turnover, reduce misery of the patients and their family members, save resources, giving patients with longer survival chances a hope to live longer.