tbuckley/cabot-search huggingface dataset:
Survivorship after lower gastrointestinal cancer: Patient reported outcomes and planning for care.
Authors: Melissa Frick, Carolyn Vachani, Margaret K. Hampshire, Christina Bach, Karen Arnold-Korzeniowski, James M. Metz, Christine E. Hill-Kayser
Journal: Journal of Clinical Oncology (2017)

695 Background: There is significant need for quality follow-up care to optimize long-term outcomes for the growing population of lower gastrointestinal (GI) cancer survivors. Patient-reported outcomes (PROs) provide valuable information regarding late- and long-term effects. Methods: Using a convenience sample from 1,129 colon, rectal and anal cancer survivors (n=792, 218, and 119, respectively) who utilized an Internet-based survivorship care plan (SCP) tool, we examined patient-reported demographics, treatment, and toxicity data. Responses from a follow-up survey were reviewed. Results: Median age of diagnosis was 51 years and median current age was 54 years. 81% of respondents were Caucasian and 58% were female. The most commonly reported late- and long-term effects for all survivors were neuropathy (65%), fatigue (56%), cognitive changes (49%), changes in GI function (43%), sexual dysfunction (22% in males, 43% in females), and radiation-induced dermatologic effects including changes in color/texture of skin (39%) and loss of flexibility in radiated areas (31%). The prevalence of these effects varied with length of time since treatment and treatment modality. Anal cancer patients reported a high prevalence of sexual dysfunction and radiation-induced dermatologic effects. Over 87% of users reported satisfaction levels of "good" to "excellent" using this tool, and 69% reported they intend to share SCP with their healthcare team. Conclusions: For lower GI cancer survivors, it is feasible to obtain PROs from an Internet-based survivorship tool. Survivors report a wide spectrum of late- and long-term side effects, which can be used to inform counseling at time of diagnosis, as well as help anticipate and respond to disease- and treatment-related sequelae during follow-up. We are among the first to report on PROs in anal cancer survivors. Further investigation on the impact of SCPs on healthcare communication and use is needed.
The outcome of patients with "nodal" peripheral T-cell lymphomas in a complete response following standard chemotherapy.
Authors: Jean-Michel Lavoie, Joseph M. Connors, Diego Villa, Richard John Klasa, Tamara Nina Shenkier, Randy D. Gascoyne, Alina Gerrie, Laurie Helen Sehn, Kerry J. Savage
Journal: Journal of Clinical Oncology (2014)

8555 Background: The outcome of peripheral T-cell lymphomas (PTCLs) treated with anthracycline-based chemotherapy (CHT) regimens is poor. Previous studies have suggested a benefit of high dose chemotherapy and autologous stem cell transplant (HDC/ASCT) in first complete remission (CR). However, in the absence of a randomized trial, the benefit is unclear. We evaluated the outcome of patients in CR following CHOP (like) CHT to provide a comparison to outcomes with HDC/ASCT. Methods: The BCCA Lymphoid Cancer database was searched to identify all cases of ‘nodal’ PTCLs between 16 and 67 y with stage 3/4, or stage 1/2 with B symptoms, bulky (>10cm) or extensive disease, that were in a CR by clinical assessment and imaging at the end of curative intent combination CHT and did not undergo consolidative transplant. Charts were reviewed to confirm response assessment. Results: Between October 1980 and January 2014, 103 cases were identified to be in a CR (6 by PET scan): PTCL-NOS = 39/94 (45%); ALK-positive (ALK-pos) ALCL = 29/34(85%); ALK-negative (ALK-neg) ALCL = 17/34 (50%); AITL= 17/37 (46%). All patients received CHOP (like) CHT. The median age at diagnosis for non-ALK-pos vs. ALK-pos patients was 57 y (23-67 y) and 29 y (17-65), respectively. Patients with ALK-pos ALCL more often had low risk disease (IPI 0, 1 48% vs. all others 23%) (P=0.036) and patients with AITL commonly had bone marrow (bm) involvement. (41%, P=0.01). With a median follow-up for living patients of 9.0 years (1.75-24.0 years), the 5 y OS for ALK-pos ALCL was 79% vs. 57% for all other subtypes (P=0.0048) and the 5 y PFS was 65% vs. 42% (P=0.010). The 5 y OS by subtype was 69%, 67% and 46% for ALK-neg, AITL and PTCL-NOS respectively (P=0.006) and the 5 y PFS was 62%, 50% and 30%, respectively (p=0.001). Interestingly, the IPI and bm involvement were not prognostic for either PFS or OS in any subtype. Conclusions: The majority of patients with PTCL-NOS ultimately relapse despite achieving a CR at the end of standard CHT. In contrast, patients with ALK-neg ALCL have an excellent outcome if a CR is achieved with comparable survival rates to patients treated with HDC/ASCT. These data support separation of these entities for the evaluation of novel treatment regimens.
Preclinical discovery and validation of high-dose androgen drug synergies for the treatment of prostate cancer.
Authors: Michael D. Nyquist, Alexandra N Corella, Ilsa Coleman, Shuai Gao, Robin Tharakan, Luke Riggan, Changmeng Cai, Peter Nelson, Elahe A. Mostaghel
Journal: Journal of Clinical Oncology (2017)

202 Background: Recent clinical studies have taken advantage of the dichotomous ability of androgen receptor signaling to elicit growth-suppressive and differentiating effects by giving hyper-physiological levels of testosterone. This approach has demonstrated safety, improved quality of life, and met primary endpoints for efficacy in clinical trials; however, novel strategies to enhance and optimize the anti-tumor efficacy of this approach are needed. Methods: We performed high-throughput drug screening in PCa cell lines to identify agents showing synergy with high-dose androgen treatment. Results: The Survivin inhibitor YM155, demonstrated a potent synergy with high-dose androgen. YM155 IC50 values shifted from 24 nM without R1881 to 3.85 nM with 160 pM R1881.Using qRT-PCT and ChIP-qPCR we establish the mechanism of this synergy was due to the direct upregulation of YM155 transporter SLC35F2 by androgen receptor transcriptional activity. Knockdown and overexpression of SLC35F2 dramatically modulated sensitivity to YM155. In two xenograft models SLC35F2 and tumor DHT levels are highly correlated and castration-induced decreases in tumor androgens cause an identical decline in levels of SLC35F2. In CRPC metastases SLC35F2 expression significantly correlated with AR activity score (r = 0.62, p &lt; 0.001). However, ~1/3 of tumors examined had transcripts for AR and SLC35F2, 1/3 AR+ but SLC35F2 negative, and 1/3 are negative for both. Conclusions: We describe a novel synergy between YM155 and high-dose androgen therapy mediated by the direct upregulation of YM155 transporter SLC35F2 by androgen receptor and implicate SLC35F2 expression as a potential biomarker for YM155 sensitivity. Whether ligand independent AR variants (AR-Vs) can constitutively mediate SLC35F2 expression is unknown, but if so would also provide a means of stratifying identifying men likely to respond to YM155.This study demonstrates a novel paradigm for precision medicine in the pharmacologic induction of drug sensitivity in a tissue restricted manner. Hormonal induction of carrier-mediated drug transport is a completely novel and unexplored concept that is poised to exploit androgen-based treatment strategies.
Disease response and survival outcomes in acute myeloid leukemia (AML) patients unfit for chemotherapy treated with 10-day decitabine as initial therapy.
Authors: Theodore Stewart Gourdin, Bhavana Bhatnagar, Alison P Duffy, Michael Tidwell, Yi Ning, Edward A. Sausville, Maria R. Baer
Journal: Journal of Clinical Oncology (2012)

6611 Background: AML is primarily a disease of older adults, with a median age of 67 years at diagnosis. Many patients are considered unfit for chemotherapy due to poor performance status and/or comorbidities, prompting investigation of less intensive approaches. A clinical trial in which 10-day courses of decitabine 20mg/m2 were given every 28 days as initial therapy demonstrated a promising complete remission (CR) rate and disease-free survival (DFS). We used this regimen to treat AML patients unfit for chemotherapy outside of a clinical trial. Methods: Charts of 32 newly diagnosed AML patients treated with 10-day courses of decitabine 20mg/m2 as initial therapy at the University of Maryland Greenebaum Cancer Center between September 2010 and November 2011 were retrospectively reviewed. If patients attained bone marrow blasts &lt;5%, 5-day courses were administered subsequently and were continued until disease progression. Results: Median age at diagnosis was 74 years (range, 52-86). 18 patients were male and 14 female. 23 were Caucasian, 7 African-American and 1 Hispanic. 10 patients (31%) had performance status ≥ 2. All had significant cardiac, pulmonary and/or renal disease. Karyotype risk group was unfavorable in 17 patients, intermediate in 14 and unknown in one. There were 9 CRs and 1 partial remission, for an overall response rate of 31%, following a median of 2 (range, 1 to 4) courses. 21 patients did not respond to treatment following 1 to 6 courses, and one died within 29 days of treatment initiation. 21 patients (65%) were hospitalized at least once for fever or infection during treatment. Of the 9 patients who achieved CR, 5 had normal, 3 complex and 1 unknown karyotypes. Median DFS was 390 days (range, 87+-468+) and median OS 180 days (range, 15-623+). Six-month OS was 37.5% and 1-year OS 16.5%. Conclusions: AML patients unfit for chemotherapy treated with 10-day decitabine 20mg/m2 outside of a clinical trial had a higher response rate than reported for 5-day decitabine, but a lower response rate than in the reported clinical trial of the 10-day regimen. Additional novel treatment approaches are needed for these patients.
Evaluation of hepatectomy, radiofrequency ablation, and transarterial chemoembolization for the local treatment of liver metastases in gastric cancer patients.
Authors: Lin Chen, Jiyang Li, Jianxin Cui, Hongqing Xi, Aizhen Cai, Kecheng Zhang, Yunhe Gao, Bo Wei
Journal: Journal of Clinical Oncology (2017)

200 Background: The optimal local treatment for liver metastases remains controversial. Except for hepatectomy, radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) are both effective and low risk treatment modality with more expanded indications in patients with liver metastases. Thus, the aim of this study is to evaluate the efficacy of different methods for the local treatment of GCLM. Methods: From January 2006 to December 2015, 97 consecutive patients were eligible and included in a prospective database. They all received multidisciplinary treatments based on curative gastrectomy and local treatments (hepatectomy, RFA and TACE) for liver metastases. The 97 patients enrolled in a cohort study were divided into two groups, Group A (37 patients, curative hepatectomy with or without other local treatments) and Group B (60 patients, palliative RFA and/or TACE).The primary endpoints were overall survival (OS) and 5-year survival rate. Results: Baseline characteristics in the two groups were comparable. Correlation analysis found that interval time of metachronous, neutrophil to lymphocyte ratio and body mass index were not significantly linear associated with survival, with ρ = 0.051, ρ = 0.014 and ρ = 0.056, respectively. The overall survival time between the two groups were 94.1 months and 57.2 months, with 1-year, 3-year and 5-year survival rate 83.3%, 50.0% and 30.6% in Group A, respectively; and 83.7%, 28.6% and 18.4% in Group B, respectively (P = 0.049). Furthermore, subgroup analyses proved that among these three local treatments, hepatectomy was the most effective method (P = 0.014), with significantly difference from RFA (P = 0.001). Nevertheless, combination with RFA and/or TACE did not improve patients’ benefits (P = 0.062). And TACE has a similar (P = 0.227) efficacy with RFA, but significantly less costs. Conclusions: Hepatectomy is the optimal local treatment for liver metastases when the surgical R0 resection was intended. And it is not necessary to combine with other local treatments. As palliative local treatment, TACE is an acceptable method with relatively high cost-effective.
Mutational profiling of protein kinases in prostate carcinoma
Authors: A. Andea, I. Osman, P. Scardino, H. Scher, W. Gerald
Journal: Journal of Clinical Oncology (2006)

4636 Background: Protein kinases are important signal transduction mediators that play a critical role in malignant transformation. However, their involvement in prostate carcinogenesis has not been fully elucidated. Methods: In this pilot study, we sequenced the coding and exon-flanking intronic regions of selected protein kinases in 15 human prostate carcinoma specimens and 2 prostate cancer cell lines using standard techniques (Agencourt Biosciences). The 15 protein kinases genes included: tyrosine kinases (EGFR, EPHA3, EPHB2, ERBB2, FES, FGFR2, KDR, KIT, MET, NTRK1, NTRK2, NTRK3), tyrosine kinase-like (BRAF), serine/threonine kinase (AKT2), and the lipid kinase (PIK3CA). We also sequenced PTEN, p53 and AR because of their known association with prostate cancer and interactions with protein kinases. Results: We identified 452 different sites of single nucleotide sequence alterations and 50 insertion/deletion changes in multiple genes in the 17 specimens. The majority were intronic or involved untranslated regions (364 single nucleotide and all indels), and therefore were not further evaluated. Of the remaining 88 coding region alterations, 59 were synonymous and 10 were previously identified single nucleotide polymorphisms leaving 19 non-synonymous coding region changes (12 in 12 patient tumors and 9 in cell lines). Sequencing of corresponding non-neoplastic tissue revealed that 4 genes with sequence alterations were also altered in the germ-line and likely represent polymorphisms (EPHA3, KDR, NTRK1 and NTRK3). Six tumor specific mutation sites have been confirmed (one mutation is yet to be studied). Three represent unreported sites of mutation in prostate cancer involving MET (1 site) and EPHB2 (2 sites) and the others involved known sites within AR (1 site) and TP53 (2 sites). Conclusions: Our study successfully identified specific mutations of tyrosine kinases occurring in prostate cancer. Evaluation of a larger sample representing natural and treated history of prostate cancer to determine frequency and clinical associations, as well as functional studies to determine the biological significance of these mutations, is needed. No significant financial relationships to disclose.
Association of genomic analysis of immune function genes and clinical outcome in the NCCTG (Alliance) N9831 adjuvant trastuzumab trial.
Authors: Edith A. Perez, E. Aubrey Thompson, S. Keith Anderson, Yan W. Asmann, Krishna R. Kalari, Jeanette Eckel-Passow, Amylou C. Dueck, Kathleen S. Tenner, Jin Jen, Jian-Bing Fan, Xochiquetzal Geiger, Ann E. McCullough, Beiyun Chen, Michael Zschunke, Robert B. Jenkins, George W. Sledge, Eric P. Winer, Julie Gralow, Monica Madden Reinholz, Karla V. Ballman
Journal: Journal of Clinical Oncology (2014)

509 Background: Some 20-25% of patients with HER2+ disease relapse after adjuvant trastuzumab (H). We used a genomic approach to define biological processes that predict benefit from H. Methods: Whole genome DASL technology was used to identify genes associated with relapse-free survival (RFS) among 1,282 patients enrolled in the N9831 adjuvant H trial (NCT00005970). Cox proportional hazard ratios (HR), adjusted for significant clinical/pathological risk factors, were used to determine the association of each gene with RFS (median follow-up 6years, 11months) for 433 patients who received chemotherapy alone and 849 patients who received chemotherapy plus H. Functional ontology analysis and network modeling were used to identify key biological processes associated with RFS in patients who received chemotherapy alone or chemotherapy plus trastuzumab. Results: Using probes with HR p<0.01, 10/13 significantly enriched biological processes associated with increased RFS (p<0.01) were linked to immune functions. These 10 processes defined a cohort of 87 immune function genes. Patients defined as immune function positive based on the 87 genes experienced a favorable outcome when treated with H (HR=0.55, p=0.0005). Patients who did not exhibit immune function enrichment and were treated with H did not have better RFS than patients with immune function enrichment who were treated with chemotherapy alone (HR=0.93, p=0.72). Among patients who received chemotherapy alone, enriched immune function was not associated with increased RFS (HR=1.01, p=0.96). Conclusions: Improved RFS following treatment with adjuvant H appears to be associated with a heightened state of immunological function. This observation may define a significant biological process that is linked to the efficacy of HER2-targeted therapy, may provide a means of predicting probability of relapse following adjuvant trastuzumab, and suggests possible routes of therapeutic enhancement.
The occurrence of grade 4 adverse events and survival outcomes in patients with nonsquamous non-small cell lung cancer receiving bevacizumab with chemotherapy in the phase III PointBreak and AVAiL studies.
Authors: Liza Cosca Villaruz, Mark A. Socinski, Jyoti D. Patel, Larry Leon, Sebastien Hazard, Martin Reck
Journal: Journal of Clinical Oncology (2013)

e19022 Background: Progression-free survival (PFS) is a key trial end point for clinical practice, as it relates to a change of treatment line. Grade 4 progression-free survival (G4PFS; defined as time from treatment start to the earlier of progressive disease [PD], onset of a G4 adverse event [AE], or death from any cause) is a composite end point incorporating a measure of tolerability to PFS. This post hoc analysis evaluates G4PFS and the effect of G4 AEs on PFS and overall survival (OS) in patients (pts) enrolled in PointBreak (PB) and AVAiL. Methods: Pts in PB were randomized to bevacizumab (BEV) 15 mg/kg q3w with carboplatin and paclitaxel (CP) or pemetrexed (CPem) for ≤4 cycles. Eligible pts received either BEV or BEV + Pem q3w until PD or unacceptable toxicity. Pts in AVAiL received cisplatin and gemcitabine for ≤6 cycles and either placebo or BEV (7.5 or 15 mg/kg) q3w until PD. AEs were graded via NCI-CTCAE v3.0. Kaplan-Meier and Cox model methods were used to estimate medians and hazard ratios (HRs) for PFS, G4PFS, and OS. PFS and OS were also compared in each arm for pts with occurrence of a G4 AE before week 12 of treatment vs those without. Results: Of those receiving BEV, ~30% of AVAiL pts and 38% of PB pts had a G4 AE. Uncomplicated neutropenia was the most common G4 AE in the CP + BEV arm of PB (26%) and in the BEV arms of AVAiL (11%). PFS, G4PFS, and outcomes by G4 AE occurrence are shown (Table). Conclusions: In both the PB and AVAiL trials, median G4PFS was numerically shorter than median PFS. G4 AE occurrence, however, did not affect subsequent PFS or OS in either trial. Clinical trial information: NCT00762034 and NCT00806923. [Table: see text]
Phase 1 dose escalation trial of intravenous radium 223 dichloride alpha-particle therapy in osteosarcoma.
Authors: Vivek Subbiah, Eric Rohren, Winston W. Huh, Cheenu S Kappadath, Peter Meade Anderson
Journal: Journal of Clinical Oncology (2014)

TPS10600 Background: Prognosis of patients with osteoblastic metastases from osteosarcoma is extremely poor. Given the heterogeneity in the biology of osteosarcoma, a novel approach is needed to overcome the current therapeutic plateau. Preclinical studies in rodents with alpha particle 223RaCl2 (223Ra) showed avid skeletal deposition, and relative sparing of the bone marrow. Experience with 223Ra in phase I, II and III trials in men with metastatic prostate cancer confirmed excellent activity against bone metastases and a low toxicity profile (i.e., a high therapeutic index) and has been US FDA approved for prostate cancer. Because of the unique physical properties of 223Ra, this agent is anticipated to be a highly effective and better-tolerated treatment for bone-forming sarcoma. We hypothesize that can be safely administered to osteosarcoma patients, and early response and / or resistance signals can be assessed by correlative imaging studies and biomarkers. Methods: We are conducting an investigator initiated, single institution, phase I, dose-escalation trial of 223Ra in recurrent or metastatic osteosarcoma patients > 15 yrs and >40 kg. To be eligible the patient must have recurrent osteosarcoma with indicator lesion that has uptake of 99mTc-MDP on bone scan. The primary objective is to determine the MTD of monthly 223Ra in recurrent osteosarcoma pts. The study design is a 3+3 Phase 1 dose escalation with expansion at highest safe dose (N=6). Comparison of safety and toxicity of 50, 75, and 100 kBq 223Ra /kg will be made.The secondary objectives are to analyze change in objective measurements of alkaline phosphatase and bone turnover markers at baseline, before dose 4 (mid study) and at end of study (after dose 6) vs change in SUV of PET- scans (18FDG and /or 18FNa) and of SPECT CT for 99mTc-MDP. Changes in uptake will be analyzed for dose response effects (between groups) and pre vs mid study and end of study (within group). The first dose cohort of the Phase 1 trial has been completed and the second cohort is being planned. The rationale and implementation of this novel radiopharmaceutical therapeutic approach for osteoblastic metastases in osteosarcoma patients will be discussed. Clinical trial information: NCT01833520.
Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.
Authors: Sylvie Zanetta, Jaafar Bennouna, Nicolas Isambert, Helene De-Montserrat, Patrick J. Squiban, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2012)

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, &gt;2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.