tbuckley/cabot-search huggingface dataset:
Patients and physicians can discuss the actual costs of cancer treatment with high interest and little conflict.
Authors: Ronan Joseph Kelly, Patrick M. Forde, Ashley Bagheri, Jenny Ahn, Arlene A. Forastiere, Shereef Elnahal, Gary L. Rosner, Thomas J. Smith
Journal: Journal of Clinical Oncology (2014)

6563 Background: As one solution to reducing costs and medical bankruptcies, experts such as the Institute of Medicine and ASCO have suggested patients and physicians should discuss the cost of care before doing the treatment. Whether these discussions are possible in an oncology setting, and their effects on the doctor-patient relationship are not known. We could find no published study of actual patients reviewing their costs in real time with their oncologist. Methods: We used the National Comprehensive Cancer Network (NCCN) Guidelines and the eviti Advisor platform to show patients with metastatic breast, lung, or colorectal cancer the costs associated with their treatment options during an oncology consultation. We measured provider attitudes and assessed patient satisfaction when the consultations included the costs of expected care. Results: We approached 107 patients: 96 (90%) enrolled in the study, 3 (3%) asked if they could be interviewed at a later date, and only 8 (7%) did not want to participate. Only 5/18 oncologists (28%) felt comfortable discussing costs, and only 1/18 (6%) regularly asked patients about financial difficulties. The majority of patients (80%) wanted cost information, and 84% reported that these conversations would be even more important if their co-pays were to increase. In total, 72% of patients responded that no health care professional has ever discussed costs with them. The majority of patients (80%) had no negative feelings to hearing cost information, and did not think it added conflict to the patient-physician relationship. Conclusions: In an era of rising co-pays, the great majority of cancer patients want cost of treatment discussions, especially if they have increased personal financial responsibility. These conversations do not lead to negative feelings in the great majority of patients. Additional training to prepare clinicians for how to discuss costs with their patients is needed.
Comparing the outcomes of noninferiority (NI) and superiority phase III trials.
Authors: Everardo D. Saad, Marc E. Buyse
Journal: Journal of Clinical Oncology (2012)

e13055 Background: We compared the outcomes of NI and superiority trials on advanced breast cancer (BC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: We searched PubMed for phase III trials on systemic antineoplastic treatments for advanced BC, NSCLC and CRC published between 1/1998 and 12/2009 in 11 leading journals. We categorized primary endpoints (PEP) as time-to-event (overall survival or any variant of progression-free survival), response rate, or other (quality of life or toxicity). We used the PEP (defined as the one stated explicitly, used for N calculation, or cited first) to ascertain trial positivity. Results: We retrieved a total of 262 trials (93 on BC, 102 on NSCLC, and 67 on CRC), 36 of which (13.7%) used a NI design (12 in each tumor type). There was no significant trend in the proportion of NI trials in the two 6-year periods compared (1998-2003 vs 2004-9). The median number of patients/arm for NI and superiority trials were 284 and 164, respectively (p&lt;0.001). There was no significant difference in the distribution of the PEP categories between NI and superiority trials. We could ascertain trial positivity in all but six trials: 24 (66.7%, 95% confidence interval [CI], 49.1% to 81.2%) NI trials were positive, compared with 89 (39.4%, 95% CI, 33.0% to 46.1%) superiority trials (p&lt;0.001). NI trial positivity could be determined by finding a CI for the estimated treatment effect that excluded the NI margin in 15 of 27 trials (otherwise, positivity was based on authors’ conclusions, or the experimental therapy was superior to control for the PEP). The overall rates of trial positivity varied across tumor types: 48.4% for BC, 31.4% for NSCLC, and 53.7% for CRC (p=0.002). When adjusted for trial size, NI design (vs. superiority; odds ratio [OR]=4.2; 95% CI, 1.7 to 10.3) and tumor type (BC [OR=2.2; 95% CI, 1.2 to 4.0] and CRC [OR=2.8; 95% CI, 1.4 to 5.5] vs. NSCLC as reference) remained significantly associated with trial positivity. Conclusions: NI trials are more likely than superiority trials to yield positive results. The influence of NI margin width on trial results should be investigated.
Telemedicine-enabled clinical trial of metformin in patients (pts) with biochemically-recurrent prostate cancer (PCa).
Authors: Matt D. Galsky, Mohamed Shahin, Ashley Olson, David R. Shaffer, Kiev Gimpel-Tetra, Che-Kai Tsao, Charles Baker, Amanda Leiter, John Holland, Tomasz Sablinski, Reza Mehrazin, John Sfakianos, Patricia Acon, William K. Oh
Journal: Journal of Clinical Oncology (2017)

243 Background: Clinical trials are critical to informing cancer care but are hampered by slow accrual and suboptimal generalizability, both contributed to by poor geographic accessibility. We previously reported that &gt; 50% of the US population resides &gt; 1 hour from the nearest PCa clinical trial site (Galsky, JAMA Int Med, 2015). We sought to test the feasibility of replacing on-site study visits with telemedicine visits in a prospective clinical trial. Methods: Castration-naïve non-metastatic pts with PCa and a rising PSA after local therapy were eligible. Pts required a single on-site visit for enrollment. Treatment consisted of metformin 850 mg QD x 1 month followed by 850 mg BID x 5 months. Telemedicine visits were conducted monthly using a HIPAA-compliant smartphone application. The primary objective was to determine feasibility defined as completion of all eligible telemedicine visits by &gt; 2/3 enrolled pts; pts were ineligible for future telemedicine visits if treatment discontinued early for toxicity or disease progression. Secondary objectives included safety, % patients with ≤ 20% PSA rise at 6 months, quality of life, and patient satisfaction. Results: 15 pts were enrolled, median age 68 (range, 57, 83), one-way driving time 1.3 hours (range, 0.2-2.8), Gleason score 7 (range, 6, 9), and pre-study PSA 4.1 (range, 0.52, 31.7). The 6 month course of metformin was completed by 11/15 (73%) pts; 2 discontinued early due to rising PSA, 1 due to adverse event (AE), and 1 remains on study. Excluding 1 pt still on study, 14/14 (100%; 95% CI 76, 100) pts completed all 78 eligible telemedicine visits. The most common AEs were diarrhea (grade 1 = 60%) and fatigue (grade 1 = 20%); 1 pt experienced grade ≥ 3 AE (dehydration). The 6-month PSA was ≤ 20% baseline in 1 pt; median % PSA change at last televisit was +52.8% (range, -3.0, +318.8). Quality of life and pt satisfaction will be reported at the meeting. Conclusions: To our knowledge, this is the first ever interventional oncology clinical trial conducted via telemedicine. Telemedicine-enabled trials are feasible and may overcome barriers to trial participation. Metformin was generally well tolerated but associated with minimal anti-PCa activity as measured by PSA. Clinical trial information: NCT02376166.
Phase II study of neoadjuvant irinotecan, capecitabine, oxaliplatin (IXO) followed by chemoradiotherapy (CRT) using concurrent capecitabine for resectable locally advanced rectal cancer.
Authors: Derek J. Jonker, Jean Alfred Maroun, Rebecca Ann C Auer, Nirit Yarom, Celia Marginean, Wael Shabana, Jason R. Pantarotto, Timothy R. Asmis, Robin P. Boushey, Rachel Anne Goodwin, Wayne Kendal, Shaheer Tadros, Laval Jacques Grimard, Husein Moloo, Martin Friedlich, Caryn Bohemier, Horia Marginean
Journal: Journal of Clinical Oncology (2014)

e14571 Background: Earlier initiation of more effective systemic therapy for stage 3 rectal cancer is of interest to reduce local and systemic recurrence. We conducted this feasibility study of neoadjuvant IXO in 15 patients (pts) with locally advanced rectal cancer. Methods: Pts with resectable cT3-4N0 or N1–2 rectal cancer received 4 cycles of IXO followed by 5 weeks of CRT with concurrent capecitabine. Total mesorectal excision was performed 6-8 weeks after CRT. Primary endpoint was pathologic complete response (pCR) rate. Secondary endpoints included objective response, disease free survival (DFS), overall survival, R0 resection rate, down staging rate, and toxicity. Results: Ten pts were enrolled between November 2010 and August 2012. Pts were: male/female, 9/1; median age, 52 years (31-76); ECOG PS 0/1, 7/3; cT3N1/T3N2, 6/4; mid/distal rectum, 6/4; fixed/mobile, 7/3. In 8 pts the following grade 3-4 adverse events occurred: diarrhea, hypokalemia (50%), nausea/vomiting, pain, neutropenia (40%), anorexia, fatigue (30%), febrile neutropenia, hand-foot reaction, leucopenia, hyponatremia, low albumin (20%), dysphagia, enteritis, lipase, mucositis, weight loss, anemia (10%). Two pts discontinued IXO and 2 pts held CRT for 1 week for toxicity. Three pts experienced postoperative fistula/leak/infection. Post IXO, complete response was reported in two and partial response (PR) in seven pts. One pt progressing during IXO reached PR post CRT. All pts underwent TME surgery with R0 resection. Downstaging in T3 and N1/N2 was achieved in 6 and 10 pts, respectively. Sphincter preservation, considered feasible in 7 pretreatment occurred in 9 pts. Two pts achieved pCR (20%). At median follow-up 30 months, one recurrence and no deaths were observed. Conclusions: While causing more toxicity than acceptable and leading to early termination, IXO induction followed by CRT for rectal cancer was associated with good tumor response, pCR rate, and prolonged DFS. Modified triple combinations should be further evaluated in rectal cancer. Supported by Sanofi-Aventis, Hoffmann La Roche, Ottawa Regional Cancer Foundation. Clinical trial information: NCT01237665.
A Novel Mechanism for the Grid-to-Place Cell Transformation Revealed by Transgenic Depolarization of Medial Entorhinal Cortex Layer II
Authors: Benjamin R. Kanter, Christine M. Lykken, Daniel Avesar, Aldis Weible, Jasmine Dickinson, Benjamin Dunn, Nils Z. Borgesius, Yasser Roudi, Clifford G. Kentros
Journal: Neuron (2017)
A phase II study of PXD101 (belinostat) in relapsed and refractory aggressive B-cell lymphomas (rel/ref ABCL): SWOG S0520.
Authors: Daniel Oscar Persky, Steven H. Bernstein, Bryan H. Goldman, Lisa M. Rimsza, Richard I. Fisher, Thomas P. Miller
Journal: Journal of Clinical Oncology (2012)

e18536 Background: The mechanism of action of histone deacetylase inhibitors (HDACI) in lymphomas is unknown. Loss of major histocompatibility Class II antigens (MHC II) in diffuse large B-cell lymphomas (DLBCL) is associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHC II is controlled by CIITA, which is itself regulated by histone acetylation, We hypothesized that PXD101 (belinostat), an HDACI, would increase MHC II expression in tumor cells, enhance immunosurveillance and improve outcome. Methods: Theprimary objective was to evaluate response rate and toxicity of PXD101 in patients (pts) with rel/ref ABCL with up to 5 prior chemotherapy regimens. Secondary objectives were to estimate the 6-month progression-free survival (PFS) and to assess MHC II and TIL. In a two-stage design, if at least 1 response was observed in the first 20 pts, another 20 pts would be accrued. PXD101 was administered at 1000 mg/m2 IV days 1-5 of 21-day cycle for up to 2 years. Results: The study was closed due to lack of response in the first stage. Of 22 pts enrolled, 19 were evaluable. Median age was 69, and median number of prior treatments was 3 (range 1-4). 18 pts had DLBCL and 1 had B-cell lymphoma, unclassifiable. Grade 4 toxicities were fatigue and muscle weakness (1) and lymphopenia (1). Despite initially finding no responses, 2 partial responses (PR) were observed at 5 and 13 months after registration, for an overall response rate (95% CI) of 10.5% (1.3-33.1%); 3 pts had stable disease (SD), lasting 4.7, 30.4+, and 40.7+ months. With a minimum follow-up of 2.0 yrs, median and 6-month PFS are 2.1 months (1.3-3.8) and 21.1% (6.6-41.0%); median and 6-month overall survival are 13.4 months (95% CI not yet estimable) and 57.9% (33.2-76.3%), respectively. Conclusions: Despite early closure, delayed PR was seen in 2 of 19 pts, and 2 pts had SD lasting 30.4+ and 40.7+ months. Therefore 4 pts (21%) who did not achieve complete response, very unusually, have not progressed for ≥2.0 yrs. Standard chemotherapy response assessment may not be appropriate for HDACI, which may require development of new biomarkers of response. Further work focuses on combining HDACI with standard chemotherapy.
A randomized, placebo-controlled, double blind, multicenter phase II adjuvant trial of the efficacy, immunogenicity, and safety of GI-4000 plus gem versus gem alone in patients with resected pancreas cancer with activating RAS mutations/survival and immunology analysis of the R1 subgroup.
Authors: Peter Muscarella, Lalan S. Wilfong, Sharona B. Ross, Donald A. Richards, Julian Raynov, William E. Fisher, Patrick J. Flynn, Samuel H. Whiting, Alexander Rosemurgy, Frank E Harrell, Nathaniel D. Mercaldo, Scott Kosten, John Quiring, Sue Speyer, Joni Richman, John Ferraro, Claire Coeshott, Allen Cohn, Timothy C. Rodell, David Apelian
Journal: Journal of Clinical Oncology (2012)

e14501 Background: Patients with resected pancreas cancer treated with standard of care Gem have a median overall survival of 22 months (vs 20 months w/ observation). Activating mutations in ras occur in &gt; 90% of pancreas cancer cases. GI-4000 is whole, heat-killed recombinant S. cerevisiae yeast that expresses mutated Ras proteins. This trial is designed to evaluate the efficacy, immunogenicity, and safety of GI-4000 plus Gem in patients with Ras mutant + resected pancreas cancer. Methods: The study enrolled 176 Ras mutant + pancreas cancer subjects post resection randomized 1:1 to GI-4000 plus Gem or placebo plus Gem (stratified by resection status; R0 or R1). Three weekly injections of GI-4000 or placebo were followed by 6 cycles of Gem 1000 mg/m 2 iv (day 1, 8, 15 every 28 days). Monthly GI-4000 or placebo were administered on the Gem off-weeks and continued monthly until intolerance, disease recurrence, or death. The primary endpoint is RFS. Data for the 39 R1 subjects (GI-4000 n=19, Placebo n=20) have been unblinded and analyzed. Results: The GI-4000 group had an 11.4 week advantage in median overall survival (524 Days vs 444 Days), 16% advantage in 1 year survival (72% vs 56%), and a 4.6 week advantage in median RFS (287 Days vs 255 days). The GI-4000 group showed a significantly higher rate of mutation specific T cell response to Ras by ELISpot assay; 7/15 (47%) vs 1/12 (8%), p=0.032,with a more pronounced survival benefit in GI-4000 treated immune responders; 21.7 week advantage in median survival (596 Days vs 444 Days) compared to placebo. No significant novel toxicities have been observed to date. Conclusions: GI-4000 in combination with adjuvant Gem showed a clinically meaningful point estimate for the treatment effect on survival in R1 subjects with Ras mutant + pancreas cancer. GI-4000 was immunogenic and well tolerated. Ras specific immune response was associated with a more pronounced benefit in median survival. These data warrant further study in a definitively powered clinical trial for GI-4000 in the adjuvant setting in R1 subjects.
Management of localized primary breast B-cell Non-Hodgkin's Lymphoma: Role of CNS prophylaxis
Authors: Y. M. Kirova, J. Dumont, P. Validire, A. Vincent-Salomon, D. Decaudin, C. B. Clough, V. Servois, A. Savignoni, A. Fourquet
Journal: Journal of Clinical Oncology (2004)

6722 Background:to evaluate the results of combined treatment modality with doxorubicin-based chemotherapy (C), locoregional radiotherapy (RT) and CNS prophylaxis in NHL of the breast. Methods: From 1984 to 1999, 20 female pts with diffuse large B-cell lymphoma of the breast, were treated at the Curie Institute. Following biopsy-established diagnosis, complete physical exam, CAT of the chest, abdomen, pelvis, and brain, CSF, gastric endoscopy, usual blood work, bone marrow biopsy were done. All pts were Ann Arbor stage I -II. The C protocols were: time-modified CHOP: D1, 10, 20,35,50,65 (n=14) or MACOP-B variant (n=3), both with IT MTX and araC. Three pts received ACVB P with IT MTX and 2 HD MTX infusions. All pts had RT to the breast and regional nodes, within a month after C. Total dose was 40 Gy in 20–22 fractions using megavoltage photons. RT to CNS (18 Gy/10 fr.) was delivered in the same time. Results: Median age was 62.8 yrs (ranged 26–86). All pts had a unilateral breast mass, median size 6 cm (2–21 cm). There were 14 IE and 6 IIE, increased LDH in 4 cases, and B-symptoms in 2. The CR rate was 100% at the end of treatment. No serious toxic event was observed. After a median follow-up of 103 months (range 60–177), 8 pts relapsed: 3 in MACOP-B group at 3, 6, and 16 months, and 5 in modified CHOP-group (at 7, 40, 66, 144, and 161 months). Relapses included lymph nodes (3); LN+breast (2); cutaneous (1), GI (1). There was only 1/8 pt with isolated CNS recurrence, which experienced 2nd CR. Currently, 8 pts followed-up 5–15 yrs, are still alive and never experienced recurrence, 1 pt is alive with a low grade LNH. Two patients had died from other diseases in CR. One pt was last seen in CR at 6 yrs. Conclusions: CNS prophylaxis by IT C and CNS RT could prevent CNS relapses in pts with primary breast LNH. Though all pts had CR following treatment, relapses occurred in 40% of the pts including late relapses. Prospective studies are needed to improve the long-term results and define the modality of CNS prophylaxis in this rare but aggressive disease. No significant financial relationships to disclose.
Oncogenic ARAF as a new driver in lung adenocarcinoma.
Authors: Luiz H. Araujo, Joseph Amann, Marcin Imielinski, Heidi Greulich, Matthew Meyerson, David Paul Carbone
Journal: Journal of Clinical Oncology (2014)

11034 Background: We recently identified a novel somatic mutation in ARAF in a lung adenocarcinoma from a patient that demonstrated a remarkable response to sorafenib. The S214C lies in a negative regulatory domain of ARAF, distinct from the catalytic domain mutations commonly found in BRAF. The aim herein was to evaluate the oncogenic potential and characterize the mechanism of ARAF S214C activation. Methods: ARAF constructs were generated and ectopically expressed in an immortalized bronchial epithelial cell line (BEAS-2B). We evaluated the acquisition of anchorage independence, MEK activation, and cell morphology. COS7 cells were used for co-immunoprecipitation (IP) and kinase assays. Results: Cells expressingARAF S214C substantially increased soft agar colony formation relative to vector, wild-type, kinase-dead (D429A), and double-mutant (S214C+D429A) variants. Accordingly, ARAF S214C cells exhibited increased phospho-MEK levels, suggesting that the transforming potential is dependent on its kinase activity. We also demonstrated that cells expressing ARAF S214C with an additional RAS-binding domain mutation (R52L) lacked MEK activation and failed to form colonies, showing that RAS binding is essential for activity. Interestingly, ARAF S214C cells acquired an elongated, fibroblast-like shape, characteristic of MEK-active cells. Conversely, none of other variants presented this morphology. To determine if either BRAF or RAF1 were necessary for ARAF S214C activity, we performed BRAF and RAF1 knockdowns. ARAF S214C-induced MEK activation was not reverted by the knockdowns, suggesting that BRAF and RAF1 are not required. Subsequently, COS7 cells were co-transfected with tagged constructs of ARAF and either BRAF or RAF1, followed by co-IP. We showed that ARAF S214C does not heterodimerize, unless stimulated with sorafenib. Importantly, sorafenib-induced heterodimers lacked kinase activity, compatible with the clinical response reported. Conclusions: ARAF S214C demonstrates the in vitro features of a driver oncogene, and also a distinct mechanism of action. This oncogenic process can be successfully suppressed by RAF inhibitors like sorafenib, and could represent a new target for personalized therapy in advanced lung adenocarcinoma.
Checkpoint expression pre and post chemoradiation in operable esophageal cancer.
Authors: Ronan Joseph Kelly, Ali Hussainy Zaidi, Matthew Smith, Ashten N. Omstead, Juliann E. Kosovec, Daisuke Matsui, Samantha A Martin, Gene Grant Finley, Jan F Silverman, E. Day Werts, Blair A. Jobe
Journal: Journal of Clinical Oncology (2017)

139 Background: PD-L1 expression has been reported in 40% of gastroesophageal cancers, but little data exists with regards to expression of other immune checkpoints. Here, we examined baseline expression levels for multiple immune modulators in 31 resected esophageal adenocarcinomas (EAC) and investigated the change in expression levels post-chemoradiation. Methods: Slides were stained on a Ventana BenchMark ULTRA automated stainer for CTLA-4 (Santa Cruz Clone F-8, dilutions 1:100) and PD-L1 (Dako clone 22C3 prediluted). Tonsil tissue was used as a control for lymphocytes, and a provided tumor control was used for PD-L1. Positivity was classified as &gt; 1%, and the stained cell type was recorded (lymphocytes or tumor). Additionally, laser capture microdissection was performed, and RNA was isolated and pre-amplified to determine expression levels of TIM-3, GITR, IDO-1, LAG-3, CD-137, OX-40, and KIR-3 using RT-PCR. Gene expression was calculated using the ΔΔ -Ct method, and intergroup comparisons were performed and normalized against a cohort of 15 pathologically confirmed normal esophageal epithelium cases. Results: Post-chemoradiation cases demonstrated increased expression for PD-L1, when compared to matched pre-chemoradiation controls [p-value = 0.0098]. Similarly, all immune modulators profiled by gene expression were significantly upregulated in matched post vs. pre samples, except for CD-137. There was no significant difference in percentage of 4-fold or more upregulation based on PD-L1 status for IDO-1, OX-40, CD-137 and KIR-1, indicating that these markers may function independently of PD-L1 positivity. Conclusions: PD-1 inhibiton in both the neoadjuvant and adjuvant setting is currently being investigated in EAC, but future studies may look to select patients according to personalized checkpoint expression patterns. [Table: see text]