tbuckley/cabot-search huggingface dataset:
Hypersensitivity skin reactions in melanoma patients treated with vemurafenib after ipilimumab therapy.
Authors: James J. Harding, Mario E. Lacouture, Melissa Pulitzer, Margaret Callahan, Michael Andrew Postow, Richard D. Carvajal, Jedd D. Wolchok, Paul B. Chapman
Journal: Journal of Clinical Oncology (2012)

8515 Background: Ipilimumab (IPI) and vemurafenib (VEM) each improve overall survival for patients (pts) with metastatic melanoma. Both are FDA-approved and are being used in pts with BRAF V600E -mutated metastatic melanoma. We previously described cases of prominent skin eruptions associated with VEM in pts who had previously received IPI. Methods: We have updated our experience of BRAF V600E -mutated melanoma pts treated with VEM who had previously received IPI. Pts were treated at our center from January 2007 to January 2012. Data were collected under an approved IRB waiver. Results: Sixteen melanoma pts were treated with VEM after having received IPI. The most common drug-related adverse event (AE) associated with VEM was rash, occurring in 13/16 patients (81.3%, 95% CI 56.5-93.2). Four pts developed a severe, Grade 3, maculopapular rash within 8 days of starting VEM. Biopsies in 2 pts revealed spongiotic and perivascular dermatitis with eosinophils consistent with a drug hypersensitivity reaction. Hypersensitivity reactions did not progress to life-threatening reactions such as anaphylaxis or Stevens-Johnson syndrome, nor did they result in VEM dose discontinuation. Reactions were managed with corticosteroids and dose modifications. Grade 3 rash strongly correlated with initiating VEM within one month of IPI (Fisher’s exact test, p = 0.007) and was not associated with the dose of prior IPI, the number of prior doses, or immune-related AEs. The incidence of Grade 3 rash in this pt cohort was significantly higher than in pts treated on the phase III trial of VEM (4/16, 25% versus 28/336, 8%; χ 2 = 5.13, Df = 1, p = 0.02). The objective overall response for VEM was 50% (95% CI 26.5-73.4), which is similar to response rates seen on the phase II and III trials. Conclusions: In pts receiving VEM who have previously received IPI, dermatologic AEs appear to be more common. This effect seemed most pronounced if VEM was given within one month of completing IPI. Although more data are necessary to confirm this apparent association, we speculate that the release of immune checkpoint inhibition by IPI may predispose pts to hypersensitivity skin reactions to VEM.
Long-term follow-up from STAMP, a phase II trial, evaluating sipuleucel-T and concurrent (CON) vs sequential (SEQ) abiraterone acetate + prednisone in metastatic castration-resistant prostate cancer patients (pts).
Authors: Eric Jay Small, Raymond S. Lance, Charles H. Redfern, Frederick E. Millard, Thomas A. Gardner, Nancy Ann Dawson, Lawrence Fong, Lawrence Ivan Karsh, John M. Corman, Luke T. Nordquist, Myron I Murdock, Brendan D. Curti, Nancy N. Chang, Neal D. Shore
Journal: Journal of Clinical Oncology (2017)

190 Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) pts, was evaluated in combination with abiraterone acetate and prednisone (abi) in the phase II STAMP trial (NCT01487863), with pts randomly assigned to receive CON sip-T + abi or SEQ sip-T followed by abi. The combination was well-tolerated and did not alter the immune response parameters that correlate with overall survival (OS) (Small Clin Can Res 2015). Here, we present long-term follow-up of clinical outcomes, including OS. Methods: mCRPC pts were randomized 1:1 to CON or SEQ therapy with sip-T and abi. Abi began 1 day after (CON) or at wk 10 (SEQ) after the first sip-T infusion and continued for 26 wk of therapy, after which continued abi therapy was permitted. Long-term clinical outcomes included OS, disease-specific death (DSS), progressive disease (PD), time to first anticancer intervention (tACI), and safety. Results: 69 pts were enrolled (35 CON; 34 SEQ). Median OS was 34.0 mo (95% CI, 24.4-not estimable [NE]; 30.0 mo CON; 34.2 mo SEQ; p = 0.921), and median time to DSS was not reached (CON vs SEQ; p = 0.733). Median time to PD was 17.3 mo (95% CI, 9.7–NE; 17.7 mo CON vs 13.9 mo SEQ; p = 0.914; consistent with higher rates of abi discontinuation due to PD in SEQ [26.5% vs 14.3% in CON]). tACI was similar between arms at 15.4 mo (95% CI, 11.0–19.9). No new safety signals were observed with the combination, and no discernable difference in clinical outcomes was observed with CON or SEQ treatments. Conclusions: Long-term follow-up data confirm that sip-T + CON or SEQ abi is well-tolerated, with no new safety signals. No clear differences were observed in clinical outcomes between arms, although the study was not powered to detect these differences. Future and more appropriately powered studies on the effect of sip-T + continuous abi for responding pts may provide further insights on the benefit of combination therapy. Clinical trial information: NCT01487863.
A nomogram associated with high probability of malignant nodes in the surgical specimen after trimodality therapy of patients with esophageal cancer (EC).
Authors: Mariela A. Blum, Yuki Hayashi, Lianchun Xiao, Akihiro Suzuki, Bradley Sabloff, Dipen M Maru, Takashi Taketa, James Welsh, Steven H Lin, Jeffrey H Lee, Manoop S. Bhutani, Brian Weston, Wayne Lewis Hofstetter, Stephen Swisher, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2012)

e14547 Background: The presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality therapy) in patients with EC portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesized that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality therapy in EC patients. Methods: We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients. Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p=0.0002) and DFS (p&lt;0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381-36.969; p=0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024-4.926; p=0.044), tumor length (OR, 1.178; 95% CI, 1.024-1.357; p=0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242-0.915; p=0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007-8.485; p=0.049), and enlarged node(s) on post-chemoradiation computerized tomography (OR, 3.465; 95% CI, 1.549-7.753; p=0.002). The normogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756. Conclusions: Our nomogram highly correlates with the presence of +ypNodes after chemoradiation and upon validation; it could prove useful in individualizing therapy for EC patients. Supported by UTMDACC and generous donors.
Molecular subtyping of metastatic urothelial bladder cancer.
Authors: Charlotte Ackerman, Sanjeev Mariathasan, Dorothee Nickles, Alfonso Gomez De Liano Lista, Akhila Ganeshi Wimalasingham, Bernadett Szabados, Thomas Powles
Journal: Journal of Clinical Oncology (2017)

326 Background: TCGA molecular sybtyping is established in metastatic urothelial bladder cancer (UBC). It remains unclear if it is of prognostic importance with chemotherapy in metastatic UBC. Data into immune therapy suggests TCGA subtyping is predictive to response. Methods: Archival formalin-fixed paraffin embedded (FFPE) tissue were analysed from 170 patients that had consented into a clinical trial (NCT00949455) after first line chemotherapy for metastatic disease. Gene expression levels were quantified by NanoString technology. Molecular subtypes were assigned according to The Cancer Genome Atlas (TCGA) subtypes. Clinical information was available for all patients and analysis on individual genes were explored. Results: 170 patients were analysed, 75% male. 107 (64%) patients received cisplatin based first-line chemotherapy, with 36% receiving carboplatin based regimen. Median overall survival (OS) was 15.73 months [95% CI: 13.87-17.58], and median progression free survival (PFS) was 10.71 months [95% CI: 8.97-12.45]. Samples were initially clustered into luminal (n=109) and basal (n=61) subtypes. Response to first line chemotherapy occurred in all subtypes but was shown to be significantly higher in the luminal subtype versus the basal subtype [58% vs 20%, p=0.01]. PFS was superior in luminal subtypes [11.8 months vs 8.9 months, p=0.005]. Exploratory analysis showed that luminal II subtype had the best outcome for OS [20.3 months, p=0.03] compared to the other subtypes. Outcomes with other genes including immune markers were explored. TCGA outcomes can be summarised in the table. Conclusions: In metastatic urothelial cancer, TCGA subclassifying influences outcome of patients post chemotherapy. [Table: see text]
The clinical significance of <i>KRAS</i> monitoring in tumor tissues and blood of patients with pancreatic tumor.
Authors: Fumiaki Watanabe, Koichi Suzuki, Kosuke Ichida, Yuji Takayama, Taro Fukui, Nao Kakizawa, Hiroshi Noda, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2017)

334 Background: Monitoring of gene alterations in blood to track circulating tumor DNAs has been attempted for a clinical application. For example, KRAS monitoring in colorectal cancer provides a valuable biomarker for diagnosis and prediction of treatment outcome. While half of of colon cancer has RAS mutation, 90% of pancreatic cancer shows KRAS mutation, suggesting that most of pancreatic cancer is a good candidate for KRAS monitoring. In this study, we elucidated the clinical significance of KRASmonitoring in patients with pancreatic tumor during treatments. Methods: KRAS mutation in tumor tissues was determined by Scorpion ARMS or RASKET methods in 39 patients with pancreatic tumors. KRASmutation in blood (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, Q61H) were investigated by using droplet digital polymerase chain reaction (ddPCR) in 24 patients treated with chemotherapy. Results: KRAS assessment in tumor tissues showed 33 patients with mutation and 6 patients without mutation. Thirty-three patients with mutation showed significantly poor prognosis of 49% in three years overall survival (OS) as compared with 100% in 6 patients with mutation (p=0.02). KRAS assessment in blood revealed that KRAS mutation was detected in 14 patients, but no detection was seen in 10 patients. Patients harboring KRAS mutation in blood exhibited significantly poor treatment outcome, including 12 patients with progressive disease, as compared with 10 patients without detection of mutation, including 6 patients with any treatment responses (stable disease in 4 patients and partial response in 2 patients, p=0.03). Fourteen patients with mutation in blood displayed poor prognosis of 20% in three years overall survival (OS), comparing to 69% in 10 patients without mutation in blood (p=0.06). Conclusions: KRAS status in tumor tissues was involved in prognosis; in addition, KRAS status in blood was implicated in treatment response of chemotherapy in patients with pancreatic tumor. KRAS monitoring in tumor tissues and blood provides useful information for the treatment strategy including chemotherapy in patients with pancreatic tumor.
A phase Ib/II study of imatinab and everolimus in patients with PDGFRA+ synovial sarcoma.
Authors: Mary Louise Keohan, William D. Tap, Mark Andrew Dickson, Sandra P. D'Angelo, Richard D. Carvajal, Mrinal M. Gounder, Rita Elena Morales, Mercedes M. Condy, M Hameed, Alan Loh Ho, S Vasuveda, Li-Xuan Qin, Jason J. Luke, Naoko Takebe, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2013)

10558 Background: Our group previously reported that PDGFRA is the most highly overexpressed kinase gene in synovial sarcoma. Our preclinical studies also demonstrated synergistic anti-tumor activity by inhibiting both PDGFRA and mTOR signaling with imatinib and rapamycin respectively in PDGFRA + synovial sarcoma cell lines. Based on these data, a phase Ib/II study to evaluate the toxicity and efficacy of imatinib and everolimus was undertaken. Methods: The primary endpoint of the phase 1b portion of the study was to determine the maximum tolerated dose (MTD) of everolimus administered with imatinib. Starting dose of everolimus and imatinib was 5 mg/day and 400 mg/day respectively. Response rate (RR) by RECIST was the primary end-point of the Phase II study. The phase II study used a Simon two stage design. 9 patients (pts) were to be accrued initially. If there were no responses, further accrual would be stopped and treatment declared ineffective. If there was at least 1 response, an additional 15 pts would be accrued for a total of 24. Key eligibility: metastatic disease, any number of priors. Pre and post treatment tumor biopsies were mandated. Results: 12 pts were treated.5 M and 7 F, median age 44 (range: 22-71), median priors 4 (range: 0 - 6). Two DLTs were observed at dose level 2 (10 mg everolimus /400 mg imatinib) with grade 3 transaminases and hypophosphatemia. Everolimus 5 mg/ imatinib 400 mg was the MTD in the phase II study. 10 pts evaluable for response, included 4 pts treated at the MTD in the Phase 1b study. There were no RECIST responses. Stable disease was observed in 3 pts (7, 7, 19 mos.). Western blot and IHC analysis of matched pair tumor biopsies indicate inhibition of p-AKT, p-S6 and decreases in Ki 67. Conclusions: Imatinib and everolimus failed to achieve its primary response endpoint. However, prolonged stable disease in 3 pts in association with inhibition of PDGFRA and mTOR suggest clinical benefit and biological effect for this drug combination. Clinical trial information: CTEP 8603.
Collaboration of AR and ERα in conferring resistance to an aromatase inhibitor.
Authors: Yassine Rechoum, Domenico Iacopetta, Ines Barone, Daniela Rovito, Sebastiano Ando', Nancy Weigel, Suzanne A. W. Fuqua
Journal: Journal of Clinical Oncology (2013)

579 Background: We have previously shown a role for AR overexpression in tamoxifen resistance in ERα-positive MCF-7 breast cancer cells; here we hypothesized that AR overexpression might similarly be involved in resistance to the aromatase inhibitor anastrazole (Anas). Methods: MCF-7 cells were transfected to express the aromatase gene (MCF-7 Arom), or the aromatase and AR (MCF-7 AR Arom cells). Western blot analysis was used to evaluate protein levels, MTT and soft agar assays to evaluate proliferation, luciferase reporter assays to evaluate transcriptional activities and confocal microscopy was used for localization. Results: Anas inhibited androstendione (AD)-stimulated growth in MCF-7 Arom cells but not in MCF-7 AR Arom cells. Similarly, Anas did not inhibit ERα transcriptional activity in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R, pIRS-1, pAKT, and pMAPK were also observed in AR Arom cells, suggesting constitutive activation of nongenomic signaling in these cells. Consistent with activation of these potential treatment “escape” mechanisms, inhibitors of AKT and IGF-1R restored sensitivity to Anas. Sensitivity to Anas was also restored using the AR antagonist MDV3100, however use of Abiraterone acetate as a single agent most effectively blocked proliferation of AR-overexpressing cells. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR overexpressing ERα-positive breast cancers. Unexpectedly, AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, as shown by inhibition with the AR antagonist bicalutamide. AR and ERα co-localized both in the cytoplasm and in the nucleus of AD+Anas-treated cells, suggesting potential activation of both non-genomic and nuclear-mediated effects when AR is overexpressed in ERα-positive cells. We confirmed these findings in breast cancer cells with acquired resistance to tamoxifen. Conclusions: These results show the necessity to block both AR and ER in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways or direct inhibition of androgen/estrogen synthesis provide alternative approaches to restore hormone sensitivity in resistant breast tumors.
Borderline resectable pancreas adenocarcinoma managed with neoadjuvant chemoradiotherapy: A prospective case series.
Authors: Hiren A. Mandaliya, Jarad Martin, Adeeb Majid, Jon Gani, Swetha Sridharan, Stephen P. Ackland, Mahesh Kumar, Kalpesh Shah, Stanley Chen, Michael Fay, James F. Lynam, Andre Van Der Westhuizen, Girish Mallesara, Stephen Philcox, Tony Bonaventura, Fiona Day
Journal: Journal of Clinical Oncology (2017)

499 Background: Borderline resectable pancreas cancers (BRPC) often require vascular reconstruction, have higher rates of operative margin positivity and confer a poor prognosis. In 2014, our high-volume pancreatectomy, gastrointestinal tumor multidisciplinary treatment (GI MDT) group endorsed a consensus anatomical definition of BRPC consistent with NCCN criteria. Diagnostic and staging tests were standardized and a neoadjuvant chemoradiotherapy protocol adopted with the goals to (1) improve R0 resection rate and (2) prevent futile surgery in rapidly progressive disease. Methods: Neoadjuvant chemoradiotherapy (CRT) consisted of 50.4Gy in 28# and concurrent capecitabine 830mg/m2 bd. Pancreatectomy was planned 4-8 weeks later unless repeat imaging showed progressive disease. Comprehensive, prospectively defined data items were collected on all patients (pts) diagnosed with BRPC. Results: Nine pts have been diagnosed with BRPC by the GI MDT. Seven pts received full dose of CRT, one pt progressed during CRT hence stopped early and one pt didn’t receive CRT due to significant deterioration beforehand. CRT was tolerable in all eight pts who received it; there were no dose modifications for toxicity. Post-CRT, three pts underwent curative-intent resection and all are still alive (494, 319 and 172 days post-CRT). One was found to have a solitary liver metastasis during surgery (resected), R1 resection (SMV margin involvement) of T3N1 tumor and is receiving palliative chemotherapy. Two other pts underwent R0 resections (T3N0, T3N1) with histopathologic response to CRT. Four pts showed progressive disease on post-CRT imaging (all local &amp; distant progression) and subsequently received palliative therapy. Median survival (first dose CRT to death) in the 5 CRT pts who have succumbed was 509 days (range 363-577). Conclusions: In this small prospective, unselected cohort the majority of pts diagnosed with BRPC demonstrated disease progression during/after neoadjuvant CRT and did not proceed to surgical resection, underscoring the poor prognosis of this pancreas cancer subset. Neoadjuvant CRT is well tolerated and did not preclude subsequent surgery in those patients with stable disease.
A phase 1, open-label, dose escalation study of AMG 337 in Asian patients (pts) with advanced solid tumors.
Authors: Hirofumi Yasui, Benny Amore, Yizhou Jiang, Swaminathan Murugappan, Toshihiko Doi
Journal: Journal of Clinical Oncology (2015)

e13538 Background: In the first-in-human study of AMG 337, an investigational, selective, oral MET kinase inhibitor, in Western pts with advanced solid tumors, headache was the main adverse event (AE); AMG 337 doses up to 300 mg QD were tolerated. This study assessed tolerability and safety, including dose-limiting toxicities (DLTs), of AMG 337 in Asian pts with advanced solid tumors. Methods: Eligible pts were Asian, aged ≥20 years, with ECOG PS ≤2 and pathologically confirmed, advanced solid tumors for which prior Tx for advanced disease was received, no standard Tx exists, or standard Tx was refused. Pts enrolled in a 3+3+3 dose escalation scheme. Two cohorts (AMG 337 150 and 300 mg QD) received AMG 337 orally in 28-day cycles. After all pts in a cohort completed a 28-day safety observation period, a dose-level review meeting was convened to determine whether DLT criteria had been met for dose escalation. Endpoints: AEs and DLTs. Results: As of JUN 18, 2014, cohort 1 (AMG 337 150 mg QD) enrolled 4 Japanese pts (female, n=2; male, n=2) aged 41–70 years with lung, hepatic, cecal, or pancreatic tumors (each n=1); 4 pts were evaluable for safety (3 for DLTs). As of OCT 13, 2014, cohort 2 (AMG 337 300 mg QD) enrolled 7 Japanese pts (female, n=2; male, n=5) aged 45–74 years with bladder, colon, or liver carcinoma (each n=1), gastric (n=2) or rectal adenocarcinoma (n=1), or duodenal neuroendocrine carcinoma (n=1); 7 pts were evaluable for safety (6 for DLTs). No DLTs were observed. All pts experienced AEs. All AEs were grade 1 or 2; headache was the most common (Table). Steady-state Cmaxand AUC mean (±SD) estimates were 3.90 (2.03) mg/L and 36.4 (20.0) mg·h/L, respectively, in cohort 2. The recommended dose of AMG 337 for the currently open phase 2 study is 300 mg QD. Conclusions: The safety profile of AMG 337 in Asian pts with advanced solid tumors was consistent with that observed in Western pts. Further evaluation of AMG 337 in pts with MET-amplified tumors is warranted. ClinicalTrials.gov identifier: NCT02096666. Clinical trial information: NCT02096666.Incidence of AEs. Cohort 1 (n=4) Cohort 2 (n=7) Pts with AEs,* n Any AE 4 7 Headache 2 6 Vomiting 3 4 Decreased appetite 2 4 Nausea 3 2 Dry skin 1 3 Rash 0 3 Malaise 0 2 Diarrhea 1 1 Hypoalbuminemia 1 1 Peripheral edema 1 1 *AEs occurring in ≥2 pts in cohort 1 + 2.
Reduced-Intensity (FB2) Vs Reduced-Toxicity Myeloablative (FB3/FB4) Fludarabine/Busulfan Based Conditioning Regimens for Non-Hodgkin Lymphoma (NHL) Allografted Adult Patients: A Retrospective Study on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Authors: Amandine Le Bourgeois, Myriam Labopin, Didier Blaise, Patrice Ceballos, Stéphane Vigouroux, Regis Peffault De Latour, Felipe Suarez, Eric Deconick, Sylvain Chantepie, Jacques-Olivier Bay, Claude-Eric Bulabois, Etienne Daguindau, Nathalie Contentin, Ibrahim Yakoub-Agha, Jerome Cornillon, Sylvie Francois, Pascal Turlure, Amandine Charbonnier, Pierre-Simon Rohrlich, Stephanie Nguyen, Natacha Maillard, Tony Marchand, Mohamad Mohty, Patrice Chevallier
Journal: Blood (2016)