tbuckley/cabot-search huggingface dataset:
PTSD and lymphoma: Two very different psychological trajectories following a common diagnosis.
Authors: Regina Jacob, Laura Robbins, John Leonard, Janey C Peterson
Journal: Journal of Clinical Oncology (2017)

195 Background: Long-term chronic lymphoma survivors report lower quality of life compared to those who are cured of lymphoma, despite an equal prevalence of PTSD symptoms in both groups. Posttraumatic Growth (PTG), or positive psychological change following a traumatic event, has been associated with greater acceptance of the disease and greater quality of life, particularly because PTG has been shown to diminish the negative effects of PTSD symptoms. Methods: Semi-structured, in-person qualitative interviews were conducted among a convenience sample of lymphoma survivors. Participants answered questions about their emotional reactions after diagnosis, during treatment, and symptoms of PTSD and positive changes—if any—that developed during the cancer experience. Interviews were audiotaped, transcribed, and analyzed using Grounded Theory methodology. Results: 77 lymphoma survivors - 75% chronic lymphoma, 25% curable lymphoma completed interviews. Themes included 1) disease: perception of health; 2) support system: physician support, social support, and healthcare system support; 3) internal processing: acquiring knowledge, and coping mechanisms; 4) fear: stigma of cancer; 5) growth: relationship with others, and appreciation of life; and 5) acceptance: preparation, and death &amp; dying. Most participants, regardless of chronic or curable diagnoses, reported distress during diagnosis and treatment within the categories: perception of health, healthcare system support, social support, and acquiring knowledge. Chronic lymphoma participants reported less fear and subsequently less growth than their curable counterparts. Participants further viewed their cancer as carrying a different stigma, which then resulted in these blunted reactions. Conclusions: Chronic lymphoma patients do not follow the same psychological trajectory as their curable counterparts with regards to long-term adjustment. They, instead, emulate patients with other chronic disease. The blunted psychological experience of both PTSD symptoms and PTG could potentially explain the lower reports of quality of life in the long term cancer survivor with indolent disease.
Identifying somatic oncogenic mutations in leukocytes that infiltrate primary breast cancers.
Authors: Elizabeth Anne Comen, Maria Kleppe, Yong Hannah Wen, Franck Rapaport, Zvika Granot, Nicholas D. Socci, Agnes Viale, Daoqi You, Robert Benezra, Britta Weigelt, Edi Brogi, Michael F. Berger, Jorge Reis-Filho, Ross L. Levine, Larry Norton, Lennart Bastian, Matthew Keller
Journal: Journal of Clinical Oncology (2015)

11000 Background: In the past decade, sequencing studies have delineated somatic mutations in human cancers. Given that cancer cells interact with their microenvironment and the presence of somatic mutations in a subset of elderly individuals with clonal hematopoiesis, we hypothesized that white blood cells within tumors might be characterized by clonally selected mutations in known cancer genes. Here we provide direct evidence of the presence of clonal somatic mutations affecting known cancer genes in tumor-infiltrating leukocytes from breast cancer (BC) patients. Methods: We evaluated tumor infiltrating leukocytes in 17 primary BC samples: 13 patients had triple negative BC, 2 had ER+, HER2+ BC, and 2 had ER+, HER2- BC. Fluorescent activated cell sorting was employed to separate CD45-positive hematopoietic cells from CD45-negative epithelial cells. Whole exome sequencing of tumor infiltrating leukocytes revealed candidate somatic mutations in known cancer genes, including BCOR, NOTCH2, TET2, NF1, EZH2 and JAK1. To validate our findings, we expanded our sample size to 20 patients and performed targeted capture massively parallel sequencing of matched tumor-infiltrating leukocytes and germline DNA. Laser-capture microdissected cancer cells were subjected to high-depth sequencing to rule out the presence in cancer cells of the somatic mutations found in leukocytes. Results: In 10 of the 20 patients, we identified and validated somatic mutations, including mutations affecting genes associated with leukemia in tumor infiltrating leukocytes but not in laser-capture microdissected BC cells from the same patients. Targeted sequencing indicated that these mutations are enriched in tumor-infiltrating leukocytes as compared to circulating leukocytes. Conclusions: We identified clonal somatic mutations in known cancer genes in tumor infiltrating leukocytes. These data suggest a novel relationship between cancer cells and mutant infiltrating leukocytes. Studies are underway to investigate functional interactions between BC cells and hematopoietic cells harboring somatic mutations.
Association between single nucleotide polymorphism (SNPs) of CYP3A4 and SLC28A3 and clinical outcome in metastatic breast cancer (MBC) patients receiving paclitaxel plus gemcitabine (PG) chemotherapy as first-line treatment.
Authors: Seock-Ah Im, Yeon Hee Park, Soo-Youn Lee, Sook Young Woo, Seonwoo Kim, Won Jin Chang, Moon Ki Choi, Jung Yong Hong, Oh-Nam Ok, Jeong Ju Seo, Jin Seok Ahn, Young-Hyuck Im
Journal: Journal of Clinical Oncology (2013)

1088 Background: Paclitaxel and gemcitabine (PG) combination chemotherapy is an effective regimen in metastatic breast cancer (MBC) patients as first-line chemotherapy. The primary purpose of our study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC patients treated with PG chemotherapy. Methods: A total of 324 MBC patients were enrolled in this prospective multicenter trial as the first-line chemotherapy. Eighty five of 324 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 15 genes (27 SNPs) from pathways that may influence cellular sensitivity to paclitaxel and gemcitabine were genotyped from PB sample. Results: Median progression free survival (PFS) and overall survival (OS) of all 324 patients was 8.7 months (95% CI: 7.5-9.6 mo.) and 26.9 months (95% CI: 23.6-30.1 mo.), respectively. Among clinical parameters, young age (p = 0.047, HR 1.03 [95% CI, 1-1.07]), positive hormonal receptor status (p = 0.0004, HR 0.26 [95% CI, 0.12-0.54]), and hepatic metastasis (p = 0.046, HR 2.30 [95% CI, 1.02-5.18]) were identified predictive factors for OS in Cox-regression analysis. SLC28A3 SNP which participates in transcription showed correlation with OS. OS of the patients with CC and CT genotypes in SLC28A3 was significantly longer than the OS of the patients with TT genotype (median OS: 31 vs. 37 vs. 21 months, p = 0.027, HR 2.6 [95% CI, 1.1-6.3]). OS of the patients with TT genotype in CYP3A4 was significantly longer than the OS of the patients with TC genotype (median OS: 37 vs. 19 months, p = 0.021, HR 5.8 [95% CI, 1.3-25.7]). After adjusting hormonal receptor status, age, and hepatic metastasis, prognostic value of SLC28A3 remained significant (HR 2.9, p = 0.047). Other SNPs were not significantly associated with PFS, OS, or toxicities. Conclusions: SLC28A3 SNP can predict with the clinical outcome of MBC patients treated with PG chemotherapy. Further studies for functional mechanism of germline polymorphisms in SLC28A are warranted.
Phase I study of the safety and tolerability of the Exportin 1 (XPO1) inhibitor Selinexor (SXR) in Asian patients (pts) with advanced solid cancers.
Authors: David Shao Peng Tan, Mei-Yan Pang, Wei Peng Yong, Ross A. Soo, Cheng Ean Chee, Yee Liang Thian, Anil Gopinathan, Andrea Li Ann Wong, Priscillia Koe, Raghav Sundar, Jingshan Ho, Sharon Friedlander, Yosef Landesman, Tami Rashal, Dilara McCauley, Sharon Shacham, Soo Chin Lee, Boon C. Goh
Journal: Journal of Clinical Oncology (2015)

2542 Background: SXR is an orally administered potent XPO1 inhibitor that forces nuclear retention and activation of multiple tumor suppressor proteins resulting in tumor cell death. SXR was evaluated in Asian pts with advanced cancer to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDn) and efficacy. Methods: SXR dose escalation was initiated in a 3+3 design on a twice weekly continuous 28 day cycle, schedule 1 (S1), but stopped due to persistent drug-related adverse events (AEs). Two further schedules were explored: S2, once weekly continuously every 28 days, and S3, twice weekly for 2 weeks of a 21 day cycle. Serial tumor biopsies were performed pre- and 6-8 weeks post SXR. RECIST/ Cheson lymphoma criteria for response was evaluated every 2 cycles. Results: 18 pts (median age 61 yrs; ECOG 0-1) received escalating doses of SXR across 3 schedules. In S1 no dose-limiting toxicity (DLT) occurred at expanded dose-level (DL) 1 (40mg/m2, 6pts), but was stopped due to persistent ≥ G2 AEs (fatigue [50%], hyponatremia [50%], anorexia [17%]) post cycle 1. In S2, at DL1 (50mg/m2, 3pts) and DL2 (60mg/m2, 3pts), G1/2 AEs were hyponatremia (67%), nausea (33%), fatigue (50%) and anorexia (50%) with no ≥ G3 AEs. In S3, at DL1 (40mg/m2, 3 pts) and DL2 (50mg/m2, 3 pts); AEs were hyponatremia G1/2 (50%) and ≥ G3 (50%), nausea G1/2 (33%) and ≥ G3 (17%), fatigue G1/2 (67%) and ≥ G3 (33%), anorexia G1/2 (67%). No DLTs occurred in S2/S3. PK analysis demonstrated SXR exposure with no accumulation and comparable half-life and clearance when compared with non-Asian pts. At 40mg/m2, AUC0-inf (5,222 ng*h/mL) was comparable to the anti-tumor exposure observed in mice and dogs. Mean Tmax = 2hrs and T1/2 = 5.7 hrs. Reduced cellularity and proliferation with increased fibrosis and apoptosis was seen in tumors post-SXR administration. Of 13 evaluable pts, best responses were PR in 2pts with refractory diffuse-large B-cell lymphoma, SD in 8 pts (colorectal [n = 2], pancreas, squamous cell tongue, non-small cell lung, ovarian and hepatocellular carcinoma [n = 2]), and PD in 3pts. Conclusions: Dose-escalation of SXR is ongoing on S2 and S3 with more G3 AEs seen in S3. Promising antitumor activity was observed. Clinical trial information: NCT02078349.
Ipilimumab for recurrent glioblastoma (GBM).
Authors: Lauren R. Schaff, Andrew B. Lassman, Samuel A. Goldlust, Timothy Francis Cloughesy, Samuel Singer, Gary K. Schwartz, Fabio Massaiti Iwamoto
Journal: Journal of Clinical Oncology (2014)

e13026 Background: Currently available treatments for recurrent glioblastoma (GBM) are inadequate, and median survival is approximately 6 months. Ipilimumab (ipi) is an immune modulator that inhibits CTLA-4 and is active in refractory melanoma, including brain metastases. Methods: We retrospectively reviewed medical records of patients treated with ipi for recurrent GBM, and explored safety, response, and survival using Kaplan-Meier methodology. Results: There were 10 patients (6 men), median age 55 years (range, 41-65). All received prior radiotherapy and temozolomide, and 9 received prior bevacizumab. Ipi (3mg/kg/dose) was administered for 1st (1), 2nd (4), 3rd (4), or 6th(1) recurrence. Bevacizumab was administered concurrently to all patients to reduce corticosteroid requirements that can blunt ipi effect. Eight patents received concurrent GM-CSF. Other concurrent chemotherapy included nitrosoureas (5), carboplatin (1), temozolomide (1), or lapatinib (1). Corticosteroids (dexamethasone, 0.75 – 4.0 mg/day) were administered concurrently in 4. All patients were evaluated for toxicity. One experienced fever, elevated LDH, and transaminitis. There were no other significant toxicities, specifically no rash, endocrinopathies, or electrolyte abnormalities. Four patients recently started treatment and were not evaluable for efficacy analyses. Among the other 6 patients, best response was stable disease in 4, and progressive disease in 2; median progression free survival (PFS) was 2.2 months and overall survival (OS) was 5.1 months. Conclusions: Ipilimumab can be administered safely to patients with GBM with concurrent GM-CSF, bevacizumab, nitrosoureas, and other therapies. Concurrent bevacizumab may reduce corticosteroid requirements. Treatment earlier in the disease course merits investigation.
Italian cohort of ipilimumab expanded access programme (EAP): Efficacy, safety, and correlation with mutation status in metastatic melanoma patients.
Authors: Paola Queirolo, Francesco Spagnolo, Maresa Altomonte, Vanna Chiarion-Sileni, Jacopo Pigozzo, Michele Del Vecchio, Lorenza Di Guardo, Ruggero Ridolfi, Alessandro Scoppola, Pier Francesco Ferrucci, Virginia Ferraresi, Maria Grazia Bernengo, Michele Guida, Riccardo Marconcini, Mario Mandalà, Giorgio Parmiani, Gaetana Rinaldi, Massimo Aglietta, Ester Simeone, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2013)

9070 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma to show a survival benefit in randomised phase III trials. Efficacy and safety of ipilimumab treatment outside of clinical trials and the correlation with BRAF and NRAS mutation status were evaluated. Methods: Ipilimumab was available upon physician request for patients (pts) aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. BRAF and NRAS mutation status was retrospectively collected for all available pts. Patients were monitored for adverse events, including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. With a median follow-up of 6.5 months (range 0.5-30), the disease control rate among 833 pts evaluable for response was 34.3%: 28 pts (3.4%) with complete response, 83 (10.0%) with partial response and 175 (20.9%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.3 months and 7.2 months respectively, with 1-year survival rate of 36%. The Table shows mutation status for available patients. Disease control rates were comparable among pts with BRAF positive tumors and BRAF wild-type (37.5% vs 39.5%) and among pts with NRAS positive tumors and NRAS wild-type (57.1% vs 49.3%). Survival curves were also comparable between groups. 399 pts (46.7%) had a AEs of any grade, with 286 (33.5%) considered IrAEs. IrAEs were reversible with protocol specific guidelines. Conclusions: Based on EAP data, ipilimumab is an effective and safe treatment for pretreated pts with metastatic melanoma regardless BRAF and NRAS mutation status. [Table: see text]
Overall survival of metastatic melanoma (mM) treated with high dose IL-2 (HD IL-2) followed by anti-CTLA4 (IPI) and/or anti-PD-1/PDL1 (aPD1) therapy: Analysis of the prospective cohort of the PROCLAIM national registry.
Authors: Michael K.K. Wong, Michael Morse, David F. McDermott, Joseph Clark, Howard Kaufman, Gregory A. Daniels, Hong Hua, Sandra Aung
Journal: Journal of Clinical Oncology (2015)

e20071 Background: PROCLAIMSM (www.proclaimregistry.com) is an IL-2 observational registry with over 40 participating sites consisting of a retrospective (n = 170, locked) and prospective cohort (n > 343 on-going). Previously, we reported a median overall survival (mOS) of 20 months (mo) with a median follow-up of 37 mo in mM patients treated with HD IL-2 between 2007 and 2012 from a retrospective cohort (ASCO 2014). We report for the first time, analysis of 240 prospective patients. Methods: Patients must have received at least one dose of HD IL-2 prior to 2014 for this analysis. Response rates are reported per standard RECIST criteria and mOS by the method of Kaplan-Meier. All patients provided informed consent. Survival is current to January 2015. Results: For the 240 prospective patients, the mOS is 17.9 mo and the ORR is 15.2% at a median follow-up of 20.1 mo. The 1 year survival rate of patients receiving aPD1 or IPI after HD IL-2 is 100% and 68% respectively, compared to 58% in the IL-2 only group. The mOS for these patients is 25.1 (n = 20), 18.4 (n = 75), and 14 mo (n = 112), and the median follow-up is 24.2, 20.6, and 17.4 mo, respectively. Of the 20 aPD1 patients, 12 received IPI first, 4 aPD1 first, and 4 aPD1 only. The median time between the last IL-2 dose and start of IPI/aPD1 is 3.8 mo. There were no differences in IL-2 treatment intensity between these 3 groups. Ten of 73 IPI patients suffered treatment-related autoimmune disease (2/10 high grade) in post treatment follow-up, compared to 0 in the 20 aPD1 patients. There were no treatment-related deaths in the combined retrospective and prospective cohorts (n = 578). Conclusions: The mOS for mM patients receiving aPD1 after HD IL-2 is significantly prolonged over either treatment with IL-2 only, or IPI therapy following IL-2. The small ‘n’ for the aPD1 group and intrinsic shortcomings of registries limits a definitive conclusion about the optimal sequencing of immunotherapies. Checkpoint therapy after IL-2 appears to be well tolerated, does not impact therapeutic activity and provides a path forward for trials designed to enhance durable, unmaintained IL-2 responses. Clinical trial information: NCT00686959.
Imatinib mesylate (IM) activity in patients (pts) with locally advanced tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT).
Authors: Philippe Alexandre Cassier, Robert G. Maki, Andrew J. Wagner, Emmanuelle Bompas, Hans Gelderblom, Judith R. Kroep, David Morgan Thomas, Antoine Italiano, Beatrice M. Seddon, Winette T.A. Van Der Graaf, Julien Domont, Jean-Yves Blay, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2015)

10561 Background: TGCT is a rare disease affecting the synovium and tendon sheaths of young adults. This usually benign neoplasm is driven by overexpression of CSF1, in some cases as a result of fusion of the CSF1 gene to the COL6A3 promoter in the t(1;2) translocation. The bulk of the tumor is made of CSF1 receptor (CSF1R) expressing cells. We previously reported on the activity of IM in this disease, here we present updated results. Methods: This is a multi-institutional retrospective study to assess the activity of IM in locally advanced/metastatic TGCT. Results: Forty-nine pts from 10 centers from Europe, Australia and the US were included. There were 31 females, median age was 38 (range 13-76) at diagnosis and 47 (range 21-80) at the time IM was started. The knee (n = 27; 55%), ankle (n = 9; 18%) and hip (n = 5; 10%) were the most common sites of disease. Most pts had locally advanced disease and/or local relapse (n = 47) and 2 pts had metastatic disease (lung and bone). The median number operations before IM was 2 (range 0-9), and only 4 patients never had surgery prior to IM. All but one pts were treated with IM 400 mg/day. Median follow-up was 18 (range 3-78) months and all pts were evaluable for response: 2 pt (4%) had a CR, 8 (16%) had a PR (ORR 20%) and 69 (37%) had SD. The two pts with metastatic disease had no response to imatinib. Ten patients were operated after a median of 6 (range 1-10) months of IM. Forty patients had symptoms at baseline of which 31 had symptom improvement on IM. The median progression-free survival was not reached. In 11 patients who had symptom improvement and stopped IM before PD, symptom control persisted beyond IM interruption (mean 27 months, median not reached). The most common side effects were grade 1 or 2 fatigue and edema, both seen in 19 (38%) pts, followed by nausea and skin toxicity reported in 8 (16%) and 5 (10%) pts respectively. Five patients had grade 3-4 events and overall, 7 patients (14%) discontinued treatment because of poor tolerance. Conclusions: These data confirm the value of IM in patients with advanced symptomatic TGCT, in some patients symptom control may persist beyond IM interruption.
TREAT-ME 1: Treatment of advanced gastrointestinal cancer in a clinical phase I/II trial with genetically modified mesenchymal stem cells: Clinical results of a phase I study.
Authors: Jobst C. von Einem, Hanno Niess, Marlies Michl, Peter J Nelson, Volker Scherhammer, Christine Guenther, Christoph Salat, Oliver J. Stoetzer, Martin K Angele, Christiane J. Bruns, Volker Heinemann
Journal: Journal of Clinical Oncology (2015)

e13535 Background: Treatment options based on genetically modified cells may add alternative therapeutic modalites to medical oncology. The investigational medicinal product is a genetically modified mesenchymal-stem-cell-suspension (gmMSC) for i.v. infusion. The integration of the therapeutic gene Herpes-Simplex-Thymidinkinase (HSV-TK) under the control of a tumor specific promoter is accomplished through the use of a SIN-gamma- vector system. Patients received gmMSC - infusion at days 1, 8, 15. Each followed by Ganciclovir (q2d) on day 3-5, 10-12, 17-19. Two dose levels of gmMSC were evaluated. Methods: Six Patients with relapsed gastrointestinal adenocarcinoma and liver and/or lung metastasis non-responsive to standard therapy were treated. No signs of active infection. Dose escalation (1.5 Mio.- to 3.0 Mio. MSC/kg BW) was determined by the German Competent Authority (PEI) after the completion of 3 patients. Patients´– safety/tolerability and technical feasibility of the MSC_acpeth_101 infusion were the main criteria. Results: We report clinical data on a phase I study for the treatment of gastrointestinal adenocarcinoma applying gmMSC. Diagnoses comprised 3 colorectal, 1 cholangiocellular and 2 pancreatic carcinomas. 3/6 patients received low-dose treatment, 3 high-dose treatment. No dose-limiting- or off-target toxicities related to the study occured. According to RECIST (1.1) 4/6 showed SD at three months follow-up, 2/6 PD. 1/6 is in sustained SD( > 5 months). Conclusions: This Phase I study demonstrated the feasibility of the protocol and the excellent tolerability of the study-drug. Safety data allow for continuation in phase II with the higher dose level. Clinical trial information: NCT02008539.