tbuckley/cabot-search huggingface dataset:
Effect of extending the original eligibility criteria for the “CROSS” neoadjuvant chemoradiotherapy on toxicity and survival in esophageal cancer.
Authors: Jan-Binne Hulshoff, Ellen C. de Heer, Daphne H. Klerk, Derk Jan De Groot, John Theodorus Plukker, Geke Hospers
Journal: Journal of Clinical Oncology (2017)

187 Background: Patients with curable esophageal cancer (EC) which proceed beyond the original CROSS eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect of extending the CROSS eligibility criteria for nCRT on treatment related toxicity and overall survival (OS) in EC. Methods: Included were 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0), treated with the CROSS schedule followed by esophagectomy. Group 1 (N = 90) consisted of patients which met the CROSS criteria and patients in group 2 (N = 71) met the extended eligibility criteria, i.e. including a tumor length of &gt; 8 cm (N = 23), &gt; 10% weight loss (N = 35), &gt; 2 – 4 cm extension in the stomach (N = 21), celiac lymph node metastasis (N = 13), and/or age &gt; 75 years (N = 2). We assessed the differences in hematologic toxicity (≥ grade 3) and 90-day postoperative mortality. Moreover, we assessed the prognostic value on OS with multivariate Cox regression analysis. Results: No difference was found in hematologic toxicity and 90-day mortality. The OS differed significantly (P = 0.003), with a median of 37.3 (95% CI 10.56 – 64.0) and 17.2 (95% CI 13.8 – 20.6) months in group I and II, respectively. Pathological N-stage (P = 0.024), ypT-stage (P = 0.044), and group II (P = 0.006) were independent prognostic factors for OS. Conclusions: Extension of the CROSS study eligibility criteria for nCRT did not affect hematologic toxicity and postoperative mortality, but was prognostic for OS.
BRCA1, RAP80, and AEG-1 mRNA expression in resectable muscle-invasive bladder cancer (MIBC) patients (p) treated with neoadjuvant cisplatin-based chemotherapy.
Authors: Albert Font Pous, Pamela Celiz, Miquel Taron, Iman Chaib, Jose Luis Gago, Pedro Mendez, Jose Javier Sanchez, Olatz Etxaniz, Luis Cechini, Nuria Pardo, Belen Sanchez, Jose Luis Cuadra, Ivana Valverde, Oscar Buisan, Luis Ibarz, Rafael Rosell
Journal: Journal of Clinical Oncology (2012)

4579 Background: Cystectomy remains the standard treatment in MIBC and only a minority of p are treated with neoadjuvant chemotherapy, suggesting that predictive markers of chemotherapy outcome are needed. Low BRCA1 mRNA expression is associated with an improvement in survival in bladder cancer p treated with cisplatin-based chemotherapy. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 is required for the accumulation of BRCA1 to sites of DNA breaks, and cells depleted of RAP80 exhibit hypersensitivity to irradiation. AEG-1 can induce BRCA1 expression and cause chemoresistance. Methods: Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results: 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low and intermediate levels (p=0.05). MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (p=0.3). No differences in MS were observed according to RAP80 mRNA levels. Conclusions: BRCA1 can be a useful marker to predict the efficacy of neoadjuvant chemotherapy. Cisplatin-based chemotherapy should be recommended in p with low/intermediate BRCA1 expression. Further studies with larger numbers of p are warranted to elucidate the role of AEG-1 in this setting.
Donor cell leukemia: evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient
Authors: S Herold, M Kuhn, M v Bonin, T Stange, U Platzbecker, J Radke, T Lange, K Sockel, K Gutsche, J Schetelig, C Röllig, C Schuster, I Roeder, A Dahl, B Mohr, H Serve, C Brandts, G Ehninger, M Bornhäuser, C Thiede
Journal: Leukemia (2017)
Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGF-i) following stereotactic body radiotherapy (SBRT).
Authors: Brandon M. Barney, Svetomir Markovic, Nadia N. Laack, Robert C. Miller, Jann Nagina Sarkaria, Orlan Kenneth Macdonald, Kenneth R Olivier
Journal: Journal of Clinical Oncology (2012)

e14507 Background: Serious gastrointestinal injury (SGI) is a rare but documented side effect that can occur independently with agents that affect the vascular endothelial growth factor (VEGF) receptor or with stereotactic body radiotherapy (SBRT). The risk of SGI in patients treated with the combination of SBRT sequentially followed by a VEGF inhibitor (VEGF-i) is not yet quantified. We explored the incidence of SGI in patients treated with SBRT with or without VEGF-i therapy at a single institution. Methods: From May 2008 to August 2011, 76 patients with 84 primary or metastatic intraabdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Twenty of these patients (26%) received a VEGF-i within two years of completing SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The most common site treated with SBRT was the liver (n=43, 57%), and the most common histology was colorectal adenocarcinoma (n=18, 24%). Other common histologies included melanoma of the skin (n=14, 18%) and non-small cell lung cancer (n=10, 13%). The incidence of SGI (CTCAE v4.0 grade 3 to 5 ulceration or perforation) after SBRT was obtained, and the relationship between SGI and VEGF-i was examined. Other factors that could potentially contribute to SGI, such as radiotherapy dose to bowel, were also analyzed. Results: Seven patients (9%) experienced SGI at a median 4.6 months (range, 3-17 months) after SBRT. All seven had received a VEGF-i prior to SGI and within 13 months of completing SBRT, and five received the VEGF-i within three months of SBRT. The six-month estimate of SGI in patients receiving a VEGF-i within three months of SBRT was 38%. No SGI was noted in the 63 patients not receiving VEGF-i therapy after SBRT. The Log-Rank test showed a significant correlation between SGI and VEGF-i therapy within three months of SBRT (p=0.0006) but not between SGI and maximum radiotherapy bowel dose (p=0.20). Conclusions: The combination of SBRT and VEGF-i therapy results in a much higher risk of SGI than would be expected with either treatment given independently. Local therapies other than SBRT should be considered if a patient is likely to be treated with a VEGF-i in the future.
Origin and Evolutionary Alteration of the Mitochondrial Import System in Eukaryotic Lineages
Authors: Yoshinori Fukasawa, Toshiyuki Oda, Kentaro Tomii, Kenichiro Imai
Journal: Molecular Biology and Evolution (2017)

Protein transport systems are fundamentally important for maintaining mitochondrial function. Nevertheless, mitochondrial protein translocases such as the kinetoplastid ATOM complex have recently been shown to vary in eukaryotic lineages. Various evolutionary hypotheses have been formulated to explain this diversity. To resolve any contradiction, estimating the primitive state and clarifying changes from that state are necessary. Here, we present more likely primitive models of mitochondrial translocases, specifically the translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM) complexes, using scrutinized phylogenetic profiles. We then analyzed the translocases' evolution in eukaryotic lineages. Based on those results, we propose a novel evolutionary scenario for diversification of the mitochondrial transport system. Our results indicate that presequence transport machinery was mostly established in the last eukaryotic common ancestor, and that primitive translocases already had a pathway for transporting presequence-containing proteins. Moreover, secondary changes including convergent and migrational gains of a presequence receptor in TOM and TIM complexes, respectively, likely resulted from constrained evolution. The nature of a targeting signal can constrain alteration to the protein transport complex.
Elderly cancer patient's desire for information about disease and treatment options
Authors: P. Tralongo, D. Respini, G. Lissandrello, G. Conti, A. Dimari
Journal: Journal of Clinical Oncology (2004)

8242 Purpose : Old patients are one of groups at risk in terms of receiving inadequate information. Clear information is determinant in the acceptance of the cancer treatment options. The present study examines the needs of elderly cancer patients (pts) to receive accurate information regarding disease and treatment outcome in a sociocultural contest where the care-givers (a family member, in the most of the cases) usually have a prevalent role in the relationship with the physician. Methods: Forty elderly cancer pts aged ≥ 70 years (mean 75), from a single outpatient clinic, were interviewed; all the pts were treated with chemotherapy; 53% were female and 47% male; 67% were married, 25% widows, and 8% never married; 25% were affected by breast cancer, 27.5% by gastrointestinal cancer, 20% by lung cancer, and 12.5% by others types. Pts were asked their perception of disease and interviewed about the information received regarding the disease, the treatment toxicity, and the need to receive more information. To evaluate their cognitive state, the Mini Mental State Examination (MMSE) was administered and the results were corrected for age and education level. Results: in 50% of pts the MMSE score was > 24; during the interview 35 (85%) pts pronounced the word “cancer” while the remainders use only the word “disease”. Regarding the information about the disease, 40% reported the desire of more information, while 20% were doubtful. Forty-five per cent express the desire of more and accurate information about the toxicity of the treatment while 15% were doubtful. Interesting, all most of the uncertainties patients were the same that never pronounced the word cancer, that is those that are not conscious of their cancer disease. Conclusions: the results of this study showed that (a) elderly cancer patient, living in south Europe, wish to be informed about the disease; (b) the awareness of the correct diagnosis of the disease influence the patients needs about the potential treatment side effects and their desire to have an active decision-making role in terms of therapeutic options; finally, they maybe indicate (c) the patients' desire of a better patient-physician relationship. No significant financial relationships to disclose.
Predictive model for survival in patients with AML/MDS receiving haploidentical stem cell transplantation
Authors: Lohith S. Bachegowda, Rima M. Saliba, Reshma Ramlal, Piyanuch Kongtim, Julianne Chen, Gabriela Rondon, Whitney Wallis, Amin Alousi, Sairah Ahmed, Chitra M. Hosing, Simrit Parmar, Muzaffar Qazilbash, Issa F. Khouri, Qaiser Bashir, Betul Oran, Uday Popat, Elizabeth J. Shpall, David Marin, Katayoun Rezvani, Partow Kebriaei, Richard E. Champlin, Stefan O. Ciurea
Journal: Blood (2017)
Final Results of a Single Arm Phase III Multicenter, Open-Label Study of Rituximab Administered by Faster Infusion in Patients with Previously Untreated Diffuse Large-B Cell (DLBCL) or Follicular Non-Hodgkin's Lymphoma (FL)
Authors: Shaker R. Dakhil, Robert Hermann, Akiko Chai, Deborah Hurst, Gregg Fine, Paul Richards
Journal: Blood (2011)
A phase 1b/2, open-label study to evaluate the safety and tolerability of MEDI6469 in combination with immune therapeutic agents or therapeutic mAbs in patients with selected advanced solid tumors or aggressive B-cell lymphomas.
Authors: John D. Powderly, Martin Gutierrez, Ding Wang, Young Kwang Chae, Daruka Mahadevan, Fadi S. Braiteh, Bonnie S. Glisson, Dongyue Fu, Michele Jordan, Jennifer T. McDevitt, Mark C. Lanasa, Brendan D. Curti
Journal: Journal of Clinical Oncology (2015)

TPS3091 Background: Anti-CTLA-4 and anti-PD-1/PD-L1 have shown antitumor activity in 10–30% of patients (pts) with select tumors. Combinations of co-stimulatory agonists, such as OX40, and antagonist Abs against the T-cell checkpoints CTLA-4 or PD-L1 could synergize to yield higher response rates. Additionally, nonclinical models show OX40 cell surface expression is induced following activation of NK cells. OX40 ligation promotes enhanced NK cell activity, suggesting greater antitumor activity could be achieved with an OX40 agonist in combination with an anti-CD20 antibody engaging NK cells for antitumor activity. Depleting B cells with rituximab could decrease immunogenicity of murine MEDI6469 by decreasing anti-drug Ab production. MEDI6469, an agonist human OX40 receptor murine mAb, showed clinical activity in a Phase 1 study and is being evaluated as monotherapy and in combination with tremelimumab (anti-CTLA-4) or MEDI4736 (anti-PD-L1) in pts with select advanced solid tumors, or with rituximab (anti-CD20) in relapsed diffuse large B cell lymphoma (DLBCL) pts. Methods: This is a Phase 1b/2, multicenter, open-label study (NCT02205333) in adult pts with select advanced solid tumors refractory to standard therapy or for which no standard therapy exists, or with histologically confirmed aggressive DLBCL. The dose-escalation phase includes single-dose IV MEDI6469 monotherapy (6+3 design) and 3 combination therapies (3+3 design): single-dose IV MEDI6469 Day 1 + repeated IV doses of (1) tremelimumab, or; (2) MEDI4736 up to 12 months or until PD, or; (3) repeated IV doses of MEDI6469 and rituximab until confirmed CR plus 1 cycle or PD. The dose-expansion phase will examine MEDI6469 combination treatments at the dose levels determined during dose escalation in pts with select advanced solid tumors or DLBCL. The primary endpoints are safety and determination of the maximum tolerated dose. Secondary endpoints are PK, immunogenicity, and antitumor activity. Enrollment of up to ~212 pts (66, dose escalation; 146, dose expansion) is ongoing. Clinical trial information: NCT02205333.
Clinical presentation, systemic therapy and prognosis of mucosal melanoma, a study of 463 consecutive cases.
Authors: Li Zhou, Chuanliang Cui, BIN LIAN, Lu Si, Zhihong Chi, Xi Nan Sheng, Li Li Mao, Xuan Wang, Bixia Tang, Xieqiao Yan, Jun Guo
Journal: Journal of Clinical Oncology (2015)

e20036 Background: Mucosal melanoma (MM) is the second common subtype in Asians with a percentage of 22-25%; but there have been few epidemiologic studies. So we performed a retrospective analysis of MM about its clinical presentation, gene mutation, systemic therapy (tx) and prognosis. Methods: Using institutional databases, we identified patients (pts) with MM who were treated in Chinese melanoma centers between 2006-2014 with basic demographics and clinical outcomes. Results: 463 MM pts were included. Median age at diagnosis 56 years (range, 17-86); 61% female; primary site: 149 anal-rectal, 125 genitourinary, 174 head/neck, 15 others. Mutation (mut) status: 14.1% (45/319) KIT mut; 9.7% (31/319) BRAF mut; 10.3% (33/319) NRAS mut. Stage I-II/ III/IV at referring – 36%/17%/47%, M1a/b/c – 17%/18%/65%. The median overall survival (mOS) was 28.0 mo (95% CI 25.1-30.9 mo). Multivariate analysis showed that clinical stage and LDH level were significant prognostic factors for OS. The application of adjuvant therapy and LDH level were significant prognostic factors for disease free survival. For 293 pts who developed stage IV, mOS was 14.0 mo, for M1a, M1b, M1c, 20.2, 16.0, 11.1 mo respectively (p = .004). In 1st-line setting, the objective response rate (RR), disease control rate (DCR) and median progress free time (PFS) was 11.8%, 54.8%, and 3.1 mo (95% CI 2.6-3.8 mo), most of the pts using dacarbazine/temozolomide, cisplatin plus rhEndostatin had RR, DCR and PFS, 12.3%, 64.6%, and 4.5 mo respectively. In 2nd-line setting, paclitaxel plus carboplatin was common regimen, RR, DCR and PFS was 8.3% 61.1% and 3.3 mo (95% CI 2.0-4.4 mo). The mPFS of 3rd-line tx (including Abraxane, investigational targeted drugs, etc) was 1.3 mo without complete regression and partial regression. 8/20 pts harboring c-kit mutation used imatinib, 3/8 pts had SD for a median PFS of 6.7 mo. 5/15 pts harboring BRAF mutation used vemurafenib, 3/5 pts got response, mPFS cannot be evaluated. Conclusions: The prognosis for MM is still poor, clinical stage has its significance for OS. For pts with stage IV, the efficacy of systemic tx includes chemotherapy and targeted therapy is modest. Further investigation into the biology and treatment of MM is needed.
Abstract 14022: Effect of Discontinuation and Nonadherence to Oral Anticoagulants on Atrial Fibrillation Stroke Risk
Authors: Xiaoxi Yao, Neena S Abraham, Peter A Noseworthy, G. Caleb Alexander, Lindsey R Sangaralingham, Nilay D Shah
Journal: Circulation (2015)

Introduction: Medicines don’t work in those who don’t take them. Although novel oral anticoagulants (NOACs) are more convenient than warfarin due to fewer drug-drug interactions and less need for laboratory monitoring, their considerable costs and lack of regular interactions with the healthcare system may also contribute to poor adherence. Little is known about the persistence and adherence in the era of NOACs, nor how such behaviors are associated with the risk of ischemic stroke and transient ischemic attack (TIA) among patients of varying baseline risk. Methods: We conducted a retrospective analysis using a large U.S. commercial insurance database, and identified 61,646 patients with atrial fibrillation who initiated one of OACs (warfarin, dabigatran, rivaroxaban and apixaban) between October 2010 and September 2014. We defined discontinuation as being off OACs for at least 3 months and adherence as the proportion of days covered of at least 80%. Cox proportional hazard models was used to examine whether the time that patients were off OACs, including both the gaps between medication fills and the time of discontinuation, increased the risk of ischemic stroke and TIA. Results: Approximately 1 in 3 patients discontinued OACs within one year after initiation and 1 in 10 switched to another OAC. The estimated likelihood of adherence was 0.77 during the time when patients were on their first-line medications. Apixaban had the highest continuation rate (65% at 1 year), while rivaroxaban had the best adherence (predicted probability of adherence 0.83). The event rate of stroke was 1.6 per 100 person years. Patients with high baseline risk (CHA2DS2-VASc ≥2) were more likely to have a stroke when they were off OACs for 1-3 months (HR=1.47, p&lt;0.01), 3-6 months (HR=1.78, p&lt;0.001) and ≥6 months (HR=2.16, p&lt;0.001), compared to off OACs for less than a week. No significant effect was found among low-risk patients (CHA2DS2-VASc 0 or 1). Switching to another OAC was related to 22% increased risk of stroke (p=0.05). Conclusions: Despite their greater convenience relative to warfarin, discontinuation and nonadherence to NOACs is high. Lack of persistence and adherence was associated with increased risk of ischemic stroke and TIA among patients with elevated baseline risk.
Association of progression-free survival with overall survival (OS) in patients (pts) with neuroendocrine tumor (NET) treated with somatostatin analogs.
Authors: Monica Ter-Minassian, Nichole V Brooks, Lauren K Brais, Jennifer A. Chan, David C. Christiani, Xihong Lin, Sylvie Gabriel, Jerome Dinet, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2015)

4090 Background: Progression-free survival (PFS) is commonly used as a primary endpoint in NET clinical trials. Whether PFS is associated with OS is uncertain. We assessed the association between PFS and OS in a large observational cohort of pts with NETs treated with somatostatin analogs (SSA). Methods: We enrolled 1330 pts to a prospective observational study, beginning in 2003. Of these pts, we identified 440 with metastatic NETs who had received single-agent SSA and were evaluable for tumor progression, based on medical record review. We used a landmark analysis to assess OS in pts with progression (PD) or without PD at 6 month intervals, from 6 to 24 months after treatment initiation. Adjusted hazard ratios were assessed with Cox proportional hazards models. Kaplan-Meier estimates were used to calculate median OS for pts with PD vs. those without PD at each landmark time. PFS was defined as time of treatment initiation to time of first progression or death. OS was defined as time of treatment initiation plus the landmark time to time of death. Results: Of the 440 pts, 224 had small bowel NETs, 93 had pancreatic NETs and 123 other NETs. 311 pts progressed and 215 died. Median follow-up was 7.6 yrs. PFS was associated with OS at the 6, 12, 18, and 24 month landmarks: those who progressed by each landmark time had shorter median OS times than those who did not progress (see table). A trend suggesting association of PFS with OS was seen across tumor subgroups. Conclusions: In this observational cohort of pts with metastatic NETs treated with SSA, PFS was associated with OS. Our findings support the use of PFS as an endpoint in NET clinical trials. PFS and OS in NET patients treated with SSA (N = 440). Landmark time No PD (N) No PD (Median OS) PD (N) PD (Median OS) Adjusted HRa (95%CI) 6 mo 327 7.52 yrs 107 3.62 yrs 1.72 (1.25, 2.37), p = 0.0009 12 mo 249 7.02 yrs 169 4.71 yrs 1.47 (1.07, 2.00), p = 0.017 18 mo 181 7.10 yrs 220 3.97 yrs 1.77 (1.25, 2.51), p = 0.0014 24 mo 147 6.79 yrs 219 4.21 yrs 1.58 (1.07, 2.32), p = 0.02 aAdjusted for age, gender, tumor grade, tumor origin, and post-progression treatment.