tbuckley/cabot-search huggingface dataset:
A pilot study of bevacizumab (Bev) and continous low-dose granulocyte-macrophage colony-stimulating factor (GM-CSF) in heavily pretreated patients with refractory solid tumors: Preliminary results
Authors: M. Schmidt, U. Reinhold, J. A. Kurbacher, O. Rieckmann, H. Huncke, A. Radmacher, I. A. Cree, C. M. Kurbacher
Journal: Journal of Clinical Oncology (2007)

3031 Bev is an important inhibitor of VEGF, a mediator of tumor-induced angiogenesis. Inhibiting generation of dendritic cells (DC) from blood and tissue precursors, VEGF is also a crucial immunosuppressive agent in anti-tumoral immunotolerance. Beyond anti-angiogenesis, inhibition of VEGF may results in an improved antineoplastic immune response, which may be further improved by GM-CSF known to effectively stimulate DCs. GM-CSF has formerly be shown to induce objective responses in refractory gynecologic and breast carcinomas [Kurbacher et al. Oncology 2005]. This ongoing prospective clinical trial was initiated to investigate the combination of Bev and GM-CSF in patients (pts) with heavily pretreated solid tumors. Toxicity was documented according to the NCI-CTC scale, responses were recorded according to the RECIST or the Rustin criteria. Statistical pre-study considerations forced termination of the trial if no responses were observed among the first 12 pts recruited. Until now, 10 pts are included: epithelial ovarian carcinoma, n=4; metastatic breast cancer, n=3; peritoneal papillary-serous carcinoma, n=2; salivary gland adenocarcinoma, n=1. Regarding their history, all pts have been considered chemo-resistant or non-treatable due to their underlying bone marrow and/organ functions. Bev was applied at a fixed dose of 6 mg/kg q2w. GM-CSF was administered sc at 125 μg/d. GM-CSF was increased every 4 weeks at 25 μg/d increments until a maximum dose of 250 μg/d until occurence of objective tumor response or leukocytosis &lt;20,000 cells/μL. Among the 10 pts treated so far, 2 partial responses (PR), 5 stable diseases (SD), and 3 progressive diseases (PD) have been recorded accounting for an objective response rate of 20%. Median time to progression is 16 weeks, with 7 pts still alive. Toxicity was generally mild and never therapy-limiting: NCI-CTC grade (G) 2 fatigue in 3 pts, G2 flu-like symptoms and G2 in either 1 pt, G1 injection site reactions in 3 pts. Preliminary results of this trial have shown Bev plus GM-CSF to produce a promising clinical activity in heavily pretreated pts with solid tumors. Thus, pts accrual is still continuing. No significant financial relationships to disclose.
Phase II study of personalized peptide vaccine for refractory breast cancer patients.
Authors: Uhi Toh, Nobutaka Iwakuma, Ryuji Takahashi, Hiroko Otsuka, Satoko Matsueda, Shigeki Shichijo, Tetsuro Sasada, Kyogo Itoh, Kazuo Shirouzu
Journal: Journal of Clinical Oncology (2012)

e13050 Background: To develop therapeutic cancer vaccine, we conducted a phase II study of personalized peptide vaccine (PPV) for refractory breast cancer patients. Methods: Thirty-four refractory breast cancer patients, including 8 triple negative (TN) cases, were enrolled to this study. A maximum of four HLA-class IA (A2, A3s, A24, A26)-matched peptides showing higher antigen-specific IgG responses were administered. Inflammatory markers, cytokines, and peptide-specific CTL and IgG responses were examined before and after vaccination to identify prognostic factors for overall survival (OS). Results: No vaccine-related severe adverse events were observed. Median numbers of preceding chemo- and/or hormone therapy regimens and median treatment duration from the recurrence to the vaccination were 2 regimens and 37 months, respectively. Three patients did not complete the 6 th vaccination because of rapid disease progression. CTL or IgG boosting by PPV was observed in 16 or 18 of 31 patients at the time of 6 th vaccination. IgG boosting was observed in all 24 patients tested at 12 th vaccination. Median survival time of 31 patients receiving &gt; 6 th vaccination after the vaccination was 474 days with 2 complete responses and 1 partial response. There were no significant differences between 8 TN cases and the other cases from points of immunological and clinical responses. Lymphocyte frequency (Hazard ratio of 0.906, p=0.019) well associated with OS by multivariate Cox proportional hazard regression analysis for pre-vaccination samples. Conclusions: Next steps of PPV for the refractory breast cancer patients were warranted because of the lower toxicity and favorite immune responses along with possible clinical benefits.
INSIGHTS INTO OUTCOMES WITH INTRACARDIAC ECHOCARDIOGRAM USE IN STRUCTURAL INTERVENTIONS
Authors: Prashant Patel, Shilpkumar Arora, Sopan Lahewala, Nirali Patel, Ambarish Pathak, Abhishek Deshmukh, Sidakpal Panaich, Apurva Badheka
Journal: Journal of the American College of Cardiology (2017)
Ipilimumab (Ipi) retreatment at 10 mg/kg in patients with metastatic melanoma previously treated in phase II trials.
Authors: Bart Neyns, Jeffrey S. Weber, Celeste Lebbé, Michele Maio, Kaan Harmankaya, Omid Hamid, Steven O'Day, Kevin M. Chin, Diane Opatt McDowell, Lori Cykowski, Brent McHenry, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2013)

9059 Background: Ipi is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In phase III study MDX010-20, where patients (pts) could be retreated if they met safety criteria and achieved an objective response or stable disease ≥3 months from the end of the induction period (q3 weeks for 4 doses), 21 of 31 pts (68%) retreated with Ipi reestablished disease control. CA184-025 is a roll-over study of extended Ipi treatment or survival follow-up in pts who received Ipi in phase II trials, with the primary objective of evaluating safety during extended treatment. We report the safety profile in pts retreated with Ipi in study 025. Methods: Eligible pts in phase II trials CA184-004, -007, -008, -022, MDX010-08, or -015 were enrolled in study 025 (N=248) to receive retreatment (at the time of progression), extended maintenance (if no prior progression), or survival follow-up only. Pts were ineligible for retreatment if they had experienced a grade 3-4 non-skin toxicity during prior Ipi therapy. Ipi was administered at 10 mg/kg, q3 weeks for 4 doses, to 111 pts who initially received Ipi induction at 0.3, 3, or 10 mg/kg in a parent study. Results: In this selected population of eligible pts, the nature and frequency of immune-related adverse events (irAEs) during retreatment were similar to those reported in previous studies, which most commonly affected the GI tract and skin (Table). There were no new types of drug-related irAEs and no grade 5 irAEs upon retreatment. Conclusions: Retreatment with Ipi at 10 mg/kg in these pts was generally well tolerated and the safety profile was similar to that during induction dosing in the parent studies. The higher frequencies of irAEs at lower doses should be interpreted with caution given the small sample sizes. An ongoing, randomized phase II trial will evaluate the clinical benefit of Ipi retreatment. Clinical trial information: NCT00162123. [Table: see text]
IMPACT OF CORONARY ANATOMICAL COMPLEXITY ON THE EFFECT OF EXTENDED DURATION DUAL ANTIPLATELET THERAPY: AN ANALYSIS FROM THE DUAL ANTIPLATELET THERAPY STUDY
Authors: Robert W. Yeh, Dean Kereiakes, Philippe Steg, Donald Cutlip, Kevin Croce, Patricia Apruzzese, Joseph Massaro, Laura Mauri
Journal: Journal of the American College of Cardiology (2017)
Immunotherapy (IT) with ch14.18/CHO for high-risk neuroblastoma: First results from the randomised HR-NBL1/SIOPEN trial.
Authors: Ruth L Ladenstein, Ulrike Poetschger, Roberto Luksch, Penelope Brock, Victoria Castel, Isaac Yaniv, Vassilios Papadakis, Genevieve Laureys, Josef Malis, Walentyna Balwierz, Ellen Ruud, Per Kogner, Henrik Schroeder, Maja Beck Popovic, Peter F Ambros, Guenter Schreier, Holger N. Lode, Hans Loibner, Andrew DJ Pearson, Dominique Valteau Couanet
Journal: Journal of Clinical Oncology (2014)

10026 Background: The HR-NBL1/SIOPEN trial randomised 2 essential treatment concepts: Randomisation R1 investigated BUMEL superiority (plenary session ASCO 2012), whilst the R2 randomisation tested the benefits of adding subcutaneous interleukin 2 (scIL2) to ch14.18/CHO mAB immunotherapy(IT) and 13 cis retinoic acid (13-cis RA). The R2 population reached the target population of 400 patients (pts) in August 2013. Methods: After Rapid Cojec induction pts were randomised in R1 (296 BuMel, 302 CEM) till 09/2010. Median follow up is 6.2 years. Eligibility included complete bone marrow remission and ≤3, but improved mIBG positive spots. Local control included surgery and radiotherapy of 21 Gy. Eligibility to R2 included previous R1 eligibility. R2 was initiated in 2009 aiming at 400pts receiving ch14.18/CHOmAB as 8-hour infusion with 20mg/m² over 5 days and 13 cis RA over a total of 5 IT cycles. The schedule requires high dose morphine to control for neuropathic pain. R2 addressed a scIL2 question, using a dose of 6x10E6/m²/day over 5 days twice in a weekly interval, given in week 2 in parallel with ch14.18/CHOmAb. Results: The superiority of BuMel in EFS and OS over CEM (3-years EFS&OS 50%/61% vs. 38%/52%; p<0.001) is maintained with a significantly lower relapse and progression rate with BuMel (48% vs. 58%) as major factor. Severe toxicity rates (ICU, toxic deaths) are below 10%, but are higher for CEM (p=0.012). Hence the MAT toxicity profile still favours BuMel in spite of a VOD rate of 24% (grade 3: 4%) vs. 10% in CEM (Grade3: 1%). Having reached the R2 target in August 2013, the randomisation is currently suspended expecting “last patient out” in 02/2014 with liberation of the randomised R2 data by the DMC thereafter. The R2 population undisclosed for treatment arms currently reveals a 2 year EFS/OS of 56%/68%. The scIL2 arm carries a significantly higher toxicity burden related to IL2 associated side effects like fever and capillary leak with a number of pts in the IL2 arm stopping treatment early. Conclusions: BuMel is maintained as SIOPEN standard treatment whilst R2 results will have a major impact on the future management of immunotherapy. Clinical trial information: NCT01704716.
COMPARISON OF AORTIC REMODELING AFTER THORACIC ENDOVASCULAR REPAIR BETWEEN ACUTE/SUBACUTE VERSUS CHRONIC TYPE B AORTIC DISSECTION
Authors: Yeongmin Woo, Young-Guk Ko, Chul-Min Ahn, Do-Yun Lee, Donghoon Choi
Journal: Journal of the American College of Cardiology (2017)
A phase 1 study of crizotinib and ganetespib (STA-9090) in ALK positive lung cancers.
Authors: Gregory J. Riely, Helena Alexandra Yu, Dennis Stephens, Maria Catherine Pietanza, Stephanie Smith-Marrone, John Joseph Fiore, Melissa Goldstein, Camelia S. Sima, Mark G. Kris, Michelle S. Ginsberg
Journal: Journal of Clinical Oncology (2015)

8064 Background: Patients with ALK + non-small cell lung cancer (NSCLC) initially respond to crizotinib, but eventually develop resistance. Treatment of patients with ALK positive lung cancer with HSP90 inhibitors leads to clinical and radiographic response. We hypothesized that treatment of patients with ALK rearranged NSCLC with crizotinib and ganetespib, an HSP90 inhibitor, would be safe. Methods: All patients had ALK rearranged metastatic non-small cell lung cancer not previously treated with crizotinib. Prior chemotherapy was allowed. Patients were treated with crizotinib 250 mg bid continuously; ganetespib was administered intravenously on days 1 and 8 of a 21-day cycle. In a standard 3+ 3 design, ganetespib was explored at 3 different dose levels. The primary objective was to determine the maximum tolerated dose of the combination of crizotinib and ganetespib. Secondary objectives included establishing the safety profile (CTCAE v4) of the combination in patients with ALK+ lung cancer, exploring the efficacy (RR by RECIST 1.1, PFS, and OS). Results: 12 patients were treated with combined crizotinib and ganetespib: 100 mg/m2(n=3), 150 mg/m2(n=3), and 200 mg/m2 (n=6). Women: 8/12, Median Age: 56 (range 41-70), Prior therapy: none (7 pts), 1 line (4 pts), or 2 lines (1 pt). Median duration of treatment: 100 mg/m2=30 weeks, 150 mg/m2=54 weeks, and 200 mg/m2= 6 weeks. There were no first-cycle DLTs. The maximum tolerated dose was crizotinib 250 mg bid/ganetespib 200 mg/m2. The most common toxicities were fatigue, diarrhea, nausea, vomiting, and dizziness. Grade 4 elevation in ALT (n=1) and Grade 3 elevations in lipase (n=2), AST (n=1), and amylase (n=1) were observed. 5 patients stopped therapy due to toxicity. 4 discontinued due to progressive disease. 3 patients continue on treatment. PR = 67% (8/12), SD= 16% (2/12), PD =8% (1/12), Not Evaluable =8% (1/12). Median OS has not been reached (median f/u = 15 months, with 10 patients still alive). Conclusions: In patients with ALK+ lung cancers, crizotinib and ganetespib can be combined, with an MTD of crizotinib 250 mg bid continuously and ganetespib 200 mg/m2 on days 1 and 8 of a 21 day cycle. Further evaluation of this combination in patients not previously treated with crizotinib is warranted. Clinical trial information: (NCT01579994).
ADIPOSITY, LEANNESS OR BOTH? CHARACTERIZING MEASURES OF ADIPOSITY AND LEANNESS WITH CARDIOVASCULAR REMODELING
Authors: Angela Su-Mei Koh, Wan Yi Yew, Xiaodan Zhao, Liang Zhong, Louis Ly Teo, Serene Chua, Yi Ying Han, Jia Ing Wong, Feiqiong Huang, Si Yi Lee, Fei Gao, Woon-Puay Koh, Ru-San Tan
Journal: Journal of the American College of Cardiology (2017)
A prospective study of R-CHOP chemotherapy induced pulmonary pneumonia in diffuse large B-cell lymphoma.
Authors: Prem Raj Shrestha, Tongyu Lin, He Huang, Huang Ming Hong, Xueying Li, Shanshan Li, Mengping Zhang, Xiaohong Fu, Xiaojie Fang, Zhao Wang, Chengcheng Guo, Xiaoting Lin, Ying Tian
Journal: Journal of Clinical Oncology (2015)

e19508 Background: Ritubximab (RTX) with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) regimen is a gold standard therapy in treatment of diffuse large B-cell lymphoma (DLBCL) now. However, adding rituximab in chemotherapy increase the possibility of infection disease including pulmonary pneumonia. There is no prospective study in RTX induced pneumonia and pulmonary toxicities. Methods: A prospective study was conducted in the cancer center of Sun Yat-sen University to evaluate the efficacy of Thyomosine α1 and intravenous immunoglobulin (IVIG) in preventing pulmonary side effect in patients with R-CHOP. Patients with untreated DLBCL enrolled in this study and were excluded primary pulmonary pneumonia and immunocompromised. Results: From Feb 2008 to Nov 2014, 270 patients were randomly assigned to receive Thymosin α1 and IVIG (n = 180) or non-Thymosin α1 and IVIG (n = 90). R-CHOP induced the pulmonary side effects in 87 cases tended to occur more frequently with interstitial pulmonary disease (IPD) (n = 60, 22.2%) than infectious pneumonia (n = 27, 10.0%). The median cycles of R-CHOP induced pulmonary side effect was the fourth cycle. IPD occurred in 18 patients (10.0%) in the Thymosin α1 and IVIG arm and in 42 patients (46.7%) in the non-Thymosin α1 and IVIG arm (p < 0.01), and chemotherapy disruption rate was significantly lower for the Thymosin α1 and IVIG group vs non-Thymosin α1 and IVIG group (11.1% vs 20.0%, P = 0.048). Staging, International prognostic index and older age were not related to pulmonary adverse events. Conclusions: Among patients with DLBCL undergoing R-CHOP chemotherapy, the addition of Thymosin α1 and IVIG resulted in a lower incidence of pulmonary side effects. If replicated, these findings support the use of Thymosin α and IVIG in these patients.
Expression of the glutathione-S-transferase π (GST-π) protein correlates with survival in patients with stage I non-small cell lung cancer (NSCLC)
Authors: A. Gajra, N. Vajpayee, M. Wade, G. P. Gamble, A. Rajan, S. L. Graziano
Journal: Journal of Clinical Oncology (2007)

21065 Background: It is important to identify prognostic markers in stage I NSCLC given the 30%-40% risk of recurrence and death despite resection. The role of platinum-based adjuvant chemotherapy remains unclear in stage I NSCLC. The glutathione pathway prevents cellular DNA damage by oxygen free radicals and cytotoxic compounds. GST-p catalyzes conjugation of glutathione to cytotoxic agents and high expression may predict for platinum resistance. The role of GST-p as a prognostic factor in early stage lung cancer is not well evaluated. Methods: In a retrospective cohort of 93 patients with resected stage I NSCLC we used immunohistochemistry (IHC) to study the association of GST-p expression with risk of tumor recurrence and death. None of the patients received adjuvant therapy. IHC was quantified by a visual grading intensity of cytoplasm staining (0= no immunoreactivity; 1=weak; 2= clear reactivity in &gt;50% cancer cells and 3= strong immunoreactivity). Grades 2 and 3 were classified as high and grades 0 and 1 as low GST-p respectively. Results: The mean age of the patients was 67 years. Of the 93 patients, there were 45 (48%) men, 71 (76%) had adenocarcinoma and 66 (71%) had stage IA disease. The median follow-up time was 5.4 years. High GST-p expression was noted in 40 (43%) and 53 had low GST expression. The overall survival at 5 years was 67% with 31 deaths. Patients with high GST expression had a higher overall survival at 5 years- 32/40 (75%) vs. 30/53 (57%) in the low GST group (p=0.018). There was no significant difference in terms of tumor recurrence or recurrence free survival. After adjusting for age, gender, histology, and T stage, patients with low GST-p expression remained at an increased risk of death with a hazard ratio of 2.86 (1.16–7.61, p= 0.015). Conclusions: In this cohort, high expression of GST-p served as an independent prognostic factor in resected stage I NSCLC. These early findings with GST-p are similar to those from the IALT trial wherein the high expression of ERCC1 was associated with chemoresistance but conferred a survival advantage in the absence of chemotherapy (Olaussen, NEJM 2006). These findings merit evaluation in larger prospective series given the small, exploratory and retrospective design of the present study. No significant financial relationships to disclose.
Sex differences in invasive pneumococcal disease and the impact of pneumococcal conjugate vaccination in the Netherlands, 2004 to 2015
Authors: Gertjan H J Wagenvoort, Elisabeth A M Sanders, Bart J Vlaminckx, Hester E de Melker, Arie van der Ende, Mirjam J Knol
Journal: Eurosurveillance (2017)

Implementation of pneumococcal conjugate vaccines in the Netherlands (PCV7 in 2006 and PCV10 in 2011) for infants caused a shift in serotypes in invasive pneumococcal disease (IPD). We explored sex differences in serotype-specific IPD incidence before and after vaccine introduction. Incidences in the pre-PCV7 (June 2004–May 2006), post-PCV7 (June 2008–May 2011) and post-PCV10 period (June 2013–May 2015), stratified by age, were compared. Incidence was higher in men for all age groups (overall in men: 16.7, 15.5 and 14.4/100,000 and women: 15.4, 13.6 and 13.9/100,000 pre-PCV7, post-PCV7 and post-PCV10, respectively), except for 20–39 year-olds after PCV7 and 40–64 year-olds after PCV10 introduction. After PCV7 and PCV10 introduction, the overall IPD incidence decreased in men aged 20–39 years (from 5.3 pre-PCV7 to 4.7 and 2.6/100,000 post-PCV7 and post-PCV10, respectively), whereas it showed a temporary increase in women (from 3.9/100,000 pre-PCV7 to 5.0/100,000 post-PCV7 and back to 4.0/100,000 post-PCV10) due to replacement disease. PCV10 herd effects were observed throughout, but in women older than 40 years, a significant increase in non-PCV10 serotype offset a decrease in overall IPD incidence. Ongoing surveillance of IPD incidence by sex is important to evaluate the long-term effects of PCV implementation.
Docosahexaenoic acid (DHA) intake during first line chemotherapy improves survival in metastatic breast cancer.
Authors: Philippe Bougnoux, Nawale Hajjaji, Marie Ange Baucher, Marie-Lise Jourdan, Caroline Goupille, Gilles Body, Olivier Le Floch
Journal: Cancer Research (2006)

5276  Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid of marine origin, increases the sensitivity of breast cancer cell lines to anthracyclins. Omega-3 fatty acids dietary supplementation of rats bearing autochthonous mammary tumors increases tumor response to anthracyclin treatment. To translate the finding to humans, we investigated whether dietary DHA might enhance the efficacy of chemotherapy against breast cancer metastasis. A clinical trial involving a dietary intervention with 1.8 g DHA daily (4.5 g of DHASCO, MARTEK Inc, USA) along with an anthracycline-based first line chemotherapy was carried out in 25 sequential patients during 18 weeks. Median age of the population was 58 (32 to 71). Performance status (WHO) at inclusion was 0 in 9 patients and 1 in 15 patients. 18/25 patients had liver and 9 had lung metastasis. 20 patients had more than one metastatic sites. Plasma phospholipids DHA level was measured at inclusion and after 10 days of DHA supplementation, time of the first administration of chemotherapy. Increase in DHA level was taken as an indicator of patient’s compliance or efficiency of the dietary intervention. Mean basal level of DHA in patient’s plasma phospholipids increased from 3.0 percent of total fatty acids (extremes 1.6 to 5.0) to 5.1 percent (extremes 2.5 to 8.3). Not all patients incorporated similarly DHA, as assessed by the variation of their DHA plasma level after 10 days of dietary intervention compared to basal level at inclusion. The median value of the variation was used as a threshold to individualize 2 groups of patients : a high DHA incorporating group (HDI, 12 patients) versus a low DHA incorporating group (LDI, 13 patients). Overall survival was greater in the HDI group than in the LDI group (p
AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis
Authors: Ni Li, Wei Xue, Huairui Yuan, Baijun Dong, Yufeng Ding, Yongfeng Liu, Min Jiang, Shan Kan, Tongyu Sun, Jiale Ren, Qiang Pan, Xiang Li, Peiyuan Zhang, Guohong Hu, Yan Wang, Xiaoming Wang, Qintong Li, Jun Qin
Journal: Journal of Clinical Investigation (2017)

Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.