tbuckley/cabot-search huggingface dataset:
Abrogation of resistance against bevacizumab (Bev) by mitochondrial inhibition: A phase 0 randomized trial of Bev plus ME344 or placebo in early HER2-negative breast cancer (HERNEBC).
Authors: Miguel Quintela-Fandino, Juan V Apala, Alfonso Cortes Salgado, Silvana Andrea Mouron, Juan Antonio Guerra, Mana Gion Cortes, Manuel Morente, Luis Manso
Journal: Journal of Clinical Oncology (2018)

2552 Background: Our preclinical data show that one mechanism of acquired resistance to anti-angiogenic therapy involves hypoxia correction, measured by decreased SUV ( ↓ SUV) on FDG-PET followed by mitochondrial up-regulation. ME344 is a potent inhibitor of mitochondrial respiration. The aims of this study were to assess 1) the fraction of HERNEBC patients that show ↓SUV in response to single dose Bev and 2) if adding ME344 to Bev inhibits cell proliferation as determined by Ki67% decrease, a surrogate marker of efficacy in neoadjuvant breast cancer. Methods: Treatment-naïve HERNEBC patients (T > 1 cm, any N, M0) received 15 mg/kg Bev on d0 and were then randomized 1:1 to ME344 10 mg/kg IV d8, 15 and 21 (arm A) or placebo (arm B) followed by physician’s choice of definitive therapy. FDG-PET was performed on d0 and d7 and tumor biopsy on day 0 and 28. The primary endpoint was Ki67% relative reduction from d0 to 28. A 40 patient sample size was powered to detect a 30% relative difference in Ki67% between arm A and B (alpha 0.05, beta 0.2). Threshold for hypoxia correction by PET was 10% ↓ SUV. A predefined interim analysis was planned when 20 patients had completed treatment. Results: 19 patients were randomized (arm A/B: 7/7 LumA, 2/2 LumB, 1/0 TNBC). Baseline characteristics: Ki67 by IHC: mean 10.3% (1%-48%), age: mean 56 (44-75), T (8 T1, 10 T2, 1 T3), N (14 N0, 5 N1) and G (4 G1, 12 G2, 3 G3) were balanced between arms. 31% of patients experienced ↓SUV > 10%. Mean absolute (relative) Ki67 decreases were 5.13 (29%) and 1.2 (9%) in arms A and B (P = 0.06). Patients with ↓ SUV > 10% experienced an absolute average Ki67 decrease of 16.6 vs. 2.3 in arms A and B (P = 0.19). Two G3 adverse events (high blood pressure) were reported (1 per arm) and deemed related to Bev. Conclusions: ME344 results in significant Ki67 reduction compared to placebo in HERNEBC patients exposed to single-dose Bev. This effect may be greater in those patients with Bev induced hypoxia correction. These clinical results are consistent with preclinical data suggesting that ME-344 can reverse resistance to anti-angiogenic therapy and warrant further studies to assess clinical efficacy of the combination. Clinical trial information: NCT02806817.
Use of simultaneous multi-site radiation therapy palliation: Patterns of care at a military hospital.
Authors: Stacie Wendt, Christopher Premo, Kenna Valentich, Brent Tinnel, Bryan Adams, Jack Ayres, Penelope Jane Harris, Anthony J. Fadell, Dusten Macdonald
Journal: Journal of Clinical Oncology (2016)

e21589 Background: The purchase and implementation of new radiation therapy technologies, such as intensity modulated radiation therapy (IMRT), volumetric arc therapy (VMAT), or on-board imaging (OBI), is expensive, and therefore these new technologies are primarily applied only to curative treatment. However, it is inevitable that benefits of their use will eventually accrue to palliative patients. For example, the technique of simultaneous multi-site palliation (MSP) is significantly improved by OBI and advanced radiation delivery technologies. We analyzed patterns of care for palliative radiation therapy in a military hospital from 2006 to 2014, and report here our findings in relation to changes in the use and costs associated with the delivery of MSP over that span. Methods: All patients treated with palliative intent from June 2006 – December 2007 (group A) and from January 2013 - June 2014 (group B) were retrospectively reviewed in this IRB-approved study. This included 75 and 72 evaluable patients, respectively. We calculated the percentage of MSP patients in each group. We then calculated the cost of treating each patient using 2015 CPT codes and the 2015 Medicare fee schedule, and compared mean cost per treated site using a paired t-test. Using just group B (to represent a modern cohort) we also compared mean cost per treated site for MSP patients to the cost per treated site for patients treated single-site-at-a-time. Results: In group A, 31% of palliative patients received MSP, and in group B, 47% received MSP. IMRT/VMAT/Arc therapy was used in 0% of group A patients and 21% of group B patients. Mean radiation therapy cost per treated site was not quite statistically significantly different between the two groups, ($2765.04 in group A and $3451.18 in group B, p = 0.0693). In group B the mean radiation therapy cost per treated site was significantly less in the MSP cohort than in the single-site-at-a-time cohort (MSP $2220.09 per treated site compared to $4552.68, p = 0.0006). Conclusions: Although new radiation therapy technologies are expensive, they open the door for increased use of MSP in palliative patients. In modern practice, MSP provides cost benefits to patients when analyzed in terms of cost per treated site.
Behavioral Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens, Michael J. Barry, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, David C. Grossman, Alex R. Kemper, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Maureen G. Phipps, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2018)

<h3>Importance</h3> More than 35% of men and 40% of women in the United States are obese. Obesity is associated with health problems such as increased risk for coronary heart disease, type 2 diabetes, various types of cancer, gallstones, and disability. Obesity is also associated with an increased risk for death, particularly among adults younger than 65 years. <h3>Objective</h3> To update the US Preventive Services Task Force (USPSTF) 2012 recommendation on screening for obesity in adults. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on interventions (behavioral and pharmacotherapy) for weight loss or weight loss maintenance that can be provided in or referred from a primary care setting. Surgical weight loss interventions and nonsurgical weight loss devices (eg, gastric balloons) are considered to be outside the scope of the primary care setting. <h3>Findings</h3> The USPSTF found adequate evidence that intensive, multicomponent behavioral interventions in adults with obesity can lead to clinically significant improvements in weight status and reduce the incidence of type 2 diabetes among adults with obesity and elevated plasma glucose levels; these interventions are of moderate benefit. The USPSTF found adequate evidence that behavior-based weight loss maintenance interventions are of moderate benefit. The USPSTF found adequate evidence that the harms of intensive, multicomponent behavioral interventions (including weight loss maintenance interventions) in adults with obesity are small to none. Therefore, the USPSTF concludes with moderate certainty that offering or referring adults with obesity to intensive behavioral interventions or behavior-based weight loss maintenance interventions has a moderate net benefit. <h3>Conclusions and Recommendation</h3> The USPSTF recommends that clinicians offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions. (B recommendation)
Ibrutinib associated infections: A retrospective study.
Authors: Caroline Chaul Barbosa, Lisa Marie DeAngelis, Christian Grommes
Journal: Journal of Clinical Oncology (2017)

e19020 Background: Ibrutinib (IBRU) is a Bruton tyrosine kinase (BTK) inhibitor that has been FDA approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom's Macroglobulinemia (WM). BTK inhibition may contribute to immunosuppression through B- and T-cell inhibition, resulting in an increase in infections. We therefore characterized IBRU-related infections retrospectively. Methods: The study was an IRB approved retrospective review. Patients (pts) treated with IBRU between 4/2014-11/2016 who developed any infection were identified using ICD10 codes in a clinical database. Study population was defined using descriptive statistics. Results: 200 pts were identified: 78 pts had CLL (39%), 30 diffuse large B-cell lymphoma (15%), 28 MCL (14%), 19 WM (9.5%), 15 (7.5%) marginal zone lymphoma, 14 (7%) follicular lymphoma, 7 (3.5%) multiple myeloma, 7 (3.5%) T-cell lymphoma and 2 (1%) primary central nervous system lymphoma (PCNSL). Median age was 68 (range 28-96), 34% were men and median ECOG was 1. The majority of pts received IBRU as second line treatment (172, 86%) with a median of 2 prior lines of treatment; 23 pts (11.5%) were post transplant. Median IBRU dose was 420mg daily (range 140-840mg), administered a median of 316 days (range 3-1780). Single agent IBRU was used in 162 pts (81%). 105 pts (52%) developed an infection, with pneumonia (30%), upper airway infection (26%); skin infection (18%); and sinusitis (13%) being the most common. 10 (9.5%) had neutropenic fever and 1 (1%) cryptococcal pneumonia. Seven (7%) developed fungal infections, with invasive aspergillosis in 5 (5%). 34 (32%) developed ≥3 infections. 46 pts (44%) were hospitalized, 10 (9.5%) interrupted IBRU and 3 pts (2.9%) died due to infections (2 pneumonia; 1 neutropenic fever). The median time to infection after starting IBRU was 70 days (range 2-1261). The highest infection rate was seen in pts with PCNSL (100%, 2/2), MZL (67%, 10/14), followed by CLL (64%, 50/78). Conclusions: We identified infections in half of the pts treated with IBRU. Pts treated with IBRU should be monitored closely for the development of infections, particularly airway infections.
A phase I study of a p53MVA vaccine in combination with gemcitabine (GEM) in recurrent ovarian cancer (OC).
Authors: Mihaela C. Cristea, Nicola Hardwick, Paul Henry Frankel, Robert Morgan, Lucille A. Leong, Don J. Diamond
Journal: Journal of Clinical Oncology (2016)

e17040 Background: We developed a modified vaccinia Ankara virus containing the wild-type p53 transgene (p53MVA) to stimulate immunity to over-expressed p53 in tumor cells. This approach is applicable to OC, in which p53 mutation is common. We previously reported that p53MVA was well tolerated at a dose of 5.6 x 108 pfu in patients (pts) with gastro-intestinal malignancies. GEM, a standard chemotherapy agent in OC, may potentiate the action of immunotherapies. Numerous early phase trials of cancer vaccines and GEM in pancreatic cancer report encouraging immunological and clinical responses. We conducted a de-escalation Phase I trial of p53MVA and GEM in pts with recurrent OC. Methods: OC pts with a platinum free interval ≤ 12 months, ≤ 2 chemotherapy lines for recurrent disease and histology showing p53 involvement were eligible. All pts received GEM at 1000mg/m2 on days 1 and 8 every 3 weeks and p53MVA at 5.6 x 108 pfu, sq on day 15 of the first 3 cycles of GEM. Dose-limiting toxicities (DLTs) were evaluable during the first 2 cycles of therapy. Results: A total of 7 pts have been enrolled [median age 63, platinum free interval ≤ 6 months 7/7, serous or mixed adenocarcinoma 6/7, carcinosarcoma (CS) 1/7]. The number of prior lines of therapy for recurrent OC was 0 in 1/7 pts, 1 in 4/7 pts and 2 in 2/7 pts. Five pts are evaluable for DLT. Two pts were inevaluable; one due to GEM allergy requiring steroids and another (with CS of the ovary) due to rapidly progressive disease and early death. No DLTs were observed, establishing the starting dose as the recommended Phase II dose. GEM related grade 3/4 AEs, not meeting DLT definition included: neutropenia (grade 3 in 1 pt, grade 4 in 1 pt), anemia (grade 3, 2pts), hyperuricemia (grade 4, 1pt) hyponatremia (grade 3, 1pt), leukopenia (grade 3, 1pt). Additional pts are being recruited at the recommended Phase II dose. Conclusions: Combination therapy of p53MVA and GEM is well tolerated with expected toxicities relating to GEM alone and no evidence of autoimmunity. To our knowledge this is the first trial combining a viral based cancer vaccine and GEM in OC. Support: NCI/NIH grant P30CA033572. Clinical trial information: NCT02275039.
Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma
Authors: Jason R. Baird, R. Bryan Bell, Victoria Troesch, David Friedman, Shelly Bambina, Gwen Kramer, Tiffany C. Blair, Terry Medler, Yaping Wu, Zhaoyu Sun, Tanja D. de Gruijl, Rieneke van de Ven, Rom S. Leidner, Marka R. Crittenden, Michael J. Gough
Journal: Cancer Research (2018)

Abstract Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell–mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo. We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response. Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308–19. ©2018 AACR.
Reducing health disparities with the establishment of a new low-dose lung CT (LDCT) screening program.
Authors: Mary Pasquinelli, Kevin Kovitz, Arkadiusz Z. Dudek, Matthew Koshy, Martha Menchaca, Lawrence Eric Feldman
Journal: Journal of Clinical Oncology (2016)

e18071 Background: While lung cancer is the leading cause of cancer death in the United States for both men and women its incidence and mortality rate differs depending on race, ethnicity, and gender. For example, African Americans/Black (AA) have significantly higher incidence/mortality rate compared to Caucasians (C). The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality with LDCT versus chest X-ray screening. The NLST study population included 91% C and only 4.5% AA individuals. The University of Illinois Hospital & Health Sciences Systems (UI Health) serves a population that is 48% AA, 16% C, 7% Hispanic/Latino (H), 24% other (O). Could LDCT screening be more effective if a higher percentage of high risk minority individuals were screened? Does the lack of a representative percentage of minorities actually increase health disparities? Methods: UI Health’s comprehensive lung cancer screening program (LCSP) was established in March 2015 and prospective subject data collected. Each LDCT screen was assessed using USPSTF/CMS screening criteria for individuals that are high risk of lung cancer. Using Chicago Health Atlas lung cancer mortality statistics we compared our screened cases with community lung cancer mortality rates. Positive screens were discussed at our Multidisciplinary Lung Tumor Board. Results: To date 154 people have been screened and 108 of them met USPSTF/CMS criteria. Compared to the NLST, UI Health’s screened population has a higher percentage of AA (65% vs. 4.5%) individuals. Using the American College of Radiology LungRADS risk stratification system, 33% of UI Health’s patients screened had a positive screen (LungRADS 3 or 4), higher than the 20% estimated prevalence rate for positive screens in LDCT studies to date. Within year one 3 patients (2.7%) were diagnosed with lung cancer, higher than the 1.1% diagnosed in the NLST. Patients diagnosed with lung cancer in our LCSP came from communities known to have high lung cancer mortality rates. Conclusions: Compared to the NLST our LCSP has a higher percentage of positive screens and diagnoses of cancer. Health disparities could be decreased by screening high-risk minority populations.
Comparison of oxaliplatin-related spleen enlargement in patient with gastric cancer who received S-1 versus capecitabine as a combination partner of oxaliplatin.
Authors: Seyoung Seo, Moonho Kim, Minju Kim, Mi-Jung Kim, Young Iee Park, Sook Ryun Park
Journal: Journal of Clinical Oncology (2018)

e22195 Background: Oxaliplatin (OX)-based chemotherapy is known to cause hepatic sinusoidal injury, resulting portal hypertension with splenomegaly (SM). We compared this OX-induced hepatopathy, SM, and their clinical significance according to combined oral fluoropyrimidines, S-1 vs. capecitabine (X) in gastric cancer (GC). Methods: We analyzed pts from two prospective trials for GC, adjuvant XELOX (X 1000 mg/m2 bid on D1-14 + OX 130 mg/m2 on D1 q3w, 8 cycles; n = 52) and palliative SOX (S-1 40 mg/m2 bid on D1-14 + OX 130 mg/m2 on D1 q3w, continuous [SOX-c, n = 52] vs. intermittent [SOX-i, discontinuing after 6th and restarting on progression, n = 53]) Spleen volume (vol) was retrospectively measured by Rapidia software. Results: Baseline sex, age, ECOG PS, BSA, spleen vol, levels of platelet (plt)/liver enzyme/bilirubin (bil) and OX cumulative dose during 8 cycles did not differ in XELOX and SOX-c. After 8 cycles, the SOX-c had more SM, hepatic enhancing heterogeneity, hyper-bil, and thrombocytopenia than the XELOX (Table). The SOX-c was a risk factor for developing SM (adjusted odds ratio, 4.7; 95% CI, 2.0-10.8; p < .001) When tracking serial spleen vol and plt at baseline, 2nd, 4th and 6th cycles in SOX-c and SOX-i, spleen vol significantly increased over time (mean, 160, 182, 216, 247 cm3; p< .001), whereas plt were decreased (mean, 290, 168, 132, 116 x103/uL; p< .001). In SOX-i group, spleen vol decreased at 6th cycles, 6, 12, 18 and 24w after stopping SOX (mean, 194, 181, 167, 158, 150 cm3; p= .016). Conclusions: S-1 seems to enhance OX-induced hepatic sinusoidal injuries than capecitabine in pts with GC with clinical significance of higher incidences of splenomegaly, thrombocytopenia, and hyperbilirubinemia. After 8 cycles, n (%) p XELOX SOX-c p No SM SM Spleen vol Mean 197.5 279.7 < .001 < 1.5 times 38 (73) 19 (36) < .001 ≥1.5 times (SM) 14 (27) 33 (63) Hepatic enhancing heterogeneity Gr 0-1 45 (86) 33 (63) .007 46 (81) 32 (68) .139 Gr 2-3 7 (13) 19 (36) 11 (19) 15 (32) Plt Mean 148k 115k .003 157k 100k < .001 > 150k 20 (38) 11 (21) .054 27 (47) 4 (8) < .001 ≤150k 32 (61) 41 (79) 30 (53) 43 (91) Bil Mean 0.8 1.1 .026 0.8 1.2 < .001 ≤1.2 44 (85) 33 (63) ..014 49 (86) 28 (60) .002 > 1.2 8 (15) 19 (36) 8 (14) 19 (40)
A multicenter randomized controlled trial of a 3-L/kg/min versus 2-L/kg/min high-flow nasal cannula flow rate in young infants with severe viral bronchiolitis (TRAMONTANE 2)
Authors: Christophe Milési, Anne-Florence Pierre, Anna Deho, Robin Pouyau, Jean-Michel Liet, Camille Guillot, Anne-Sophie Guilbert, Jérôme Rambaud, Astrid Millet, Mickael Afanetti, Julie Guichoux, Mathieu Genuini, Thierry Mansir, Jean Bergounioux, Fabrice Michel, Marie-Odile Marcoux, Julien Baleine, Sabine Durand, Philippe Durand, Stéphane Dauger, Etienne Javouhey, Stéphane Leteurtre, Olivier Brissaud, Sylvain Renolleau, Aurélie Portefaix, Aymeric Douillard, Gilles Cambonie
Journal: Intensive Care Medicine (2018)
Modeling of the tumor microenvironment to highlight nonlinear interactions between chemotherapeutic response and macrophage polarization state.
Authors: Louis Talbert Curtis, Fransisca Leonard, Biana Godin, Hermann B, Frieboes
Journal: Journal of Clinical Oncology (2018)

e24120 Background: The influence of tumor microenvironment characteristics on cancer progression and efficacy of chemotherapy has been the focus of intensive research. In particular, macrophages are a dynamic cell population that can assume various phenotypes based on tumor microenvironment characteristics. The influence of macrophage phenotype on therapeutic efficacy remains poorly understood. Macrophages can either aid or hinder tumor growth, with disease prognosis hinging on the proportion of pro-inflammatory and anti-tumorigenic M1 vs. anti-inflammatory and pro-tumorigenic M2 phenotypes. Repolarization of macrophages in the tumor microenvironment from the M2 to M1 phenotype has emerged as a potential approach that harnesses the body's own immune system to fight cancer. Methods: Understanding the complex interactions between chemotherapy and macrophage populations in the tumor microenvironment could benefit from mathematical and engineering principles. We implement a modeling framework to evaluate tumor response to chemotherapy, including the effect of macrophage phenotypes in the tumor microenvironment on tumor growth and therapeutic outcome. M1 and M2 phenotypes are integrated into a model of tumor growth representing a metastatic lesion in a highly vascularized organ such as the liver. Behaviors simulated include M1 release of cytotoxic nitric oxide and M2 release of growth-promoting factors. Results: We simulate a hypothetical therapy-induced macrophage repolarization regimen from the anti-inflammatory M2 phenotype to the pro-inflammatory M1 phenotype in conjunction with chemotherapy administration. Surprisingly, the model predicts that chemotherapy applied in a tumor microenvironment that contains mixed M1 and M2 macrophage phenotypes is more effective than with only M1 macrophages. Conclusions: Fine-tuning the ratio of macrophage phenotypes in the tumor microenvironment during chemotherapy may be therapeutically beneficial. A proposed mechanism is that M2 macrophages potentiate the chemotherapy effect by promoting tumor cell proliferation that sensitizes these cells to agents acting on dividing cells.