tbuckley/cabot-search huggingface dataset:
Body composition as a predictor of sunitinib toxicity in patients with renal cell carcinoma.
Authors: Samantha Cushen, Aoife M Ryan, MinYuen Teo, Peter MacEneaney, Patrick McLaughlin, Frances Fitzpatrick, Nataliya Rozumna-Martynyuk, Raymond S. McDermott, Derek Gerard Power
Journal: Journal of Clinical Oncology (2013)

e15566 Background: Sunitinib is a standard first-line option for metastatic renal cell cancer (mRCC). Identification of biomarkers associated with outcome or toxicity is a challenge. Body composition is a prognostic factor in cancer and sarcopenia is associated with treatment toxicity and survival. We investigated if body composition by CT scan predicted dose limiting toxicity (DLT) from sunitinib in mRCC. Methods: Patients (pts) with mRCC receiving sunitinib 50mg as 1 st line therapy between 2007-2012 were included. Ethical approval was obtained and prospectively maintained databases analysed. Skeletal muscle cross-sectional area at L3 was measured by CT. Sarcopenia was defined using published cut offs. Toxicity was assessed after 4 cycles of drug (CTCAE, v4.0). Results: 55 pts (43 male), mean age 64yrs (±10.6) were included. 67% were overweight/obese (BMI&gt;25kg/m 2 ). Sarcopenia was present in 33% (56% of normal BMI, 44% overweight group). Overall 40 pts (73%) experienced DLT (51% M, 100% F, p&lt;0.016). DLT occurred in &lt;6 months in 53% (44% M vs 83% F, p&lt;0.016) and these pts were older (mean 68 yrs vs 60 yrs, p&lt;0.01), had lower skeletal muscle mass (51.8 cm 2 /m 2 vs 59.4 cm 2 /m 2 , p&lt;0.012), and fat free mass (FFM) (51.4kg vs 57.7kg, p&lt;0.03), and received higher drug dose in mg/kg FFM (1.01 vs 0.89, p&lt;0.02). Common toxicities were GI (65%) and fatigue (47%). Of pts &lt;25 th percentile skeletal muscle mass 92% experienced DLT, higher than pts &gt;75 th percentile (p&lt;0.05). Pts &lt;25 th percentile had an average of 5 toxicities vs 2 in those &gt;75 th percentile (p&lt;0.003). All toxicities were more common in muscle wasted patients (p&lt;0.05). 77% (n=10) of pts receiving a drug dose &gt;75 th percentile (1.105mg/FFM) experienced DLT in &lt;6 months vs 44% (n=17) receiving a dose &lt;75 th percentile (&lt;1.099mg/FFM; p&lt;0.037). Conclusions: Sarcopenia is prevalent in patients with mRCC, is easily measured, is an occult condition in pts with normal/high BMI, and is a significant predictor of DLT in pts receiving 1 st line sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity. The role of sarcopenia in targeted therapy is evolving and its potential to predict toxicity should be further studied.
Strengthening the Free Healthcare Initiative through a pharmacy and supply chain intervention: Partners in Health's experience in rural Sierra Leone
Authors: Sheriff L Bangura, Katrina Hann, Ameet Salvi, Rebecca Kahn, Kerry L Dierberg, Joseph Gassimu, Alpha Kabbah, Regan H Marsh
Journal: The Lancet Global Health (2017)

BackgroundTo improve high maternal and under-5 mortality—among the worst globally—Sierra Leone's Ministry of Health and Sanitation (MOHS) enacted the Free Healthcare Initiative in 2010. Under this initiative, pregnant and lactating women and children aged younger than 5 years receive medical treatment and essential medicines free of charge at public facilities. However, the availability of medicines remains inconsistent, which results in patients paying for medicines and an undermining of the quality of care and trust in the health-care system. These gaps between services and medicines promised under the Free Healthcare Initiative and actual resources delivered worsened during the 2013–15 Ebola epidemic, which strained an already weak health-care system. Here, we describe an approach to strengthen pharmacy and supply chain systems to improve access to essential medicines at a district hospital in Sierra Leone.MethodsIn 2015, Partners In Health undertook a gap analysis to understand the barriers to drug availability for patients eligible for the Free Healthcare Initiative at Koidu Government Hospital (KGH). A multidisciplinary task force identified priorities and created a partnership with the MOHS. Partners In Health's Director of Pharmacy led meetings with hospital management, shadowed clinical staff, and performed an inventory of drugs and medical supplies.FindingsThe gap analysis revealed challenges in the areas of human resources, infrastructure, storage, and information systems. The results led to the following interventions: decentralisation of medication distribution from hospital to ward level; the hiring of four pharmacy technicians; expansion of central warehousing; and implementation of electronic reporting tools to improve consumption data. MOHS pharmacy staff were mentored to improve feedback mechanisms between central and district levels. Between November, 2015, and August, 2016, these changes resulted in nearly 100% availability of essential drugs—with 80% provided via the strengthened MOHS system—and elimination of out-of-pocket expenses for patients. Additionally, trust in the public health-care system has improved: compared with a 2012 and 2013 pre-Ebola baseline at KGH, paediatric and maternity admissions have increased by 47%, with a 95% increase in hospital-based deliveries.InterpretationThe success of the Free Healthcare Initiative is rooted in its shared ownership with the MOHS and the integration of central-level and district-level information systems. The approach described here could be used to guide new interventions to strengthen pharmacy supply chains elsewhere in Sierra Leone and other low-resource settings.FundingPartners In Health, Sierra Leone.
State-Specific Rates of Primary and Secondary Syphilis Among Men Who Have Sex with Men — United States, 2015
Authors: Alex de Voux, Sarah Kidd, Jeremy A. Grey, Eli S. Rosenberg, Thomas L. Gift, Hillard Weinstock, Kyle T. Bernstein
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

In 2015, the rate of reported primary and secondary syphilis in the United States was 7.5 cases per 100,000 population, nearly four times the previous lowest documented rate of 2.1 in 2000 (1). In 2015, 81.7% of male primary and secondary syphilis cases with information on the sex of the sex partner were among gay, bisexual, and other men who have sex with men (collectively referred to as MSM) (1). These data suggest a disproportionate incidence of disease among MSM. However, attempts to quantify this disparity have been hindered by limited data on the size of the MSM population at the state level. To produce the first estimates of state-specific rates of primary and secondary syphilis among MSM, CDC used MSM population estimates based on a new methodology (2) and primary and secondary syphilis case counts reported in 2015 to the National Notifiable Diseases Surveillance System. Among 44 states reporting information on the sex of sex partners for ≥70% of male cases, the overall rate of primary and secondary syphilis among all men (aged ≥18 years) in the United States in 2015 was 17.5 per 100,000, compared with 309.0 among MSM and 2.9 among men who reported sex with women only. The overall rate of primary and secondary syphilis among MSM was 106.0 times the rate among men who have sex with women only and 167.5 times the rate among women.* These data highlight the disproportionate impact of syphilis among MSM and underscore the need for innovative and targeted syphilis prevention measures at the state and local level, especially among MSM. It is important that health care providers recognize the signs and symptoms of syphilis, screen sexually active MSM for syphilis at least annually, and provide timely treatment according to national sexually transmitted diseases treatment guidelines (3).
Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma
Authors: Valentina Di Gialleonardo, Hannah N. Aldeborgh, Vesselin Miloushev, Kelly M. Folkers, Kristin Granlund, William D. Tap, Jason S. Lewis, Wolfgang A. Weber, Kayvan R. Keshari
Journal: Cancer Research (2017)

Abstract Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multimodality approach to evaluate the phenotypic effects and metabolic changes that occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate production in vitro, followed by cell growth inhibition. In vivo, we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas. Cancer Res; 77(11); 3113–20. ©2017 AACR.
It Takes a Village to Unmask HSTL
Authors: Noriaki Yoshida, David M. Weinstock
Journal: Cancer Discovery (2017)

Abstract Summary: In this issue of Cancer Discovery, McKinney and colleagues describe the genetics of hepatosplenic T-cell lymphoma, a rare subtype of T-cell lymphoma with unique clinical characteristics. The findings, specifically frequent mutations of STAT5B, PIK3CD, and the histone methyltransferase SETD2, may help guide translational efforts to target this deadly disease. Cancer Discov; 7(4); 352–3. ©2017 AACR. See related article by McKinney et al., p. 369.
KRAS and EGFR status as predictive markers of response and time to progression in EGFR wild-type stage IV non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine-kinase inhibitors.
Authors: Manuel Domine, Federico Rojo, Tatiana Hernandez, Sandra Zazo, Gloria Serrano, Cristina Chamizo, Cristina Carames, Juan Madoz, Irene Moreno, Nuria Perez-Gonzalez, Carolina Ortega, Nerea Carvajal, Francisco Lobo, Carmen Laura Auz, Victoria Casado, Gustavo Rubio, Mauro Oruezabal, Alberto Lendinez, Ana Leon, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2013)

e19000 Background: KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of epidermal growth factor receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI-treated patients. Methods: 84 samples from NSCLS patients treated with erlotinib or gefitinib were analyzed for KRAS and EGFR mutation status by cobas KRAS and EGFR Mutation Tests (Roche). EGFR copy number was determined by fluorescent in situ hybridization (FISH, Abbott Molecular) and amplification was defined with three or more gene copies in tumor. Results: KRAS mutation was detected in 15 (17.8%) cases, EGFR mutation in 27 (32.1%) and EGFR amplification in 8 (9.5%). Significant differences were detected in response rates for wild-type (0.2) and mutant KRAS (0.0) (p=0.023), for wild-type (0.12) and mutant EGFR (0.39) (p=0.007), and for non-amplified (0.18) and EGFR-amplified (0.71) patients (p=0.005). Additionally, significant benefit from TKI therapy was observed for KRAS wild-type compared with KRAS-mutated patients (median TTP 7 vs. 3 months, p=0.001), for EGFR-mutated compared with wild-type patients (14 vs. 4 months, p=0.004) and for EGFR-amplification in contrast to non-amplified cases (11 vs. 5 months, p=0.001). KRAS and EGFR mutations or EGFR amplification did not correlated with overall survival (18 vs. 19 months, p=0.406; 16 vs. 21 p=0.094; 25 vs. 17 months, p=0.103, respectively). Combined analysis of favourable status of three biomarkers strongly predicted benefit to TKI therapy (median TTP 15 vs. 3 months, p&lt;0.001). Conclusions: Combined analysis ofKRAS mutation, EGFR mutation and EGFR amplification in EGFR TKI-treated NSCLC might provide superior predictive information than single biomarker study in these patients.
Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib, leading to massive tumour necrosis and inhibition of angiogenesis
Authors: Khong Bee Kang, Ting Ting Wang, Chow Thai Woon, Sor Tin Cheah, Xiao Lei Moore, Congju Zhu, Meng Cheong Wong
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4428 

Despite standard therapy of surgery, radiotherapy and chemotherapy, the median survival for glioblastoma multiforme patients is less than 15 months. We sought to determine whether celeCOXib, a selective cyclooxygenase-2 (COX-2) inhibitor, could enhance brain tumour radiosensitivity in vitro and in vivo . Methods: The effect of combined celecoxib (30 μM) and irradiation (9 Gy) on U87 cell viability and angiogenic factor proteins (vascular endothelial growth factor VEGF, angiopoietin-1 and angiopoietin-2), were assessed by MTT assay and Western blot, respectively. In vivo , we determined the survival time of nude mice intracranially transplanted with U87 cells, and treated with celeCOXib (100 mg/kg for 2 weeks), irradiation (total 24 Gy), combined therapy and vehicle dimethyl sulfoxide (DMSO). Brain tumors were isolated and in a blinded manner, two independent observers measured the tumor sizes and necrotic regions of haematoxylin and eosin-stained tumors. Tumor microvascular density, represented by immunohistochemical staining of von Williebrand factor endothelial marker, was also analyzed by 2 independent observers. Findings: At 24, 48 and 72 hours in vitro , combined celecoxib and irradiation significantly reduced U87 cell viability by approximately 50%. At 72 hours, angiopoietin-1 and VEGF proteins were decreased, whereas angiopoietin-2 increased after celeCOXib treatment alone, and when celecoxib was combined with irradiation. Control (DMSO-treated) mice had median survival of 18 days, necrotic regions constituted 2.2 ± 1.4% of tumour region, and tumour microvascular density of 91.3 ± 7.3 microvessels per mm2. Celecoxib treatment significantly extended the median survival of irradiated mice, from 33 to 41 days. When combined with irradiation, celecoxib caused extensive tumor necrosis constituting 24.5 ± 8.6% of tumour region, compared to irradiation alone (1.5 ± 1.1%), whereas tumour microvascular density was significantly decreased from 65.4 ± 4.0 (irradiation alone) to 52.9 ± 2.9 (combined celeCOXib and irradiation) microvessels per mm2. Conclusion: Celecoxib enhanced glioblastoma radiosensitivity, reduced tumor cell viability and prolonged survival of implanted glioblastoma mice by inhibition of tumor angiogenesis and causing extensive tumor necrosis. These findings have the potential to be translated clinically to improve survival of glioblastoma multiforme patients.
A phase II study evaluating the safety and efficacy of sunitinib with weekly paclitaxel followed by doxorubicin and daily oral cyclophosphamide plus G-CSF as neoadjuvant chemotherapy (NC) for locally advanced (LABC) or inflammatory breast cancer (IBC).
Authors: Jennifer M. Specht, Brenda F. Kurland, Hannah M. Linden, Julie Gralow, Vijayakrishna K. Gadi, Georgiana Kehr Ellis, Eve T. Rodler, Xiaoyu Chai, Jinny Eun, Ursa Abigail Brown-Glaberman, Robert B. Livingston
Journal: Journal of Clinical Oncology (2013)

1090 Background: Sunitinib (S) is an oral tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity. The primary objective of this trial was to assess the pathologic complete response rate (pCR) in patients (pts) treated with NC consisting of S with weekly paclitaxel (T) followed by doxorubicin and daily oral cyclophosphamide plus G-CSF (AC+G-CSF). Correlative studies including circulating biomarkers are reported separately. Methods: Pts with HER2 negative LABC or IBC were eligible for this multicenter, phase II trial. Pts received S 25 mg po daily with T 80 mg/m 2 IV Qweek (wk) x 12 wks, then AC+G-CSF (doxorubicin 24 mg/m 2 IV Qwk + oral cyclophosphamide 60 mg/m 2 po daily + G-CSF 5 mcg/kg SC days 2-7) x 15 wks. pCR in the breast and axilla was assessed at surgery, and the MDACC CPS+EG score (validated score combining clinical and pathologic results for predicting survival in the neoadjuvant setting) was calculated. Results: 70 pts (ages 33-79) were enrolled; 68 received protocol therapy. 37 (53%) had ER and/or PR positive tumors. 2 patients were unevaluable (hypersensitivity to T, toxicity possibly related to S) and 3 withdrew consent prior to surgery. 61 pts reported any grade AE in S+P period. Among grade 3 or 4 AEs, neutropenia was most common in S+P period occurring in 31/68 (46%). pCR in the breast was observed in 27% (17/63, 95% CI 17%-40%) and breast and axilla in 15/63 (24%). In pts with ER positive tumors, pCR rate in breast was 8/34 (24%) and 9/29 (31%) for pts with ER negative tumors. 18 evaluable pts (29%) had CPS+EG scores ≤2, 40 (63%) had CPS+EG scores of ≥3, and 5 had insufficient information to calculate the CPS+EG score. When response was defined as pCR and/or CPS+EG score ≤ 2, 28 pts (44%) were responders. Conclusions: NC with T+S followed by AC+G-CSF was well tolerated. Using a combined definition of response of pCR and/or CPS+EG score ≤2, 28/63 (44%) pts had response; 19/34 (56%) for ER positive and 9/29 (31%) for ER negative disease. The addition of S to NC may result in promising incremental benefit for pts with ER positive breast cancer. Clinical trial information: NCT00513695.
Effect of atrasentan (ABT-627, ATN) on the pharmacokinetics (PK) of midazolam (MDZ)
Authors: J. Z. Peng, T. Doan, D. Burt, D. Baran, T. Yanke, P. Wang, N. McCracken, G. Roske, R. A. Carr, A. Allen
Journal: Journal of Clinical Oncology (2004)

4725 Background: ATN is an oral selective endothelin A receptor antagonist, currently in phase 3 clinical development for the treatment of hormone-refractory prostate cancer. In humans, extensive ATN metabolizm is equally distributed between oxidation (CYP3A) and glucuronidation. In vitro, ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). The sedative MDZ is extensively metabolized by CYP3A in both gut and liver. MDZ plasma concentrations are sensitive to CYP3A inhibition; MDZ is an FDA-recommended probe CYP3A4 substrate. Methods: To assess the effect of ATN on MDZ PK, a phase 1 double-blind, randomized, two-period crossover study was conducted in 16 healthy subjects (13 M and 3 F; mean±SD 41±11 yrs, 78±13 kg). Subjects received ATN 10 mg or placebo PO QD from Day 1 through 7; in both regimens MDZ was given on Day 4 (1 mg IV) and Day 6 (5 mg PO). Blood samples for MDZ assay were collected predose and over 48 h after each MDZ dose. Plasma concentrations of MDZ were determined using a validated LC/MS/MS method. Results: MDZ PK are summarized (mean±SD; N=15) in the following table. MDZ Cmax and AUC were bioequivalent (+/- ATN). One subject withdrew from the study after the first period (MDZ alone), and was excluded from the PK analyses. Both regimens were well tolerated. Sleepiness and headache were the most common AEs, and all AEs were mild. Conclusions: ATN had no effect on MDZ PK, indicating 10 mg QD ATN does not alter CYP3A4 activity in gut or liver. Therefore, PK interactions would not be expected between ATN and drugs metabolized by CYP3A4. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories
Interactive Voice Response–Based Self-management for Chronic Back Pain
Authors: Alicia A. Heapy, Diana M. Higgins, Joseph L. Goulet, Kathryn M. LaChappelle, Mary A. Driscoll, Rebecca A. Czlapinski, Eugenia Buta, John D. Piette, Sarah L. Krein, Robert D. Kerns
Journal: JAMA Internal Medicine (2017)

Recommendations for chronic pain treatment emphasize multimodal approaches, including nonpharmacologic interventions to enhance self-management. Cognitive behavioral therapy (CBT) is an evidence-based treatment that facilitates management of chronic pain and improves outcomes, but access barriers persist. Cognitive behavioral therapy delivery assisted by health technology can obviate the need for in-person visits, but the effectiveness of this alternative to standard therapy is unknown. The Cooperative Pain Education and Self-management (COPES) trial was a randomized, noninferiority trial comparing IVR-CBT to in-person CBT for patients with chronic back pain.To assess the efficacy of interactive voice response-based CBT (IVR-CBT) relative to in-person CBT for chronic back pain.We conducted a noninferiority randomized trial in 1 Department of Veterans Affairs (VA) health care system. A total of 125 patients with chronic back pain were equally allocated to IVR-CBT (n = 62) or in-person CBT (n = 63).Patients treated with IVR-CBT received a self-help manual and weekly prerecorded therapist feedback based on their IVR-reported activity, coping skill practice, and pain outcomes. In-person CBT included weekly, individual CBT sessions with a therapist. Participants in both conditions received IVR monitoring of pain, sleep, activity levels, and pain coping skill practice during treatment.The primary outcome was change from baseline to 3 months in unblinded patient report of average pain intensity measured by the Numeric Rating Scale (NRS). Secondary outcomes included changes in pain-related interference, physical and emotional functioning, sleep quality, and quality of life at 3, 6, and 9 months. We also examined treatment retention.Of the 125 patients (97 men, 28 women; mean [SD] age, 57.9 [11.6] years), the adjusted average reduction in NRS with IVR-CBT (-0.77) was similar to in-person CBT (-0.84), with the 95% CI for the difference between groups (-0.67 to 0.80) falling below the prespecified noninferiority margin of 1 indicating IVR-CBT is noninferior. Fifty-four patients randomized to IVR-CBT and 50 randomized to in-person CBT were included in the analysis of the primary outcome. Statistically significant improvements in physical functioning, sleep quality, and physical quality of life at 3 months relative to baseline occurred in both treatments, with no advantage for either treatment. Treatment dropout was lower in IVR-CBT with patients completing on average 2.3 (95% CI, 1.0-3.6) more sessions.IVR-CBT is a low-burden alternative that can increase access to CBT for chronic pain and shows promise as a nonpharmacologic treatment option for chronic pain, with outcomes that are not inferior to in-person CBT.clinicaltrials.gov Identifier: NCT01025752.