tbuckley/cabot-search huggingface dataset:
The influence of gastrointestinal resection on sunitinib exposure in GIST patients.
Authors: Djoeke de Wit, Nielka P van Erp, Reza Khosravan, Robin Wiltshire, Randy U. Allred, George D. Demetri, Henk-jan Guchelaar, Hans Gelderblom
Journal: Journal of Clinical Oncology (2013)

10547 Background: GIST patients often have an altered anatomy of the GI tract due to either primary resection of the tumor or palliative surgery. It is unknown whether such GI resections affect the exposure to sunitinib and its active metabolite SU12662. Previous studies showed that the exposure to imatinib and nilotinib was decreased in GIST patients with prior major gastrectomy. Therefore, we postulated that GI resections might similarly affect sunitinib exposure. Methods: A retrospective analysis was performed to assess the effect of GI resections on sunitinib exposure. Pharmacokinetic data from 305 GIST patients included in 4 phase I-II trials were analyzed. Patients were subdivided into 6 groups according to prior GI surgery: 1)Major gastrectomy: 2)Partial gastrectomy: 3)Small bowel resection: 4)Combination of gastrectomy and small bowel resection: 5)Colon resection and 6)Controls with no prior GI surgery. Patients with uncertain GI resections were excluded. Dose normalized exposure (AUC 0-24hr ) of sunitinib and SU12662 was estimated with a population PK approach using NONMEM. Analysis of covariance was performed to test for significant differences in AUC between each of the subgroups and controls. Results: The geometric mean of total exposure to sunitinib and SU12662 was decreased by 21% and 28% in subgroup 4, (n=8; sunitinib: 931 ng*hr/mL (95%CI;676-1283) and SU12662: 354 ng*hr/mL (95%CI;174-720)) compared to controls (n=63; sunitinib: 1177 ng*hr/mL (95%CI;1097-1263) and SU12662: 491 ng*hr/mL (95%CI;435-555)), with the differences being significant (p&lt;0.05) on the log scale. However, no significant differences in total exposures were observed between each of the other subgroups and control. Conclusions: In patients with a combined gastrectomy and small bowel resection, sunitinib and SU12662 exposure is significantly decreased as compared to subjects with no prior GI surgery. Contrary to previous results for imatinib, gastrectomy alone does not appear to influence sunitinib exposure. This should be taken into consideration for the treatment of GIST patients who had a gastrectomy. In theory, such patients might have better outcomes if treated with sunitinib, given the risk of subtherapeutic exposure to imatininb.
A phase II single arm study of pazopanib and paclitaxel as first-line treatment for unresectable stage III and stage IV melanoma: Interim analysis.
Authors: John P. Fruehauf, Beverly Alger, Basmina Parmakhtiar, James G. Jakowatz, Claudette Bettis, Tony Chuang, Shlomit Y. Ein-Gal
Journal: Journal of Clinical Oncology (2012)

8524 Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm &gt;3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.
Prognostic factors affecting survival in malignant pleural mesothelioma.
Authors: Berna Eren Komurcuoglu
Journal: Journal of Clinical Oncology (2013)

e18535 Background: Determining the pre-treatment prognostic factors in malignant pleural mesothelioma (MPM) is of importance in terms of both estimating the course of disease and determining the patients who are candidate to multimodal therapy. Aim of the current study was to determine the prognostic factors affecting survival in the patients with MPM. Methods: One hundred and twenty five patients who had been diagnosed histologically as having MPM over the past 5 years were evaluated retrospectively. Relationships of survival of the patients with their age, gender, exposure to asbestos, smoking history, platelet, hemoglobin, leukocyte (WBC), serum lactate dehydrogenase (LDH) values, their histology, performance scores and stage of disease were examined. Results: Advanced clinical stage, N2 nodal involvement and presence of distant metastasis were found to be related to survival. Sarcomatous histology was found to be poor prognostic factor independently of other factors. Conclusions: We showed that histological subtype and stage of disease were the most important parameters in planning the treatment, especially in determining the patients who were candidate multimodal treatment and estimating the prognosis.
Results of a phase II trial of h-R3 monoclonal antibody (nimotuzumab) in the treatment of resistant or relapsed high-grade gliomas in children and adolescents
Authors: U. Bode, S. Buchen, G. Janssen, T. Reinhard, M. Warmuth-Metz, F. Bach, G. Fleischhack
Journal: Journal of Clinical Oncology (2006)

1522 Background: Children and adolescents suffering from high grade gliomas (HGG) have a poor prognosis when they relapse during or after primary treatment. Thus novel therapeutic approaches as the inhibition of growth-signalling pathways are needed. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (Nimotuzumab) in the treatment of these patients. Methods: Pediatric patients with glioblastoma multiforme, anaplastic astrocytoma or intrinsic pontine glioma (PG) with radiologically proven progressive disease following primary or relapse treatment were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m 2 Nimotuzumab for six weeks, and in case of non-PD a subsequent consolidation therapy of four infusions in a three week interval. The response was documented by MRI in week 8 and 21. Results: Between June 2004 and August 2005 34 patients aged 5.0 to 17.4 years (median 10.9 years) were enrolled in this study. According to RECIST 12 out of 34 patients showed response (PR n=1, SD n=11) in the MRI of week 8 after the induction therapy with a median change in the largest diameter of the index lesion of −5% (−39 to +16%) accompanied by clinical deterioration in four and markedly clinical improvement in two patients. Surprisingly, 9 PR/SD were seen in the 14 patients with PG. Eight patients continued with the consolidation therapy. So far 5 out of 8 Patients are evaluable for response after consolidation therapy and showed three PR, one SD and one PD in week 21. Eight patients with consolidation therapy are free of progression for a median of 7.5 months (1.2–13.2 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of Nimotuzumab is well tolerated and safe. It has cytotoxic efficacy in heavily pre-treated relapsed HGG, especially in intrinsic pontine glioma. A phase III study for patients with newly diagnosed PG is warranted. [Table: see text]
Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation
Authors: Pavan Bhargava, Matthew D. Smith, Leah Mische, Emily Harrington, Kathryn C. Fitzgerald, Kyle Martin, Sol Kim, Arthur Anthony Reyes, Jaime Gonzalez-Cardona, Christina Volsko, Ajai Tripathi, Sonal Singh, Kesava Varanasi, Hannah-Noelle Lord, Keya Meyers, Michelle Taylor, Marjan Gharagozloo, Elias S. Sotirchos, Bardia Nourbakhsh, Ranjan Dutta, Ellen M. Mowry, Emmanuelle Waubant, Peter A. Calabresi
Journal: Journal of Clinical Investigation (2020)

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.
INCREASED PERICARDIAL DELAYED HYPERENHANCEMENT (DHE) IS ASSOCIATED WITH RECURRENCE IN PATIENTS WITH MULTIPLE RECURRENT IDIOPATHIC PERICARDITIS TREATED WITH ANAKINRA
Authors: Paul Cremer, Michael Chetrit, Jay Ramchand, Beni Rai Verma, Muhammad Furqan, Bo Xu, Christine Louise Jellis, Deborah Kwon, Allan Klein
Journal: Journal of the American College of Cardiology (2020)
Pathologic distribution of disease at the time of interval debulking versus primary tumor reduction in women with primary peritoneal, ovarian, or Fallopian tube carcinoma.
Authors: Tarrik M. Zaid, Marilyn Huang, Alaina J. Brown, Nyla Balakrishnan, Hemendra Mhadgut, Navdeep Pal, Caimiao Wei, Russell Broaddus, Diane C. Bodurka, Karen H. Lu, Shannon Neville Westin
Journal: Journal of Clinical Oncology (2013)

5584 Background: The surgical approach for interval debulking after neoadjuvant chemotherapy (NACT) for primary peritoneal, ovarian, or fallopian tube carcinoma has largely been extrapolated from experience with primary tumor reductive surgery (PTRS). It is unknown whether procedures considered mandatory in PTRS, such as hysterectomy, contribute to comparable removal of macroscopic disease in the NACT setting. Our study compared the difference in pathologic distribution of disease at interval debulking surgery versus primary tumor reduction. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Involvement of organs at the time of surgery was categorized as either macroscopic, microscopic and no tumor. Statistical analyses included Wilcoxon Mann-Whitney and Fisher’s exact tests. Results: Of the 163 patients identified, 111 (67%) received NACT and 54 (33%) underwent PTRS. Median age was 62 and the majority of patients had stage IIIC high-grade serous carcinoma (91%). Macroscopic ovarian involvement was more common at time of PTRS (92 % vs 63 %, p &lt;0.001). Gross uterine involvement was significantly less in the NACT group compared to PTRS, with the majority of specimens in the NACT group free of disease (Macroscopic 11 % vs 42%, no tumor 62% vs 44 %, p &lt;0.002). However, 27% of the NACT had microscopic uterine serosal disease. Macroscopic large bowel involvement was 50 % in the PTRS vs 26 % in NACT(p&lt;0.005). There was no difference in disease involvement of the small bowel or omentum. Conclusions: The pathologic disease distribution at the time of interval tumor debulking is significantly different from that encountered during primary cytoreductive surgery.. NACT appears to reduce macroscopic large bowel and uterine tumor involvement and may negate the need for hysterectomy and/or large bowel resection at the time of interval debulking to achieve no gross residual.
Burnout and career satisfaction among U.S. oncologists: Results of the 2012 ASCO survey.
Authors: Tait D. Shanafelt, William Gradishar, Michael P. Kosty, Daniel Satele, Helen K. Chew, Leora Horn, Quyen Chu, Jeff Sloan, William B. Clark, Amy E. Hanley, John E. Pippen, Marilyn J. Raymond
Journal: Journal of Clinical Oncology (2013)

6533 Background: Although it can be rewarding, caring for patients with cancer is also demanding and stressful. Oncologists work long hours, supervise administration of highly toxic therapy, and continually observe death and suffering. While isolated studies have explored burnout in national samples of U.S. oncologists (last in 2003), little is known about the personal and professional characteristics related to burnout and career satisfaction. Methods: Between October 2012 - January 2013, ASCO conducted a national surveyof ~3000 U.S. oncologists evaluating burnout and career satisfaction. The survey sample was constructed from the member registry to include an equal number of men/women and an equal proportion of individuals from all career stages (&lt;10 yrs, 10-19 yrs, &gt;20 yrs). Validated tools were used to assess burnout and well-being. Results: As of January 2012, 1041 (35%) oncologists had returned surveys (median age 52 years; 50% women). Among responders, 355 (34%) were in academic practice (AP) and 447 (43%) in private practice (PP) with the remainder in other settings (e.g. military, veterans, industry). Oncologists worked an average of 51 hours/week and saw a mean of 51 outpatients/week. Although average hours worked for oncologists in PP and academic practice were similar (AP=54.6/wk; PP=54.2/wk), profound differences in other practice characteristics were observed with respect to sub-specialization (AP=81%; PP=17%), time devoted to clinical care, patients seen per week (AP=37; PP=74), time devoted to education, and method of compensation. Relative to 2011, 23% of oncologists reported a &gt;10% decline in take home pay in 2012 (&gt;10% decline AP=8%; PP=34%). Overall, 454 (45%) of oncologists had at least one symptom of burnout (e.g. emotional exhaustion, depersonalization) on the Maslach Burnout Inventory (AP=47%; PP=51%; p=0.19). While a majority were satisfied with their career (83%) and specialty (80%) choice, both measures of career satisfaction were lower for PP relative to AP (all p&lt;0.005). Conclusions: Burnout is common among oncologists. Detailed multivariate analyses to identify personal and professional characteristics associated with burnout and career satisfaction are underway and will be presented.
ACUTE MYOCARDITIS WITH OR WITHOUT ACUTE HEART FAILURE. DIFFERENTIAL FEATURES AND OUTCOMES IN A POPULATION-BASED STUDY OVER 14 YEARS IN SPAIN
Authors: Manuel Anguita Sanchez, Martin Ruiz Ortiz, José L. Bernal-Sobrino, Cristina Fernández-Pérez, Juan L. Bonilla-Palomas, Francisco Marín-Ortuno, Francisco J. Elola-Somoza
Journal: Journal of the American College of Cardiology (2020)
NANO ENCAPSULATED CYCLOSPORINE-A REDUCES THE CARDIAC INFLAMMATION AND MITOCHONDRIAL DYSFUNCTION IN A NON-ISCHEMIC MODEL OF CARDIOMYOPATHY
Authors: Omar Lozano, Gerardo García-Rivas, Eduardo Vázquez-Garza, Noemí García, Héctor Chapoy-Villanueva, Martín Ramos, James Bolton, Guillermo Torre-Amione
Journal: Journal of the American College of Cardiology (2020)
Results of a prospective study with FOLFOX and Ca/Mg infusions for treatment of advanced and metastatic gastric carcinoma
Authors: G. Des Guetz, S. Assouad, J. Spano, K. Chouahnia, M. Gil-Delgado, P. Wind, J. Morere, J. Breau
Journal: Journal of Clinical Oncology (2006)

14131 Background: Gastric cancer is often diagnosed in locally advanced or metastatic stages and prognostic is particularly bad. Results of a Phase II study of oxaliplatin, fluorouracil, and folinic acid was previously published (Louvet et al, J Clin Oncol. 20:4543–8, 2002). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. For these patients, tolerance of chemotherapy must be considered. Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy (Gamelin et al, Clin Cancer Res 15: 4055–61, 2004). Methods: In this study, in our medical Oncology department, we treated a first group of patients with FOLFOX 4 and a second group with FOLFOX S (FOLFOX S: LV5FU2 Simplified (Folonic acid 200 mg/m 2 , 2h, 5FU 400 mg/m 2 ,bolus, 5FU infusion 1200 mg/m 2 , 44h) + oxaliplatin: 85 mg/m 2 , 2h, d1-d15) combined with infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin and then we evaluated efficacy and toxicity. Results: Of the seventeen patients with advanced and/or metastatic stomach carcinoma enrolled between August 2000 and December 2004: Median age was 59 range (26;73) years, 12 were male, 5 female with a WHO performance status (PS) &lt;3. There were 7 patients with objective response. Of the 13 evaluable patients for neurotoxicity, 6 were treated with FOLFOX 4 and 7 with FOLFOX S combined with Ca/Mg infusions. Neurotoxicity gr II was noted for 3/6 patients of the FOLFOX 4 group but for 1/7 patients also treated with Ca/Mg infusions. No grade 3/4 leukopenia, or thrombocytopenia were observed. Conclusions: This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. This regimen combining FOLFOX and Ca/Mg infusions seems to have a more favourable toxicity profile. No significant financial relationships to disclose.
Fe‐Doped Polyoxometalate as Acid‐Aggregated Nanoplatform for NIR‐II Photothermal‐Enhanced Chemodynamic Therapy
Authors: Yunhao Shi, Jiaojiao Zhang, Han Huang, Changyu Cao, Jiajia Yin, Wenjing Xu, Wenjun Wang, Xuejiao Song, Yewei Zhang, Xiaochen Dong
Journal: Advanced Healthcare Materials (2020)

Abstract The combination of reactive oxygen species‐involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe‐doped polyoxometalate (Fe‐POM) cluster is fabricated via a simple method. The Fe‐POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near‐infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less‐reactive H 2 O 2 into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self‐assembling properties at lowered pH values, the Fe‐POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe‐POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT‐enhanced CDT in a NIR‐II biowindow.
Impaired Bile Secretion Promotes Hepatobiliary Injury in Sickle Cell Disease
Authors: Ravi Vats, Silvia Liu, Junjie Zhu, Dhanunjay Mukhi, Egemen Tutuncuoglu, Nayra Cardenes, Sucha Singh, Tomasz Brzoska, Karis Kosar, Mikhil Bamne, Jude Jonassaint, Adeola Adebayo Michael, Simon C. Watkins, Cheryl Hillery, Xiaochao Ma, Kari Nejak‐Bowen, Mauricio Rojas, Mark T. Gladwin, Gregory J. Kato, Sadeesh Ramakrishnan, Prithu Sundd, Satdarshan Pal Monga, Tirthadipa Pradhan‐Sundd
Journal: Hepatology (2020)

Background and Aims Hepatic crisis is an emergent complication affecting patients with sickle cell disease (SCD); however, the molecular mechanism of sickle cell hepatobiliary injury remains poorly understood. Using the knock‐in humanized mouse model of SCD and SCD patient blood, we sought to mechanistically characterize SCD‐associated hepato‐pathophysiology applying our recently developed quantitative liver intravital imaging, RNA sequence analysis, and biochemical approaches. Approach and Results SCD mice manifested sinusoidal ischemia, progressive hepatomegaly, liver injury, hyperbilirubinemia, and increased ductular reaction under basal conditions. Nuclear factor kappa B (NF‐κB) activation in the liver of SCD mice inhibited farnesoid X receptor (FXR) signaling and its downstream targets, leading to loss of canalicular bile transport and altered bile acid pool. Intravital imaging revealed impaired bile secretion into the bile canaliculi, which was secondary to loss of canalicular bile transport and bile acid metabolism, leading to intrahepatic bile accumulation in SCD mouse liver. Blocking NF‐κB activation rescued FXR signaling and partially ameliorated liver injury and sinusoidal ischemia in SCD mice. Conclusions These findings identify that NF‐κB/FXR‐dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these processes could potentially benefit the development of therapies to treat sickle cell hepatic crisis.
EARLY LEFT VENTRICULAR THROMBUS FORMATION AFTER ST-ELEVATION MYOCARDIAL INFARCTION: A PROSPECTIVE OBSERVATIONAL CMR STUDY
Authors: Magdalena Holzknecht, Sebastian Johannes Reinstadler, Martin Reindl, Christina Tiller, Agnes Mayr, Gert Klug, Bernhard Metzler
Journal: Journal of the American College of Cardiology (2020)