tbuckley/cabot-search huggingface dataset:
Comparison of the pharmacokinetics (PK) of galeterone novel oral formulations.
Authors: William G. Kramer, Bradley Vince, Carolyn McGarry
Journal: Journal of Clinical Oncology (2013)

e16075 Background: Galeterone (gal) is an orally available steroid analog for the treatment of castration resistant prostate cancer (CRPC). A significant food effect, similar to abiraterone, was found when gal, as powder in capsule (PIC), was dosed in a phase I CRPC trial and confirmed in a PK study in human volunteers.The objective of this study was to assess single-dose PK of gal after reformulation and to evaluate effect of food. Methods: In this single-center open-label study, 24 male subjects were assigned to receive once daily doses of between 100 and 3400 mg in either a 3-treatment, 3-period or 4-treatment, 4-period dose scheme. Treatment periods were separated by 7-day washout intervals. Plasma concentrations were measured over 72 hours to assess PK. Two novel tablet formulations were administered in 100 mg doses under fasted and/or fed condition compared to 2600 mg-PIC administered under fed conditions. Escalating doses of PIC (975 to 2600 mg) and tablet (850 to 3400 mg) formulations were evaluated to assess linearity. Results: Gal was well tolerated. Food effect has been negated with the tablet. Exposure from 1700 mg galeterone tablet (fed or fasted) is comparable to a 2,600 mg dose of PIC (fed) (Table). For tablet, AUC(inf) increased in a dose-related and dose-proportional manner from 6,689 ± 2,602 hxng/mL (850 mg) to 20131 ± 9,930 hxng/mL (2,550 mg). Conclusions: The tablet formulation negates the food effect previously observed. Gal may be dosed either fed or fasted with no difference in absorption, which reduces intra-patient variability in exposure. Tablet has more consistent bioavailability and a linear increase in AUC between escalating doses. [Table: see text]
Threefold Increases in Population HIV Viral Load Suppression Among Men and Young Adults — Bukoba Municipal Council, Tanzania, 2014–2017
Authors: Duncan MacKellar, Claire Steiner, Oscar E. Rwabiyago, Haddi J. Cham, Sherri Pals, Haruka Maruyama, Omari Msumi, Gerald Kundi, Johnita Byrd, Rachel Weber, Caitlin Madevu-Matson, Kokuhumbya Kazaura, Thomas Rutachunzibwa, Eunice Mmari, Fernando Morales, Jessica Justman, Kevin Cain, Anath Rwebembera
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Reducing HIV-related morbidity and mortality, and effectively eliminating HIV transmission risk, depends on use of antiretroviral therapy (ART) to achieve and maintain viral load suppression (VLS)* (1,2). By 2020, sub-Saharan African countries are working to achieve VLS among 90% of persons using ART and 73% of all persons living with HIV infection (1). In Tanzania, a country with 1.4 million persons with HIV infection, 49.6% of HIV-positive persons aged 15-49 years had achieved VLS in 2017, including only 21.5% of men and 44.6% of women aged 25-29 years (3). To identify interventions that might increase VLS in Tanzania, and reduce VLS-associated sex and age-group disparities, the Bukoba Combination Prevention Evaluation (BCPE) scaled up new HIV testing, linkage to care, and retention on ART interventions throughout Bukoba Municipal Council (Bukoba), Tanzania, during October 2014-March 2017 (4,5). Located on the western shore of Lake Victoria, Bukoba is a mixed urban and rural municipality of 150,000 persons and capital of Kagera Region. Of the 31 regions of Tanzania, Kagera has the fourth highest prevalence of HIV infection (6.8%) among residents aged 15-49 years (3). CDC analyzed data from BCPE preintervention and postintervention surveys and found that VLS prevalence among HIV-positive Bukoba residents aged 18-49 years increased approximately twofold overall (from 28.6% to 64.8%) and among women (33.3% to 67.8%) and approximately threefold among men (20.5% to 59.1%) and young adults aged 18-29 years (15.6% to 56.7%). During 2017, BCPE facility-based testing and linkage interventions were approved as new service delivery models by the Tanzania Ministry of Health, Community Development, Gender, Elderly and Children (4,5). After a successful rollout to 208 facilities in 11 regions in 2018, BCPE interventions are being scaled up in all regions of Tanzania in 2019 with support from the United States President's Emergency Plan for AIDS Relief (PEPFAR).†.
Radiotherapy (RT) dose escalation study with concurrent cisplatin and S-1 in patients with inoperable stage III non-small cell lung cancer (NSCLC)
Authors: H. Harada, M. Nishio, H. Murakami, F. Ohyanagi, T. Kozuka, S. Ishikura, A. Horiike, M. Morota, T. Nishimura, N. Yamamoto
Journal: Journal of Clinical Oncology (2009)

7542 Background: Standard treatment for inoperable stage III NSCLC is concurrent chemoradiotherapy using 3-D conformal RT to a total dose of 60 Gy, but the outcome is still dismal with median survival time (MST) of 16 months and 5-year survival of 15%. We conducted a phase II trial using cisplatin, S-1 and concurrent RT of 60 Gy (J Clin Oncol 2008;26:a7556). MST (33months) was encouraging, however, local failure rate with this trial remained still high. The purpose of this study was to establish the recommended dose (RD) of RT with concurrent cisplatin and S-1. Methods: The eligibility criteria were: histologically or cytologically proven NSCLC, 20–75 years old, performance status 0–1, without any prior chemotherapy or RT. Patients were treated with cisplatin (60 mg/m 2 on day 1) and S-1 (orally at 40 mg/m 2 /dose b.i.d., on days 1–14) repeated every 4 weeks for 4 cycles and RT was started on day 1. Radiation dose was escalated from 66 Gy in 33 fractions (Arm 1) to 70 Gy in 35 fractions (Arm 2), then 74 Gy in 37 fractions (Arm 3). The dose was to be escalated if DLTs were observed in 2 or less patients. The target volume of RT included primary tumor and metastatic node only and elective nodal irradiation was not performed. Dose constraints to the organs at risk were: the lung, V20 &lt; 30%; the esophagus, mean dose &lt; 34 Gy and V55 &lt; 30%; the spinal cord, max dose &lt; 50 Gy. Results: Six patients in each arm were enrolled. Two patients in Arm 1 experienced DLTs: one patient developed grade 3 febrile neutropenia, grade 3 mucositis in oral cavity and grade 3 diarrhea and one patient developed grade 3 febrile neutropenia. One patient in Arm 3 has not been completed evaluation yet. Otherwise no DLT was observed. Conclusions: The radiation dose of 74 Gy in 37 fractions with concurrent cisplatin and S-1 seemed to be tolerable and was judged to be the RD. This study is still open to accrue another six patients to confirm the safety of the RD. No significant financial relationships to disclose.
Randomized phase II trial of irinotecan plus cisplatin (IP) versus irinotecan, cisplatin plus etoposide (IPE) every three weeks in patients with extensive disease small cell lung cancer (ED-SCLC)
Authors: I. Sekine, H. Nokihara, K. Takeda, Y. Nishiwaki, K. Nakagawa, H. Isobe, K. Mori, K. Matsui, N. Saijo, T. Tamura
Journal: Journal of Clinical Oncology (2006)

7087 Background: A promising complete response rate and median survival time were obtained in our previous phase II study of IPE chemotherapy repeated every 4 weeks in patients with ED-SCLC, but the infusion of irinotecan on day 15 was omitted in 77% of patients. Methods: The objective was to evaluate toxicities and antitumor effects of IP and IPE regimens every 3 weeks and to select the arm for subsequent phase III trials. The primary endpoint was overall survival. Previously untreated ED-SCLC patients aged between 20 and 70 years old with a performance status (PS) of 0–2 were randomized to receive either IP (I 60 mg/m 2 days 1, 8 and P 60 mg/m 2 day 1) or IPE (the same dose of IP and E 50 mg/m 2 days 1–3 with G-CSF support) every 3 weeks for 4 cycles. The projected sample size was 110 patients (Liu’s Selection design for pilot studies on survival). Results: From March 2003 to May 2005, 53 patients (43 males/10 females, median age 63) were randomized to IP and 57 patients (48 males/9 females, median age 62) to IPE. Body weight loss and PS were well balanced between the arms. Full cycles were administered in 75% of patients in the IP and in 67% in the IPE arm. Dose reduction was required in 17% of patients in the IP and 28% in the IPE arm. Grade 3–4 neutropenia, anemia and thrombocytopenia were observed in 53%, 34% and 4% of patients in the IP, and 93%, 45%, and 23% of patients in the IPE arm, respectively. Grade 3–4 infection, malaise, anorexia, and diarrhea were noted in 15%, 2%, 0%, and 15% of patients in the IP, and 30%, 11%, 15%, and 24% of patients in the IPE arm, respectively. No treatment related death occurred. Complete and partial responses were noted in 8% and 68% of patients in the IP, and 11% and 75% of patients in the IPE arm, respectively. Conclusion: Toxicity was more severe, but tumor responses seemed better in the IPE arm. The survival analysis will be carried out in April 2006. No significant financial relationships to disclose.
Immune Activation in Mismatch Repair–Deficient Carcinogenesis: More Than Just Mutational Rate
Authors: Jason A. Willis, Laura Reyes-Uribe, Kyle Chang, Steven M. Lipkin, Eduardo Vilar
Journal: Clinical Cancer Research (2019)

Mismatch repair (MMR)-deficient colorectal cancers (dMMR colorectal cancer) are characterized by the expression of highly immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as upregulation of inflammatory cytokines. These features are key to understanding why immunotherapy (specifically PD-1 and/or CTLA-4 checkpoint blockade) has proved to be highly effective for the treatment of patients with advanced dMMR colorectal cancer. Importantly, preclinical studies also suggest that this correlation between potent tumor neoantigens and the immune microenvironment is present in early (premalignant) stages of dMMR colorectal tumorigenesis as well, even in the absence of a high somatic mutation burden. Here, we discuss recent efforts to characterize how neoantigens and the tumor immune microenvironment coevolve throughout the dMMR adenoma-to-carcinoma pathway. We further highlight how this preclinical evidence forms the rational basis for developing novel immunotherapy-based colorectal cancer prevention strategies for patients with Lynch syndrome.
Utility of positron emission tomography (PET) scans on the management of cancers of unknown primary.
Authors: Hao Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2012)

6066 Background: PET scans can be potentially useful in the diagnostic and staging workup of certain cancers. Although frequently ordered, its precise role in the investigation and management of cancers of unknown primary (CUP) remains poorly defined. Our main study aims were to 1) compare the utility of PET vs. CT scans in determining the primary site, lymph node status, and metastases for patients with CUP, and 2) describe the overall survival of patients for whom the primary site was determined by PET vs. those who were not. Methods: Patients diagnosed with CUP in British Columbia, Canada from 2006 to 2009, evaluated at 1 of 5 regional cancer centers in the province, and underwent a PET scan were reviewed. We measured concordance rates between PET and CT scans and constructed regression models to characterize the effect of PET scans on treatment and survival. Results: A total of 175 patients were included: median age was 60 years and 76% were men. PET scans were most commonly performed for the following indications: locating primary (45%); staging (42%); and others (13%). Among those in whom CT did not detect the primary site, PET revealed the location of the primary in 9% of cases. CTs and PETs were concordant in demonstrating nodal status and metastases in 91% and 95% of patients, respectively. PET scans were able to show additional nodal involvement and uncover metastatic disease in 9% and 5%, respectively, when compared to CT scans. Identification of the site of primary cancer by PET did not substantially modify subsequent therapy (p=0.37) and it also failed to significantly improve the median overall survival (10.1 vs. 7.3 months, p=0.57) when compared to those in whom the location of the primary was unconfirmed. Conclusions: In this retrospective cohort of CUP patients, CT and PET scans appear to provide a similar level of diagnostic and staging information. For a small proportion of CUP patients, PETs were superior in clarifying the primary site, nodal status, and metastases, but these did not alter therapy or increase overall survival. Based on these findings and considering the cost implications of intensive imaging studies, the diagnostic value of PET scans over CT scans appears limited to a small subset of patients with CUP.
Association of mesenchymal phenotype in circulating tumor cells with poor prognosis in metastatic colorectal cancer.
Authors: Arvind Dasari, Hui Gao, Laurel Deaton, Michael J. Overman, Siegfried Hauch, Scott Kopetz, James M. Reuben
Journal: Journal of Clinical Oncology (2013)

e14567 Background: Although the prognostic relevance of circulating tumor cells (CTCs) is well established in metastatic colorectal cancer (mCRC), their clinical use is currently constrained by the phenotypic definition of such cells that is largely limited to epithelial markers. Our objective in this study is to characterize the prognostic significance of a larger group of CTCs including those with characteristics of epithelial-mesenchymal transition (EMT) or cancer stem cells (CSCs) in a cohort of pre-treated mCRC patients (pts). Methods: Peripheral blood was collected in AdnaCollect preservation tubes from pts for immunomagnetic tumor cell enrichment using the AdnaTest ColonCancer Select kit and multiplex qRT-PCR analyses of tumor-associated epithelial (CEA, EPCAM, EGFR), cancer stem cell (ALDH1) and mesenchymal (TWIST1, AKT2, PIK3CA) transcripts. Results: In the initial phase, 41 previously treated mCRC pts (median prior therapies 3) were enrolled over a 4 month period and were followed prospectively. In this cohort, there was a low rate of CEA, EPCAM, and EGFR expression in the CTCs (12%, 2%, and 0%, respectively), consistent with loss of epithelial markers. Conversely, ALDH1, an established CSC marker was expressed in 30% of pts, with only one pt’s CTCs expressing both ALDH1 and CEA expression. ALDH1 expression was associated with very poor prognosis (HR 24.6, p=0.037) and 57% 60-day mortality, compared to 0% 60-day mortality for pts with no detectable ALDH1 expression. The mesenchymal markers of TWIST1, AKT2, and PIK3CA were strongly correlated with ALDH1 expression (Spearman r=0.55, 0.59, 0.63, respectively, p &lt; 0.01 for each). Conclusions: The majority of CTCs detected in refractory mCRC pts have lost epithelial markers. Acquisition of markers associated with EMT or CSCs appear to be associated with poor prognosis, and may provide important insights into better prognostication and also biology of refractory colorectal cancer. Further enrolment into this study is ongoing and updated results will be presented.
JC papovavirus leukencephalopathy in a patient with B-CLL receiving long-term chemotherapy in combination with an anti-CD20-antibody
Authors: B. L. Hartmann, T. Winder, M. Sandholzer, K. Gasser, I. Jäger, A. H. Lang, M. Längle, G. Hartmann, C. Bartenstein, C. Luger
Journal: Journal of Clinical Oncology (2009)

e18007 Background: Progressive multifocal leukencaphalopathy (PML) is a rare demyelinating infection of the central nervous system caused by viruses (CMV, JC, BK). It is almost exclusively described in profound immunocompromised patients developed as a primary infection or by reactivation of the virus after a latent infection. PML is typically observed among patients with severe immunodeficiency like HIV or in the setting of autologous or allogenic transplantation. Methods: Our patient was a 64-year-old woman with B-CLL diagnosed in 2000 in state B of Binet treated with 12 cycles of fludarabin until July 2007 in a B-cell and lymphoma-reducing manner. For the reason of progressive disease 3 cycles of rituximab, fludarabin, mitoxantrone, and cyclophosphamide were added (dose reduced causing hematologic toxicity) until October 2007 continuing rituximab once a month up to Mai 2008. Results: In a CT scan mixed response was observed with progressive disease infradiafragmatic and regression supradiafragmatic. Corticosteroids could stop B-symptoms and leads to a distinct shrinkage of the lymphomas within 2 weeks. Later on she presented with confusion and disorientation. An MRI of the brain showed subcortical and periventricular lesions with increased signal on T2-weighted and fluid attentuated inversion recovery (FLAIR) suggestive of a vascular origin. Her symptoms progressed by aphasia and weakness of the right leg corresponding to increased size and number of cerebral lesions. A lumbar puncture showed no malignant cells and no evidence of inflammation. A PCR analysis was negative for Toxoplasma gondii, HSV, VCV, CMV, EBV, and enterovirus but positive for JC-DNA (215.000 copies/ml). A rapid progression leads to death two months after onset of symptoms. Conclusions: Antibody deficiency syndrome corresponding to CLL under treatment with chemotherapy and rituximab lead to a severe immunosuppression enabling unusual viral infections such as PML. No significant financial relationships to disclose.
Outcomes of patients older than 60 years with acute lymphoblastic leukemia: Survey from the Surveillance, Epidemiology, and End Results (SEER) program.
Authors: Jae Hong Park, Sean Devlin, Martin S. Tallman, Dan Douer
Journal: Journal of Clinical Oncology (2012)

6532 Background: The cure rate of pediatric acute lymphoblastic leukemia (ALL) has increased over the last 4 decades to above 80%, compared to a much smaller improvement in adults aged &lt; 60 years. However, outcome information on older ALL patients (age ≥ 60 years) is limited. Only a few clinical trials include the older patients, apply the same regimens developed for adults of all ages, and report a very poor outcome with no improvement over time. We therefore conducted a population-based survey of older ALL patients focusing on early death (ED) rates and changes in outcome over the last 30 years. Methods: Data from 9 population-based cancer registries that participate in the National Cancer Institute’s SEERprogram were used to identify patients aged 60 or older with a diagnosis of ALL. Survival rates at 1, 6, 12 and 24 months were estimated using actuarial methods for 4 calendar periods: 1980-1985, 1986-1992, 1993-1999, and 2000-2006. ED was defined as death occurring within one month of ALL diagnosis. Results: A total of 1066 ALL patients were identified. The ED rate significantly improved over the four study time periods from 20.2% in 1980-1985 to 13.2% in 2000-2006 (p=0.03). The overall survival (OS) at 6 months improved from 32.8% in 1980-1985 to 45.3% in 2000-2006, but at 24 months, only a modest difference in OS was noted across the time period (13.1% in 1980-85 vs. 17.5% in 2000-06). The median survival increased from 3 months to 6 months from the period 1980-1999 to 2000-2006. Conclusions: Although the long-term OS for patients aged 60 and over remains poor, there has been a slight improvement in early mortality and median OS from 1980s to the early 21 st century. While the progress in reducing ED and increasing survival at 6 months is encouraging, and may be reflecting better supportive care measures, the limited improvement indicates poor tolerance and lack of efficacy of the toxic, long and complex chemotherapy regimens designed for younger adults. Therefore, future studies should be designed specifically for older ALL patients, focusing on novel, effective, but less toxic therapies, to further improve the short-term OS seen in the past decades and possibly a better overall outcome.
A pilot study comparing objective physical activity to the physical component of the Eastern Cooperative Oncology Group (ECOG) performance status scale
Authors: J. Walsh, J. Hussey, D. O'Donnell
Journal: Journal of Clinical Oncology (2009)

e20501 Background: The ECOG performance status (PS) scale is widely used in oncology for clinical decision-making, being a good predictor of survival, prognosis, and treatment response. It has never been formally compared to objective measures of physical activity (PA). Accelerometers are now established as detailed valid measures of PA. The aim of this study was to compare the ECOG PS scale to objectively measured PA. Methods: Accelerometer data (RT3) as well as self-report (International Physical Activity Questionnaire (IPAQ)) was collected for at least 3 days immediately before cancer outpatient assessment on 15 patients (6 males, 9 females) with a mean age of 65 years (range 47–51), all with solid tumours. RT3 and self-report data were compared to the ECOG PS score assigned by the treating physician. Time ‘up and about’ is all activity, however minimal, detected by the RT3, except lying flat. Institutional ethics committee approval was gained. Results: Most subjects were assigned an ECOG score of 1. In all subjects, the score assigned over-estimated PA levels ( Table ). Spearman's rank correlation coefficient showed poor correlation between percentage waking time ‘up and about’ and the ECOG PS score assigned (p = -0.1), and between the IPAQ and ECOG scores (p = 0.1). Conclusions: Although ECOG PS is recognized as a good predictor of clinical outcome, a poor correlation was found between ECOG PS assigned, objective PA, and self-report. Subjects were far more sedentary than estimated using physician-assigned ECOG PS. A large study to investigate these relationships further is ongoing. [Table: see text] No significant financial relationships to disclose.
Abstract P115: Race, Sex, and Geographical Variation in Perceived Racial Discrimination: The Coronary Artery Risk Development in YoungAdults (CARDIA) Study
Authors: Ganga S Bey, Sharina D Person, Catarina I Kiefe
Journal: Circulation (2018)

Introduction: Variation in exposure to discrimination has been proposed as a contributor to disparities in cardiovascular disease (CVD) among black and white women and men in the U.S. Yet, evidence is conflicting, perhaps due to insufficiently studied race-sex and geographical differences in the pathogenicity of discrimination. We hypothesized that the prevalence of perceived racial discrimination in a variety of settings differs by race, sex, and geographic location. Methods: We used data from CARDIA, a population-based cohort of black and white adults recruited in Birmingham, AL; Chicago, IL; Minneapolis, MN, and Oakland, CA in 1985-6 (year 0). Racial discrimination perceived in several scenarios was assessed using the Lifetime Discrimination Scale at years 7, 15, and 20 (2005-6). We assessed the prevalence at each of these exams and in each scenario, stratified by race-sex group. Results: Prevalence of reported discrimination did not differ markedly over time; we report on year 7 only (n=4,025, figure), with qualitatively similar findings at the other years. Reported discrimination in ≥2 scenarios ranged from 52% in Birmingham to 70% in Minneapolis among black women; among black men, from 65% in Birmingham and 75% in Minneapolis and Oakland. This prevalence was &lt;20% among white women and men in every city. Within all groups, discrimination on the street or in a public setting was most prevalent (p&lt;0.001) and least prevalent in receiving medical care (p&lt;0.001). The proportion of black men reporting discrimination by the police or courts was substantially greater than the other three race-sex groups in each of the four cities (all p&lt;0.001). Conclusions: We found variation in the prevalence of reported racial discrimination across race, sex, and geography. Differences in the experience of discrimination may lead to differences in the health-damaging effects of exposure and partially explain inconsistencies in the evidence of discrimination as a cause of disparities in cardiovascular disease between black and white women and men.