tbuckley/cabot-search huggingface dataset:
Interspecies comparison of the pharmacokinetics and metabolism of SAHA
Authors: Paul A. Andrews, Thomas A. Miller, Gohar Mushtaq, Lorraine M. Rusch, J. Paul Secrist, Victoria M. Richon
Journal: Cancer Research (2004)

4015  Suberoylanilide hydroxamic acid (SAHA) is an orally administered histone deacetylase inhibitor in advanced clinical trials. Oral SAHA has single agent antitumor activity in a variety of refractory solid tumors and hematologic malignancies at dosages associated with reversible constitutional symptoms. We sought to characterize the metabolism and pharmacokinetics of SAHA so as to understand better the clearance of SAHA, and the relationship of systemic exposure to toxicity and activity. When SAHA was incubated with mouse, rat, dog, and human liver microsomes 77%, 79%, 92%, and 83%, respectively, of the drug remained intact after 60 minutes. To survey for potential metabolites in vitro, SAHA was incubated with S9 fractions from rat, dog, monkey, and human livers. SAHA glucuronide (the predominant metabolite), SAHA amide, SAHA acid, SAHA acid glucuronide, methylated SAHA, and hydroxylated SAHA were detected by LC-MS in the incubations. Sera from rats, dogs, and humans administered oral SAHA were also analyzed by LC-MS. SAHA, SAHA glucuronide, SAHA succinate, SAHA amide, SAHA acid, SAHA adipic acid, and acetanilide were detected. The in vivo metabolite profiles were similar in these species, with SAHA glucuronide and SAHA succinate being the major metabolites. The substantial levels of the succinate detected in vivo but not in S9 fractions in vitro suggests that it arose by successive β-oxidations in mitochondria. None of the metabolites detected in sera inhibited histone deacetylase or cell proliferation in vitro. SAHA glucuronide was the only metabolite detected in dog bile. In rat, dog, and human urine, various hydroxylated metabolites as well as conjugates of acetanilide were observed in addition to all of the serum metabolites. Toxicokinetics of SAHA, SAHA glucuronide, and SAHA succinate in serum were obtained on Days 1 and 28 in rat and dog oral toxicology studies. The pharmacokinetics of SAHA and SAHA succinate were comparable in male and female rats over doses ranging from 20 to 150 mg/kg/day and did not appear to change with repeated dosing. The pharmacokinetics of SAHA glucuronide showed that female rats had a greater exposure than males at the 50 and 150 mg/kg/day doses. Serum concentrations of these 3 analytes increased in a linear but less than dose proportional manner between 20 and 150 mg/kg/day. The serum AUC0-6 hr for SAHA in the high-dose rats approximated the AUC0-t in human plasma following a 400 mg oral dose. Pharmacokinetic parameters in dogs were highly variable, but showed a dose-dependent trend and accumulation of all 3 analytes. In summary, metabolite profiles in serum were similar in rats, dogs, and humans. The main metabolic clearance pathways appear to be direct glucuronidation of the hydroxamate, and hydrolysis followed by successive β-oxidations to generate SAHA succinate.
Immune signature in sarcoma with prognostic and predictive implications.
Authors: Shailaja KS Raj, Lance Miller, Melissa Winters, Gregory Russell, Triozzi Pierre, Paul Savage
Journal: Journal of Clinical Oncology (2018)

11584 Background: While immunotherapy has established its benefit in the management of many solid tumors, its efficacy in sarcoma is still not well understood. In this study, we sought to evaluate the protective effects of intrinsic anti-tumor immunity in sarcoma by analyzing genomic measures of immune response and tumor immunogenicity in a multi-institutional convenience cohort of sarcoma patients. Methods: Publicly available RNAseq and exome mutation data were assembled from The Cancer Genome Atlas (TCGA) sarcoma cohort (n = 259). For each tumor, a relative measure of abundance of tumor-infiltrating effector immune cells was estimated using three previously published immune gene signatures, reflective of T-cells, cytotoxic T lymphocytes and/or natural killer cells derived from co-expressed, leukocyte-specific genes (named CYT, CD8T and T/NK). Tumor mutational burden (TMB), expressed as the rate of non- synonymous mutations per megabase of sequenced DNA, was used as a measure of tumor immunogenicity. Interactions between immune infiltration, tumor immunogenicity and patient overall survival (OS) were assessed by Cox regression and Kaplan-Meier analysis. Results: In the full cohort, the 3 immune signatures were highly correlated with one another and univariately associated with patient OS (T/NK; p < 0.001; CYT; p < 0.001 and CD8; p = 0.004 Cox regression). A single immune signature T/NK, selected for further analyses was associated with OS in TMB-high tumors (p < 0.001) but not TMB-low tumors (p = 0.129). Univariable and multivariable survival analysis of T/NK with significant variables included age, and tumor size, that were significant. Conclusions: Our findings fit a model where patients whose tumors were characterized by a TMB-high genotype and elevated effector immune infiltration exhibited the highest survival rates (p < 0.035). In the full cohort multivariable analysis we showed that T/NK remained a significant prognostic factor independent of age, tumor size, radiation therapy, margin status, tumor necrosis and subtype analysis indicating that the T/NK signature provided additive prognostic information and can utilized in the future for therapeutic stratification.
Contemporary management of advanced non-small cell lung cancer (aNSCLC) in a large, real-world cohort.
Authors: Carolyn Jean Presley, Eoghan Harrington, James Gippetti, Vineeta Agarwala, Bryan Bowser, Kerin B. Adelson, Roy S. Herbst, Amy Pickar Abernethy, Cary Philip Gross
Journal: Journal of Clinical Oncology (2016)

e20621 Background: In the era of precision medicine for NSCLC, the use of tumor genotyping and novel therapies in routine clinical practice is unknown. Methods: Patient characteristics, genotype testing, and treatment patterns were evaluated using the Flatiron Health database of patient-level data abstracted from electronic health records at > 150 (largely community) oncology practices across the U.S. We identified a representative random cohort of aNSCLC patients who received care during 2011 through 2015. We used chi-square analyses to identify characteristics associated with genotype testing. Results: Among the 17,696 patients identified, 54.5% (9,639) of patients had recommended genotype testing (EGFR or ALK) documented in their chart and 43.5% (7,692) had no documented testing. We also identified a cohort of 365 patients who received documented NGS tumor profiling as part of routine care. Younger age at diagnosis, white race, non-smoker, commercial insurance, and non-squamous histology were all significantly associated with documented NGS testing (p<0.001). Among NGS-tested patients, the most commonly altered genes were TP53 (62%), KRAS (30%), EGFR (18%), STK11 (15%), and CDKN2A/B (14%). Between 2012 and 2015, chemotherapy use decreased (90.7% to 82.8%), while targeted therapy and immunotherapy use grew substantially (16.6% to 19.7%, and 0.3% to 16.5%, respectively). Conclusions: The management of aNSCLC in community practice is rapidly evolving due to targeted therapy and immunotherapy, but disparities in access to biomarker testing persist. Contemporary management of NSCLC. NGS-tested (n=365) EGFR/ALK only (n=9,639) No docu mented bio marker testing (n=7,692) P-value* Age <65 yrs, % 44.9 36.6 30.4 <0.001 >65 yrs, % 55.1 63.4 69.6 Race White, % 69.9 58.0 59.3 <0.001 Black, % 3.0 7.0 7.3 Other/Unknown, % 27.1 35.0 33.4 Smoking History, % 72.6 79.8 89.3 <0.001 Biomarker EGFR+, % 17.5 15.3 - ALK+, % 3.0 3.1 - Treatment 2012 2015 2012 2015 2012 2015 Total - 263 1,370 3,899 965 2,022 Chemotherapy, % - 84.8 87.4 79.3 95.4 89.3 Anti-VEGF, % - 35.4 13.5 31.4 15.3 12.8 Targeted, % - 30.4 20.9 24.9 10.5 8.4 Immunotherapy, % - 23.6 0.1 14.2 0.4 19.9 *difference between 3 genotype testing groups.
Testicular cancer ethnic disparities in the Waikato region, New Zealand.
Authors: Prashanth Hari Dass, Michael B. Jameson
Journal: Journal of Clinical Oncology (2016)

e18065 Background: Indigenous New Zealand Maori have higher rates of malignant testicular germ cell tumours than individuals of European ancestry. Higher rates of cryptochrodism in Maori compared to Europeans are possible explanantions, suggesting prenatal risk factors. US data demonstrated ethnic disparities in stage and survival of testicular cancer for unclear reasons. Limited data linking ethnicity to outcomes of testicular cancer are available in New Zealand. Methods: Retrospective review of prospectively-collected patient data in the Medical Oncology database at Waikato Hospital, searching for all testicular germ cell tumor patients first seen between 01 January 2001 and 31 December 2013. Patient demographics, disease characteristics, treatment details and outcomes were collected and compared by ethnicity, separately for seminoma and non-seminoma. Results: 325 patients were seen over 13 years. 95 patients identified as Maori, 210 of European ancestry and 20 of other ethnic origins or not recorded. 182 were diagnosed with seminoma (147, 24 and 11 with stages 1, 2 and 3 respectively) and 143 with non-seminoma (80, 21 and 42 with stages 1, 2 and 3 respectively). Maori represented 27.5% of seminoma patients and 31.4% of non-seminoma patients. Median age of presentation among Maori was 31 years versus 39 years in non-Maori. While stage distribution of seminoma at diagnosis was similar for Maori and non-Maori (chi-square p = 0.31), proportionately more Maori had higher-stage non-seminoma than non-Maori (stage 3 in 44% and 22% respectively, chi-square p = 0.014). Across all stages overall survival for patients with seminoma did not differ significantly by ethnicity (logrank p = 0.18), with 10-year survival being 93.5% in Maori compared to 97.4% in non-Maori. Overall survival for patients with non-seminoma did not differ significantly by ethnicity (logrank p = 0.49), with 10-year survival being 90.1% in Maori compared to 86.5% in non-Maori. Conclusions: Maori presented at an earlier age with disproportionately high rates of testicular cancer compared to non-Maori. Maori present with more advanced non-seminomatous tumours. However, overall survival appears to be comparable between the ethnic groups for both seminoma & non-seminoma.
RCT of brief behavioral therapy (BBT-CI) for cancer-related insomnia and circadian rhythm during chemotherapy in a community oncology setting (NCORP).
Authors: Oxana Palesh, Caroline Scheiber, Bingjie Tong, Melissa Packer, Shelli Kesler, Michelle Christine Janelsins, Joseph John Guido, Charles E. Heckler, Karen Schmidt, Karen Michelle Mustian
Journal: Journal of Clinical Oncology (2017)

10094 Background: Insomnia is experienced by up to 80% of cancer patients, and it frequently co-occurs with circadian rhythm disruption. The relationship is reciprocal in that disruption in circadian rhythm can cause or result from insomnia and vice versa. There are no effective brief behavioral interventions that can be delivered directly in infusion centers. We aimed to evaluate the efficacy of a novel intervention, BBT-CI, for improving sleep and circadian rhythm disruption in BC patients undergoing chemotherapy. Methods: In our phase II, two-arm, randomized clinical trial, 71 BC patients (mean age = 52.5) who reported moderate insomnia were randomized to: 1) BBT-CI or 2) a healthy eating behavioral control (HEAL). BBT-CI and HEAL were delivered over 6 weeks (2 face-to-face sessions + 4 phone calls) at 5 NCI-funded NCORP clinics by trained assistants. Sleep disruption was measured with the Insomnia Severity Index (ISI) and circadian rhythm with the Actiwatch-64 (Mesor, Amplitude, and Acrophase for 12- and 24-hour cycles). Participants completed the ISI at baseline and post-intervention and wore the Actiwatch for 7 days prior to each visit. Results: The study showed excellent feasibility and acceptability of BBT-CI as reflected by a recruitment rate of over 75% and an intervention adherence of 74%, with 75% of intervention components successfully delivered by trained community staff. ANCOVA results indicate that patients who received BBT-CI exhibited improvements in insomnia compared to HEAL at post-intervention (p = .049) and at 1-month follow-up (p = .002). Furthermore, results reveal a significant treatment effect in circadian rhythm at post-intervention for 24-hour amplitude (p = .009) and 12-hour Acrophase (p = .012) as well as a trend for Mesor in favor of BBT-CI (p = .10). Conclusions: BBT-CI demonstrated greater improvements in insomnia and circadian rhythm than HEAL. In addition, this novel intervention has shown efficacy in community oncology clinics. BBT-CI has the potential of changing clinical practice as it reduces patients’ psychophysiological symptoms and burden due to its behavioral design and capacity to be delivered directly in infusion centers. Clinical trial information: NCT02002533.
Risk-adapted therapy for pediatric Hodgkin lymphoma (HL) results in lower risk of late effects: a report from the Childhood Cancer Survivor Study (CCSS).
Authors: Kevin C. Oeffinger, Kayla Stratton, Melissa M. Hudson, Wendy Leisenring, Rebecca M. Howell, Suzanne L. Wolden, Louis S. Constine, Lisa Diller, Tara O. Henderson, Charles A. Sklar, Paul C. Nathan, Sharon M. Castellino, Dana Barnea, Susan A Smith, Gregory T. Armstrong, Leslie L. Robison
Journal: Journal of Clinical Oncology (2018)

10510 Background: The goal of multi-modal, risk-adapted therapy for HL is to increase cure rates while decreasing risk for late effects; this is particularly important for children due to their vulnerability to cytotoxic therapy and life expectancy. Methods: Severe, disabling, life-threatening and fatal chronic conditions (CTCAE v4.03 grades 3-5) were determined for 2,996 5-yr HL survivors from CCSS diagnosed age < 21 from 1970-1999. Cox models evaluated hazard ratios (HR) and 95% confidence intervals (CI), comparing risks of grade 3-5 chronic conditions by age 40 among treatment regimens with historical total lymphoid irradiation (TLI) as the referent group. Results: HL survivors were a mean age of 35.6 years (range, 12-58). The cumulative incidence of any grade 3-5 condition by age 40 was 43.6% (95% CI 41.1-46.1). Risk-adapted therapy using ‘hybrid’ chemotherapy with or without radiotherapy (RT) was associated with a substantial reduction in risk for serious late effects (Table). While omitting radiation was associated with a 3-fold reduction in risk of late effects, HL survivors with a history of recurrence and/or a hematopoietic transplant (HCT) had an overall risk similar to those treated with TLI. Conclusions: Risk-adapted therapy has resulted in a reduction in serious long-term outcomes. While omitting radiotherapy is associated with a further reduction in risk, this consideration must be balanced with the risk of recurrence and the serious morbidity associated with salvage therapy. HR (95% CI) for selected treatment groups, adjusted for sex, age at HL, and other treatment regimens, for a grade 3-5 condition, subsequent malignant neoplasm (SMN), cardiopulmonary disease (CPD), or endocrinopathy (Endo). Treatment Group N CTCAE Grade 3-5 Chronic Condition Any SMN CPD Endo TLI ≥ 35 Gy (referent) 570 1.0 1.0 1.0 1.0 Recurrence or HCT 296 1.2 (0.9-1.5) 0.6 (0.4-0.9) 2.2 (1.6-3.1) 0.9 (0.6-1.4) Chest RTq 15.0 - 34.9 Gy + hybrid* chemo 383 0.7 (0.5-0.9) 0.7 (0.5-1.1) 0.7 (0.4-1.1) 0.8 (0.6-1.2) Hybrid chemo without RT 216 0.3 (0.2-0.4) 0.4 (0.2-0.8) 0.3 (0.1-0.8) 0.2 (0.1-0.5) qwith / without abdominal RT; *hybrid chemotherapy including an anthracycline plus an alkylator
MSLN-targeting bispecific t-cell engaging antibody, MG1122, for treatment of solid tumors.
Authors: Yongyea Park, Yang-Mi Lim, Kisu Kim, Jun-Hong Jung, Sua Lee, Ok-Jae Lim, Yun-Jung Lee, Sojung Lim, Jiwon Lee, Sungkeun Kim, Hae-Nam Kwon, Jonghwa Won
Journal: Journal of Clinical Oncology (2018)

e14500 Background: Engaging T cells to attack tumors is a new class of immunotherapy. Tumor-specific T cell-engaging antibodies have an ability to redirect and activate T cells to target tumor cells, thereby amplifying anti-tumor effects. Mesothelin (MSLN) is a 40 kDa GPI-anchored glycoprotein which is highly expressed in several cancers, including mesotheliomas, pancreatic cancer, lung cancer, and ovarian cancer, while expressed at relatively low levels in normal mesothelial cells of the pleura, peritoneum and pericardium. Methods: We developed MG1122 and analyzed the function as a new therapeurics in vitro Results: MG1122, which binds to CD3 on T cells and to MSLN on tumor cells. MG1122 activated T cells in the presence of MSLN expressing tumor cells. Moreover, MG1122 efficiently induced the T cell-mediated killing of lung and pancreatic cancer cell lines in a MSLN expression-dependent manner. Our in vitro data indicate the T-cell engager, MG1122, efficiently attacked the MSLN-positive cancer cells by using T cells. Conclusions: These data suggest that MG1122 may be a potential treatment option for patients with MSLN-positive solid tumors.
Retroperitoneal lipo-leiomyomata in a woman with history of breast cancer and antiestrogen therapy.
Authors: Jung Joo Moon, Daniel D Mais
Journal: Journal of Clinical Oncology (2017)

e22542 Background: Retroperitoneal lipo-leiomyomata are extremely rare. The usual-type retroperitoneal leiomyoma is itself a rare tumor that is mistaken preoperatively for malignant retroperitoneal tumors or thought of as an exophytic subserosal leiomyoma of the uterus. Lipo-leiomyoma is a variant of leiomyoma with an incidence in uterus ranging between 0.03% - 0.2%, but its presentation as a retroperitoneal mass has not been documented in literature yet. We present a unique case of retroperitoneal lipo-leiomyoma that presented as a diagnostic challenge due to its unique location and unusual histologic appearance. Methods: A 68-year-old female patient with a history of breast cancer diagnosed 4 years ago, currently on antiestrogen therapy (Fulvestrant) and Herceptin, presented to our university hospital with symptomatic left pelvic mass. An abdominal CT showed a heterogeneous low-density pelvic mass with foci of internal calcification and fat with surrounding intermixed intermediate and high density fluid in the expected location of the uterus. Results: A debulking surgery including radical hysterectomy was planned. Intraoperatively, a normal sized uterus was found, the myometrium of which contained multiple variable-sized intramural leiomyomata. In addition, a huge left retroperitoneal mass was found that had no connection to the uterus. Histopathological examination revealed abenign lipoleiomyomatous tumor, composed of an encapsulated proliferation of benign adipocytes and myoid cells intimately admixed. Immunohistochemistry confirmed myoid differentiation, with negative reactions for HMB45 and CKIT, and . MDM2 gene amplification by fluorescence in situ hybridization (FISH) was negative. Conclusions: Some unusually located extra-uterine leiomyomata have been reported; retroperitoneal leiomyoma being among them. Such a tumor with the added feature of lipomatous differentiation presents a differential diagnosis that includes leiomyosarcoma, liposarcoma, angiomyolipoma, and gastrointestinal stromal tumor. The association of an uncommonly located leiomyoma with subsequent lipomatous change withantiestrogen therapy is an unexplored issue that merits further investigation.
Outcomes and prognostic factors for acral lentiginous melanoma in Peruvian patients.
Authors: Cindy Elizabeth Alcarraz, Zaida Morante, Luis Mas, Silvia P. Neciosup, Gabriela Calderon, Jorge Antonio Dunstan, Julio E. Abugattas Saba, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2016)

e21061 Background: Acral lentiginous melanoma (ALM) is the most common subtype of malignant melanoma in acral locations. It has a more aggressive behavior and poorer prognosis. The age – specific incidence rate of melanoma in Lima - Peru between 2004 - 2005 was 2.04 cases per 100,000 population. The aim of this study was to describe the clinical and pathological features and overall survival, in addition to the differences between subgroups of patients. Methods: We retrospectively reviewed a database of patients diagnosed with malignant melanoma since january 2009 to december 2011 at the Instituto Nacional de Enfermedades Neoplasicas (INEN). Overall survival (OS) curves were estimated using the Kaplan-Meier method and comparisons were done using the log-rank test. Multivariate analysis for overall survival (OS) was perfomed with the cox proportional hazard regression model. A p-value < 0.05 was considered statistically significant. Results: ALM was observed in 62.2% of the all-histologic types. The median age was 62.48 years (range: 26 - 96) and it was more frequent in the age group of 60-69 years. Men represented 55.1% of the study population. The most affected location was on the foot (24.3%). Fourteen (13.1%) patients were clinical stage I, 47 (43.9%) II, 27 (25.2%) III and 8 (7.5%) IV. 3yrs-OS was 55.3%. The age and sex were not prognostic factors. The pathologic factors significant for overall survival were clinical stage (p < 0.05), lymph node involvement (p < 0.05), the Breslow (p < 0.04), presence of ulceration (p < 0.012), vascular (p < 0.05) and perineural invasion (p < 0.008). The Independent prognosis factor in only patients with clinical stage I, II and III was lymph node involvement (N3) (p < 0.008). Conclusions: In our patients with acral lentiginous melanoma without metastatic disease, the most important independent prognostic factor was the nodal involvement (N3).