tbuckley/cabot-search huggingface dataset:
ADI-PEG 20 plus docetaxel (DOC) in men with castrate resistant prostate cancer (CRPC): Results from a phase Ib trial.
Authors: Ben Kent Tomlinson, John S. Bomalaski, Monica Diaz, Taiwo Akande, Tianhong Li, Thomas John Semrad, Karen Kelly, David R. Gandara, Chong-xian Pan, Primo Lara
Journal: Journal of Clinical Oncology (2015)

e16116 Background: ADI-PEG20 is a pegylated enzyme that degrades arginine, a required amino acid in argininosuccinate synthetase (ASS) deficient tumors. Immunohistochemical staining suggests most prostate cancer (PC) is ASS deficient. Preclinical studies suggest arginine deprivation by ADI-PEG20 is synergistic with DOC-induced cytotoxicity in PC models. We previously established a recommended phase II dose of 36mg/m2 of ADI-PEG20 (IM on days 1, 8, 15) plus 75mg/m2of DOC (IV day 1) and prednisone 5 mg orally BID, given on 21 day cycles. An expansion cohort with CRPC was treated to evaluate safety and obtain early efficacy estimates. Methods: Eligible CRPC patients (pts) were > 18 years and had adequate end organ function & performance status (PS) 0-2. Radiographic response (RECIST) was assessed every 2 cycles. PSA response was defined as a 50% reduction from baseline. Physicians had discretion for protocol discontinuation on basis of PSA progression. Assuming a historical response rate of 35%, an increase to 70% was considered clinically meaningful. 15 pts would have a power of 87% to detect this increase with a type I error of 0.05. Results: Of 32 pts in the parent phase Ib trial, 15 (47%) were in the CRPC expansion cohort with median age of 72, 66% with PS 1, and 80% with Caucasian ethnicity. A median of 5 cycles and 12 ADI-PEG20 doses were delivered (range: 1 to 54). In pts with evaluable response data (14), one radiographic partial response and two PSA responses were identified. There was one on-study death unrelated to ADI-PEG20. Two pts stopped treatment due to therapy related toxicity. Conclusions: Despite promising preclinical data, combination ADI PEG20 + DOC did not appear to exceed a priori estimates of clinical activity. Assessment of ASS expression in baseline tumor tissue may clarify the observed response rates. Clinical trial information: NCT01497925.
Analysis of <i>HER2</i> mutant bladder urothelial carcinomas reveals unique mutational signature.
Authors: Luke Juckett, Russell Madison, Jon Chung, Alexa Betzig Schrock, Brian Alexander, Vincent A. Miller, Siraj Mahamed Ali, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

460 Background: Early work has described the presence of HER2 alterations in metastatic urothelial carcinomas (UC), particularly the micropapillary urothelial carcinoma (MPUC) subtype. We reviewed the genomic profiles of a large set of UC cases to further characterize HER2 altered UCs and how such alterations would suggest benefit from the expanding array of anit-HER2 therapeutics. Methods: Tissue from 2,150 UCs were assayed using hybrid capture-based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly arranged in cancer. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Results: Within the UC dataset 74.6% of cases were male (1603/2150), with a median TMB of 7 mut/Mb. 383 genomic alterations (GA) of HER2 were identified in 15.5% (334/2150) of cases which exhibited a median TMB of 8.7 mut/Mb (p &lt; 1E-5) vs patients with wildtype HER2, median TMB of 7 mut/Mb. The most frequent HER2 alterations were amplification HER2 amp (45.7%, 175/383), S310F (19.8%, 76/383), and S310Y (7/6%, 29/383). Patients harbouring a HER2 amp , S310 (n = 105) exhibited a median TMB of 8.7 and 12.2 mut/Mb, respectively. 42 patients presented with multiple ( &gt; 1) HER2 GA and exhibited a median TMB of 11.3 mut/Mb (p &lt; 0.1) vs patients with single HER2 GA, median TMB of 12.3 mut/Mb. Of patients with multiple HER2 alterations, 57% (24/42) harbored a HER2 amp . The most common co-occuring HER2 alteration pair was an amplification and extracellular S310X alteration (38.1%, 16/42). Of these 16, the median TMB was 19.5 mut/Mb (average 22.7 mut/Mb). Morphological assessments were performed on the 24 cases harbouring a HER2 amp and an additional HER2 GA. 8 cases displayed MPUC features 44.4% (8/18; 6 cases histology unavailable); of these MPUC cases, 75% (6/8), harboured a HER2 amp and S310 extracellular mutation. Conclusions: CGP of bladder urothelial (transitional cell) carcinomas reveals subclasses of HER2 altered cases. Drawing on recent advances in targeting HER2 alterations in breast cancer, dual HER2 blockade (e.g. combinations of mAB/TKI/mAB+ADC) may be needed for HER2 amp cases. For cases with both HER2 amp and S310 GA, neratinib monotherapy may be the agent of choice and thus may be effective in MPUC.
Abstract P302: Hand Osteoarthritis is associated With Subclinical Cardiovascular Disease in Mexican Women
Authors: Rodrigo R Flores-Mariñelarena, Mario H Flores-Torres, Ruy Lopez-Ridaura, Martín Lajous, Carlos Cantú-Brito, Andres Catzin-Kuhlmann
Journal: Circulation (2019)

Introduction: Osteoarthritis is a growingly common joint disorder affecting older adults. It is characterized by chronic low-grade inflammation, a phenomenon by itself considered a cardiovascular risk factor. However, data on its potential impact on cardiovascular disease (CVD) is scarce. Assessing hand osteoarthritis (HOA) might be advantageous when studying CVD as this particular location might be less affected by traditional cardiovascular risk factors such as overweight and physical activity. Hypothesis: HOA is associated with subclinical CVD. Methods: We cross-sectionally assessed the relationship between HOA and CVD in 1,803 women from the Mexican Teachers’ Cohort, excluding those with history of myocardial infarction, cerebrovascular disease, and rheumatoid arthritis. From 2012 to 2016, a subsample of the MTC participants from Mexico City and the states of Nuevo LeÓn, Chiapas, and YucatÅn were invited for clinical examinations in which standardized neurologists measured their carotid intima-media thickness (IMT) with ultrasound and a standardized HOA questionnaire was applied. HOA was defined as having ≥45 years, hand joint pain, and morning stiffness that lasts no longer than 30 minutes. Subclinical CVD was assessed through log-transformed IMT, and carotid atherosclerosis (CAS) was defined as mean right or left carotid IMT ≥0.8 mm or the presence of atherosclerotic plaque. Multivariable linear and logistic regression analyses were used to evaluate the association between HOA and IMT and CAS adjusting for age, state, smoking, alcohol consumption, diabetes, hypertension and body mass index. Results: Among participants with a mean age of 51 years (±4), 18.4% met the criteria for HOA, and the prevalence of CAS was 23.1%. After multivariable adjustment, women diagnosed with HOA had 1.6% (95%CI 0.2, 3.1) higher mean IMT than those without the joint disease. Similarly, women with HOA had 35% (95%CI 1.01, 1.81) higher odds of CAS. Sensitivity analyses using a less stringent definition of OA (pain regardless of stiffness), as well as incapacitating pain, did not have a significant association with CAS. Conclusion: Among middle-aged women, HOA was associated with subclinical CVD. This relation might be due to low-grade chronic inflammation, but further research is needed to clarify the underlying mechanisms, the role of screening for HAO as part of cardiovascular risk profiling, and the value of potential interventions such as anti-inflammatory drugs.
First results of Expression V Study, a survey by the North-Eastern-German Society of Gynaecological Oncology (NOGGO), assessing the therapy expectations of breast and ovarian cancer patients with different ethnicity in Germany.
Authors: Desislava Dimitrova, Baharan Naghavi, Konrad Neumann, Matthias David, Radoslav Chekerov, Elena Ioana Braicu, Uwe Torsten, Christel Kronenberger, Gülten Oskay-Özcelik, Ilona Blau, Ulrich Keilholz, Jalid Sehouli
Journal: Journal of Clinical Oncology (2015)

e16582 Background: An effective doctor-patient communication is crucial for patient compliance and clinical outcome. In the context of increasing international migration and because of lacking data on this topic we conducted a survey to explore the needs and preferences of patients with different ethnical origin with a special focus on doctor-patient communication and therapy expectations. Methods: A 58-item questionnaire was developed in four languages: German, Russian, Arabic and Turkish. This study was approved from Charité ethics committee. The survey recruited patients with primary or recurrence of breast, ovarian, peritoneal or fallopian tube cancer. The patients filled out a paper form, participated via Internet or were interviewed by trained staff. The questionnaire was divided in 3 parts: in the first part ethnicity specific data was asked, the second part included questions about disease course and in the third part the patients were asked to evaluate their experience with therapy. Results: A total of 190 patients responded from August 2014 until December 2014: 169 (90 %) were interviewed, 5 (2.6 %) took part via Internet and 16 (8.4 %) filled out a paper form. The most effective source of information for 90.5 % of the patients was the communication with their doctors. The majority of the patients were highly satisfied with the completeness and understandability of the explanations about the therapy from their doctors. There was no significant difference between patients with different ethnical origin. The groups differ significantly in regard to rating the therapy success (p = 0.007), evaluating the postoperative stress (p = 0.05) and the frequency of participating in clinical trials. Patients with other ethnical origin than German were less often considered to participate in clinical trials (p = 0.001). Conclusions: This study underlines the keyrole of a good doctor-patient relationship regardless of ethnical origin and indicates that further improvements are needed to eliminate barriers for different ethnical groups and enable access to health research for minority populations.
Mutant and Wild-Type Isocitrate Dehydrogenase 1 Share Enhancing Mechanisms Involving Distinct Tyrosine Kinase Cascades in Cancer
Authors: Dong Chen, Siyuan Xia, Mei Wang, Ruiting Lin, Yuancheng Li, Hui Mao, Mike Aguiar, Christopher A. Famulare, Alan H. Shih, Cameron W. Brennan, Xue Gao, Yaozhu Pan, Shuangping Liu, Jun Fan, Lingtao Jin, Lina Song, An Zhou, Joydeep Mukherjee, Russell O. Pieper, Ashutosh Mishra, Junmin Peng, Martha Arellano, William G. Blum, Sagar Lonial, Titus J. Boggon, Ross L. Levine, Jing Chen
Journal: Cancer Discovery (2019)

Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP+ or NADPH) binding. Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. SIGNIFICANCE: We demonstrated an intrinsic connection between oncogenic TKs and activation of WT and mutant IDH1, which involves distinct TK cascades in related cancers. In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.See related commentary by Horton and Huntly, p. 699.This article is highlighted in the In This Issue feature, p. 681.
Abstract P252: Stress Echocardiography in Assessment of Symptoms in Obese Patients
Authors: Stephanie Windish, Steven Smart
Journal: Circulation (2019)

Introduction: Obesity and obesity related illness continues to be an epidemic in the United States and worldwide. Obesity carries substantial risk of cardiovascular disease (CVD), and symptoms (shortness of breath, decreased exercise tolerance, etc) related to CVD can be nonspecific. Stress testing may identify the cause of these symptoms in obese patients (body mass index (BMI) &gt; 30.) Stress echocardiography has evolved to be capable of comprehensive hemodynamic assessment as well as functional and myocardial perfusion analysis and may be ideal for symptom evaluation in the obese. Methods: 1,615 consecutive patients (52% women, age 61±41 yrs, BMI 28±6) underwent stress perfusion ECHO (treadmill in 913, supine bike in 623 and dobutamine in 79 patients) between 2012 and 2014. Imaging included contrast/perfusion imaging and multi-method assessment of regional and global left and right heart systolic and diastolic function, left ventricular (LV) volumes, quantitative valve function, left and right heart pressures, peak/mean pulmonary artery pressures, pulmonary vascular resistance, and LV mass. Standard statistical methods were used. Results: Of the 1,615 patients analyzed, 516 (32%) were obese patients (BMI 36±5) and in the obese group females were 48% (vs 53% in non-obese). Both groups underwent similar stress modalities (58% vs 56% treadmill, 6% vs 4% dobutamine, and 36% vs 40% bike). Diabetes (21% vs 10%) and hypertension (57% vs 44%) were more common in obese (p&lt; 0.05). LV mass is disproportionately higher (113±30 vs 97±33 gm/M2) in obese patients (P&lt; 0.01). Additionally, obese patients had statistically significant findings (p&lt; 0.01) of LV hypertrophy (62% vs 26%), diastolic dysfunction (65% vs 44%), and at least moderate pulmonary hypertension (48% vs 34%). Overall, abnormal tests were more common in obese (83% vs 59%, p&lt;0.01). Multiple abnormalities were more common (p&lt;0.01): 1-3 abnormalities (13% vs 16%) and &gt; 4 abnormalities (70% vs 43%). Unexpectedly, the data showed no statistically significant difference between obese and non-obese in the incidence of ischemia (10% vs 11%), myocardial infarction (5% vs 4%), and cardiomyopathy (6% vs 5%). Conclusions: Comparative analysis of the data from stress ECHO revealed obese patients had disproportionally higher LV mass index/LV hypertrophy. Stress testing provoked worse diastolic dysfunction and much worse pulmonary vascular dysfunction in the obese patients. The triad of LV hypertrophy/diastolic dysfunction/pulmonary vascular disease with provoked moderate to severe pulmonary hypertension was the main cause of symptoms in obese patients. Hemodynamic stress ECHO is the ideal modality for evaluation of nonspecific symptoms of CVD in obese patients, as it can classify the cause of symptoms and the extent of pathology. Thereby, it may be the ideal test to guide treatment.
What do young adults with cancer indicate as their primary need for financial grant support?
Authors: Celeste Bunny Leach, Kurt A. Jaeckle
Journal: Journal of Clinical Oncology (2015)

e12658 Background: There are few data regarding the effect of cancer on the future goals of young adults. These individuals have limited resources, with career plans in early development. We studied young adults with active cancer who applied for financial support, to gain insight into their greatest needs, given their uncertain future. Methods: We prospectively collected data from 217 U.S. adults (age 15-29), who applied for unrestricted financial support from the Nicki Leach Foundation, a non-profit organization that supports young adults with cancer. Applicants were required to provide demographic data, a personal statement, and a supporting letter from the treating oncologist. Data fields included: age; sex; time from cancer diagnosis to application; histologic subtype; treating facility location [West (W); South (S); Midwest (MW); Northeast (NE)]; type of facility [University (U); Academic Medical Center (AMC); Community Medical Center (CMC)]; independence status for ADLs [independent (I) vs. dependent (D)]; and primary future goal for which funding was requested. Descriptive statistical methods were performed. All patients gave written consent for use of data. Results: The mean age (N = 217) was 20 yrs (S.D., 2.97, range 15-29); 66% were women and 34% men. Mean time from diagnosis was 20.4 mos. (S.D., 2.97, range 1-245). Patients were from 40 different states (Midwest, 32%%; South - 29%; Northeast -24%; West - 15%), and 181 different centers (CMC-40%; U-33%; AMC--27%). Histologic subtypes included leukemia (30%); CNS malignancy (18%); lymphoma (15%); sarcoma (9%) or other ( < 5% frequency each, 29%). Most applicants (84%), despite active disease, declared independence for ADLs. The stated primary intention for use of funding included: college expenses (71%); daily living expenses (15%); medical expenses (7%); computers (3%); automobiles (2%); or other educational expenses (2%). Conclusions: The majority of young adults with cancer indicated they would utilize unrestricted financial support to defray college tuition/expenses. These data suggest that young adults focus on the retention of control over their life and career goals, despite the uncertainty introduced by their cancer diagnosis.
The impact of the stage and tumor size on brain metastasis of cervical cancer.
Authors: Fatma Teke, Senem Yaman Tunc, Memik Teke, Yahya Turan, Zuhat Urakcı, Suleyman Altin, Bekir Eren, Mustafa Unsal
Journal: Journal of Clinical Oncology (2015)

e16502 Background: The aim of our study was to investigate the clinical features, prognostic factors and survival times of cervical cancer patients with brain metastasis. Methods: We retrospectively reviewed the medical records of 820 patients with cervical cancer. Data were analyzed using SPSS version 12.0 statistical software (SPSS, Chicago, IL, USA). Overall survival, time interval from diagnosis of cervical cancer to identification of brain metastasis, and median survival time after diagnosis of brain metastasis were calculated using Kaplan–Meier curve analysis. The log-rank test was used to compare differences in survival. Differences were assumed statistically significant when p-values were < 0.05. Results: The incidence of brain metastases from cervical cancer in our institution was 1.82% (15/820) over a ten year period. The median age at time of initial diagnosis of cervical cancer was 50 years old (range: 32–77 years old). Concerning the initial FIGO stage, seven (46.7%) patients had stage IIB disease, two (13.3%) had stage IIA disease, two (13.3%) had stage IVA disease, and one (6.7%) each had stage IB1, IB2, IIIA and IVB disease. Tumor diameter was ≥ 4 cm in twelve patients (80%). Five patients had only brain metastasis. Treatment for brain metastasis was whole brain radiation therapy (WBRT) in 60% of patients using median doses of 30 Gy (range:10-30 Gy). The median time interval from diagnosis of cervical cancer to detection of brain metastasis was 12.5 months (range: 2.9–91.9 months). Median overall survival of fifteen cases with brain metastasis from cervical cancer was 22.2 months (range: 4.6–98.2 months). Stage and tumor diameter were found to be significant relating to the interval from diagnosis of cervical cancer to detection of brain metastasis (p = 0.001 for both). Conclusions: This retrospective study provides much needed information about the prognosis of patients with brain metastases from cervical cancer and highlights the importance of initial stage and tumor diameter when determining the time interval until development of brain metastasis.
Abstract MP59: The Differential Effects of Amount and Intensity of Aerobic Exercise Training on MVX, a Novel Mortality Risk Multimarker
Authors: Leanna M Ross, Cris A Slentz, Irina Shalaurova, Margery A Connelly, James D Otvos, Joseph A Houmard, William E Kraus
Journal: Circulation (2019)

Introduction: Metabolic Vulnerability Index (MVX) is a novel spectroscopic multimarker of mortality risk. MVX reflects components of nutrition and systemic inflammation status and is hypothesized to enhance disease and mortality risk stratification. As Studies Targeting Risk Reduction Interventions through Defined Exercise (STRRIDE) has previously demonstrated the ability of aerobic exercise training to improve traditional markers of cardiometabolic health, we hypothesized that aerobic exercise intervention also would result in beneficial changes in the components of MVX. Methods: Participants (n=222, previously sedentary, overweight men and women with mild to moderate dyslipidemia from STRRIDE) were randomized to either a 6-month control group or to one of three supervised aerobic exercise groups for 8-months: 1) low amount moderate intensity (LM): 14 kcal/kg/wk at 40-55% VO 2peak ; 2) low amount vigorous intensity (LV): 14 kcal/kg/wk at 65-80% VO 2peak ; 3) high amount vigorous intensity (HV): 21 kcal/kg/wk at 65-80% VO 2peak . Blood samples were obtained after an overnight fast at both baseline and study completion (16-24 hr after the final training bout for exercisers). Nuclear magnetic resonance spectroscopy was performed on the Vantera ® clinical analyzer at LabCorp to determine MVX score. MVX has two components: inflammation index [INFX; combined concentrations of GlycA and small HDL particle subspecies (diameters &lt; 9 nm)] and metabolic malnutrition index (MALNX; combined concentrations of total branched chain amino acids and ketone bodies). MVX, INFX, and MALNX are all scaled from 1 (lowest risk) to 100 (highest risk). Paired t-tests determined whether the post- minus pre- intervention change scores within each group were significant (p&lt;0.05). We used analysis of covariance accounting for baseline values to determine difference between groups. Results: The inactive control group did not exhibit significant changes in any of the multimarkers. After 8-months of exercise training, the LM group experienced significant decreases in all three scores: INFX (-2.1 ± 5.2), MALNX (-3.1 ± 11.3), and MVX (-3.9 ± 9.1). The LV group significantly decreased their INFX score (-1.5 ± 3.8), yet significantly increased MALNX (2.2 ± 6.8). The HV group significantly decreased their INFX (-1.6 ± 4.8) and MVX scores (-1.9 ± 5.6). For the LM group, the beneficial changes in MALNX and MVX were significantly greater than the LV group. Conclusion: Aerobic exercise improved components of the novel risk-prediction multimarker MVX, with the LM group displaying the best responses across all three scores. As ongoing research investigates the clinical utility of these mulitmarkers, this study provides evidence for the ability of exercise intervention to beneficially change MVX score.
In Elderly Patients with Newly Diagnosed Aggressive B-Cell Lymphoma, the Rate of Change in Body Weight after the First Course R-CHOP (-like) Chemo Therapy Has Effect on Their Survival
Authors: Muramatsu Ayako, Nagata Hiroaki, Kuriyama Kodai, Hirakawa Yoshiko, Oshiro Muneo, Iwai Toshiki, Uchiyama Hitoji
Journal: Blood (2018)