tbuckley/cabot-search huggingface dataset:
Concomitant intake of abiraterone and food to increase pharmacokinetic exposure: Real-life data from a therapeutic drug monitoring program.
Authors: Stefanie L. Groenland, Andre M. Bergman, Alwin Huitema, Neeltje Steeghs
Journal: Journal of Clinical Oncology (2019)

3117 Background: Abiraterone acetate is registered for the treatment of metastatic castration resistant prostate cancer. Pharmacokinetic (PK) exposure has been linked to efficacy, since patients with C min ≥ 8.4 ng/mL have a significantly longer progression free survival compared to patients with a C min below this threshold (7.4 vs. 12.2 months, p = 0.044) (Carton, 2017). At the recommended fixed dose of 1000 mg QD administered in a modified fasting state, 35% of patients do not reach this efficacy threshold (Carton, 2017), providing a strong rationale for therapeutic drug monitoring (TDM). Since a clinically relevant food effect has been established, concomitant intake of abiraterone and food could offer a cost-neutral solution in case of low exposure (Chi, 2015). This study aims to evaluate whether PK-guided abiraterone dosing is feasible and results in an increased proportion of patients with concentrations above the target. Methods: Patients starting regular treatment with abiraterone were included. PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Abiraterone concentrations were measured and C min was calculated. In case of C min &lt; 8.4 ng/mL and acceptable toxicity, a PK-guided intervention was advised. As a first step, concomitant intake of abiraterone and a light meal or a snack was advised. Results: In total, 35 patients were included, of which 18 patients (51%) had at least one C min &lt; 8.4 ng/mL. These patients were advised to take abiraterone concomitantly with food, after which C min increased significantly from 5.6 (47%) ng/mL [mean (CV%)] to 40.6 (110%) ng/mL (p = 0.006) without additional toxicities. This intervention led to adequate exposure in 15 patients (83%). Seventeen patients had all C min levels ≥ 8.4 ng/mL, in these patients mean C min was 31.5 (65%) ng/mL. Conclusions: TDM of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted into a significant increase in C min and offers a cost-neutral opportunity to optimize treatment for patients with low PK exposure. Up to 100 patients will be included to evaluate the effect of PK-guided abiraterone dosing on treatment efficacy. Clinical trial information: NL6695.
National cancer expenditure analysis in the United States Medicare population, 2013.
Authors: Emily S Ruiz, Kira Seiger, Arash Mostaghimi, Chrysalyne Schmults
Journal: Journal of Clinical Oncology (2019)

6647 Background: Cancer is the second leading killer in the United States, but there is no comprehensive analysis evaluating total cancer costs by cancer and treatment modality. Methods: Data from the 2013 inpatient (100%), outpatient (100%), and carrier (5%) Medicare Limited Data Set Standard Analytic Files were queried for claims filed for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for all cancer diagnoses. Claims associated with the ICD-9 codes for professional fees were analyzed by Current Procedure Terminology (CPT) code to determine resource allocation by disease. Outpatient oral chemotherapy costs were obtained from the National Average Drug Acquisition Cost database for 50 drugs used for cancer treatment in 2013. Results: $27.9 billion was spent on cancer treatment of which $12 billion (43%), $6.5 billion (23%), and $1.1 billion (4%) was allocated to professional, inpatient facility, and outpatient facility fees, respectively. Oral and hospital-based chemotherapy accounted for 17% ($4.7 billion) and 15% ($4.3 billion) of all cancer costs, respectively. Lung/thoracic cancer ($2.9 billion) had the highest total annual cost and multiple myeloma ($9,019, SD $19,962) is the most expensive cancers to treat annually per patient. Average out-of-pocket expenses are $470 (SD 287), which is 12% of the annualized per patient costs. Conclusions: In 2013, cancer accounted for only 5% of Medicare spending. Chemotherapy costs accounted for approximately a third of total spending and are likely to rise as innovation continues. Out-of-pocket spending can place a financial burden on cancer patients requiring more expensive treatments.
Prediction of attendance to the "60 days law" within the patient navigation program to breast cancer in Rio de Janeiro, Brazil.
Authors: Sandra Gioia, Lindsay Krush, Sandra San Miguel, Renata Galdino, Lucia Brigagao, Paul Goss
Journal: Journal of Clinical Oncology (2019)

e13100 Background: An applied study was conducted on how the use of machine learning techniques can help in the process of identifying compliance with the "60 Day Law", which states that all patients with cancer within the public system must initiate the treatment within 60 days after the diagnosis of cancer. Within the Patient Navigation Program (PNP) for breast cancer in Rio de Janeiro, the study aims to: 1) identify barriers to compliance with the Law; 2) ensure that at least 70% of patients recruited with breast cancer initiate treatment within the mandatory 60-day period; and 3) to construct a model that accurately predicts whether or not a patient meets the period established in the Law. Methods: From August 2017 to May 2018, 105 patients aged 33-80 years (mean 59 years) were recruited for navigation. For the development of the statistical analysis, three learning models were used AdaBoost, Decision Tree and GaussianNB. Results: Patients presented 0-I (17%), II-III (78%) and IV (5%) staging. The main barriers to compliance with the Law were fear and fatalistic thoughts (99%), financial problems (79%), and uncoordinated health care (76%).The PNP had 100% patient satisfaction and in 52% of the cases it helped at the beginning of the treatment within the period established by law. The AdaBoost learning model had superior results in relation to accuracy and f-score (0.8889 and 0.8333, respectively). Conclusions: The PNP generated a positive experience in the public health system, because it is an intentional and proactive process of individual assistance through the health system, accessing services, and actively overcoming the barriers to quality care. The study did not reach the success rate of 70% compliance with the Law as intended (having reached 52%). However, the barriers that NP cannot overcome, such as the lack of human resources and medical supplies, have been reported to health authorities and hospital administrators. We identified 38 important attributes for compliance with the Law, which simplifies the information required for model learning. In the Brazilian context, the PNP may represent an opportunity to adequately implement existing legislation and, as such, would have great potential for integration into federal, state, and local health systems. Clinical trial information: 62728616.5.0000.5274.
Case 14-1988
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Thomas R. Hedges, William C. Schoene, Daniel M. Albert
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 40-year-old man was admitted to the hospital because of progressive visual loss and neurologic decline.He was well until two months earlier, when there was the onset of an unremitting bilateral retro-orbital headache, which did not respond to analgesic medications. A physician found crepitus at the left temporomandibular joint, with tenderness in the external auditory canal. A computed tomographic (CT) scan of the head was reported to be normal, and imipramine was begun. During the next few weeks the patient began to notice clouding of vision in the left eye, followed by reduced vision in the . . .
Patient-reported outcomes (PROs) with first-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic NSCLC: Results from MYSTIC.
Authors: Edward B. Garon, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Gilles Robinet, Sylvestre Le Moulec, Ronald Natale, Jeffrey Gary Schneider, Frances A. Shepherd, Marina Chiara Garassino, Sarayut Lucien Geater, Zsolt Papai-Szekely, Tran Van Ngoc, Feng Liu, Urban J. Scheuring, Anna Rydén, Solange Peters, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2019)

9048 Background: MYSTIC, an open-label, Phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum CT in mNSCLC, showed an improvement in overall survival (OS) with D vs CT in pts with tumor cell PD-L1 expression ≥25% (TC ≥25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02], p = 0.036; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17], p = 0.202). Here we summarize PROs from MYSTIC. Methods: Immunotherapy/CT-naïve mNSCLC pts were randomized (1:1:1) to D, D+T, or CT. Symptoms, function, and global health status/quality of life (QoL) were assessed using the EORTC QLQ-C30 v3 questionnaire and its lung cancer module, QLQ-LC13. A change in score from baseline ≥10 points was predefined as clinically meaningful (CM). Mean changes from baseline (over 12 mos) for prespecified symptoms were analyzed using a mixed model for repeated measures (MMRM). Time from randomization to the first CM deterioration (TTD) was analyzed. Results: Among pts with PD-L1 TC ≥25% (n = 488), there were no differences between arms in symptoms, function, or global health status/QoL at baseline. Compliance with completing the questionnaires was ≥60% to wk 120 in the D±T arms, and to wk 40 (C30) and wk 44 (LC13) in the CT arm. MMRM analysis showed significant between-arm differences in changes from baseline in favor of D for fatigue (difference vs CT −9.5) and appetite loss (−11.9; CM), and D+T for fatigue (−11.7; CM). Significantly longer TTD (median, mos) was seen with D and D+T vs CT for appetite loss (12.8 and 5.6 vs 4.5), constipation (14.6 and 9.0 vs 5.5), nausea/vomiting (16.7 and 9.7 vs 4.5), and dyspnea (10.6 and 7.4 vs 5.6); D vs CT for diarrhea (16.3 vs 9.0), insomnia (9.3 vs 6.2), and hemoptysis (not reached vs 10.3); and D+T vs CT for fatigue (5.6 vs 2.0). Significantly longer TTD (median, mos) was also seen with D and D+T vs CT for function (cognitive [9.1 and 6.6 vs 5.2], physical [9.0 and 7.4 vs 4.2], role [D vs CT only; 7.3 vs 3.7], social [12.9 and 5.4 vs 5.2]), and global health status/QoL (5.9 and 6.8 vs 5.5). Conclusions: Pts with PD-L1 TC ≥25% treated with D±T had a reduced symptom burden over time and longer TTD for symptoms, function, and global health status/QoL compared to pts receiving CT. Clinical trial information: NCT02453282.
RDI as a method for reviewer performance monitoring in BICR setup for improving data quality.
Authors: Manish Sharma, Oliver Bohnsack, Michael O'Connor, Yibin Shao, Nicholas Enus, Sayali Karve, A. Kassel Fotinos-Hoyer
Journal: Journal of Clinical Oncology (2019)

e18082 Background: Double read with adjudication is a preferred independent review model of regulatory authorities for blinded independent central review (BICR) in order to minimize reviewer bias in clinical trials. Adjudication rate (AR) and adjudication agreement rate (AAR) are commonly used indicators for monitoring independent reviewer performance quality. We will present data on Reader Disagreement Index (RDI), an innovative indicator for accurately monitoring reviewer performance and triggering timely intervention when applicable. Methods: A detailed review of BICR adjudication data was performed for 12 oncology clinical trials, with a total of 5,369 subjects (ranging from 119 to 894 per individual study) with 27,056 time points using RECIST, the Lugano classification or iwCLL assessment criteria. RDI for each reviewer was calculated as RDI = (# of cases where adjudicator disagreed with given reviewer ÷ Total # of all cases read) × 100, with high RDI indicating high % disagreement. RDI was used to identify the discordant reader (i.e. reviewer with the highest level of cases disagreed with by the adjudicator) when approximately 10% of the total reads were completed for each study. RDI was also calculated and compared with AR and AAR on an ongoing basis throughout the study. Mean RDI + standard deviation (SD) were used to identify outlier readers. Results: RDI reliably identified the most discordant reader consistently across all 12 studies, while AR &amp; AAR did not. The results confirm the advantage of RDI as a lagging and leading indicator for independent reviewer performance across indications and criteria using double read with adjudication review model. RDI, when calculated as early as at the 10% of total reviewed cases benchmark, demonstrated a positive predictive value of 91% and negative predictive value of 93% (Sensitivity 71%; Specificity 98%). Conclusions: Early identification of an outlier reviewer as per RDI (i.e. after reviews completed for ~ 10% study visits), followed by detailed analysis and corrective measures, such as retraining of the reviewer can serve as timely intervention to improve review quality. Thus, RDI proves to be a better indicator for not just monitoring reviewer performance, but also as an excellent tool for triggering timely corrective intervention. [Table: see text]
Is Trimming the Fat Enough? Fibroblast Growth Factor 21 as An Emerging Treatment for Nonalcoholic Fatty Liver Disease
Authors: Jody Dushay, Michelle Lai
Journal: Hepatology (2019)

Dushay, Jody M.D.; Lai, Michelle M.D., M.P.H.Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information
Heterozygous Spink1 c.194+2T&gt;C mutant mice spontaneously develop chronic pancreatitis
Authors: Chang Sun, Muyun Liu, Wei An, Xiaotong Mao, Hui Jiang, WenBin Zou, Hao Wu, Zhuan Liao, Zhaoshen Li
Journal: Gut (2019)

Recent publication of Hegyi and Sahin-Toth reported that CPA1 p.n256K mutant mice developed chronic pancreatitis (CP) through endoplasmic reticulum stress.1 This, along with other animal models based on CP genetic variants, revealed that the clinical course and mechanism of CP are better recapitulated with in vivo methods.2 

Previously, we found that SPINK1 c.194+2T>C mutation is the most frequently observed variant in Chinese patients with idiopathic CP. Function of c.194+2T>C variant has been characterised through in vitro studies as resulting in the absence of serine protease inhibitor secretion.3 4 However, the unavailability of SPINK1 c.194+2T>C animal model hindered the study into its role in CP development. To date, the only in vivo study focused on phenotype of homozygous Spink1 (also known as Spink3) deleted mice and found that they died of autophagic acinar cell death within 15 days after birth.5 Considering over 80% of Chinese CP patients with SPINK1 c.194+2T>C variant carry heterozygous mutation,6 we hypothesise that a heterozygous c.194+2T>C variant animal model may practically sketch the clinical pattern of …
Cytoplasmic cyclin E independently predicts recurrence in older patients with primary breast cancer.
Authors: Simon Johnston, Ruth Parks, Binafsha Manzoor Syed, Andrew R. Green, Kelly Hunt, Khandan Keyomarsi, Ian O. Ellis, Kwok-Leung Cheung
Journal: Journal of Clinical Oncology (2019)

3128 Background: Primary breast cancer in the older ( &gt; 70 years) population has distinct biological characteristics associated with favourable outcome, such as higher rate of estrogen receptor (ER) positivity. Due to comorbidities, older patients with primary breast cancer are more likely to die of non-breast cancer-related causes compared to their younger counterparts. Biomarkers that may influence treatment strategy therefore require interpretation in the specific biological and clinical context of older women. Cyclin E regulates cell cycle transition from G1 to S phase, and its deregulation is implicated in breast cancer pathogenesis. Tumour-specific isoforms of cyclin E localise to the cytoplasm. Expression of cytoplasmic cyclin E (c-cyclin E) is linked with poor clinical outcome. We now present multivariate analysis of breast cancer-specific survival (BCSS) by c-cyclin E and clinical markers of disease biology from a cohort of older women. The primary outcome, BCSS, excludes deaths from competing causes and is used as a surrogate for tumour biology. Methods: Between 1973 and 2010, 813 older women underwent initial surgery for early breast cancer and were followed up in a dedicated clinic in Nottingham. Excised tumours from 517 of these patients were successfully incorporated into a tissue microarray (TMA). Expression of c-cyclin E was assessed by IHC using an assay developed at MDACC, along with a panel of 24 biomarkers. Of these, ER, progesterone receptor (PR), human epidermal growth factor 2 (HER2) and Ki67 are in current clinical use and are analysed alongside c-cyclin E. Grade was assessed from the primary tumour. Multivariate analysis of BCSS was performed by Cox proportional hazard test. Results: In multivariate analysis alongside markers of disease biology currently used in the clinic (ER, PR, HER2, Ki67 and grade), c-cyclin E is the only factor that independently predicts BCSS in this cohort of older women (HR 5.0, 95% CI 2.1 – 12.0; p&lt; 0.001). Conclusions: In the older population with primary breast cancer, c-cyclin E expression is the only independent biological marker of BCSS. Patients with low c-cyclin E expression are unlikely to die of breast cancer. These data have potential to influence treatment strategy in older patients. For example, patients with ER+, c-cyclin E negative disease plus multiple co-morbidities may be suitable for primary endocrine therapy. This hypothesis warrants prospective clinical evaluation.
Accumulation of active metabolite M-2 predicts overall survival (OS) of chemorefractory metastatic colorectal cancer patients treated with regorafenib (REGO).
Authors: Benoit Rousseau, Arezki Khaled Boukerma, Julie Henriques, Romain Cohen, Olivier Lucidarme, Christophe Borg, Christophe Tournigand, Stefano Chong Hun Kim, Jean-Baptiste Bachet, Thibault Mazard, Christophe Louvet, Benoist Chibaudel, Luis A. Diaz, Dewi Vernerey, Thierry Andre, Anne Hulin
Journal: Journal of Clinical Oncology (2019)

3121 Background: TEXCAN, a prospective phase II GERCOR study of treatment with REGO in chemorefractory metastatic colorectal cancer (mCRC) patients (NCT02699073) included a prospective pharmacokinetic (PK) ancillary study aiming to investigate correlations between OS and concentrations (C) of REGO and its active metabolites M-2 and M-5. Methods: 55 patients were included, with the same inclusion/exclusion criteria as CORRECT (NCT01103323), and treated orally with 160 mg REGO daily for 3 weeks on and 1 week off. 34 patients had PK samples at C1D15 and 26 at C2D15 for Cmin. REGO, M-2 and M-5 Cmin were measured by LC-MS/MS. PK analyses studied the link between OS and PK parameters: Cmin of REGO, M-2 and M-5 at C1 and accumulation of pharmacological active metabolites between C1 and C2, assessed by the C2/C1 ratio of M-2 or M-5 Cmin concentrations. Results: REGO, M-2 and M-5 Cmin [median (Q1-Q3)] were respectively 1.99 (1.03-2.73), 1.44 (0.89-2.49) and 1.61 (0.79-2.37) mg/L at C1D15 and 1.90 (1.10-2.76), 1.29 (0.77-2.24) and 1.17 (0.45-2.42) mg/L at C2D15. C2/C1 M-2 ratio and M-5 ratio medians were 0.82 (0.50-1.78) and 0.75 (0.41-1.93), respectively. Univariate analyses showed a major OS benefit in patients with C2/C1 M-2 ratio ≥median vs &lt; median (12.6 vs 4.0 months respectively, hazard ratio = 0.35, 95% confidence interval 0.14-0.86, p-value = 0.023) but not for C2/C1 M-5 ratio ≥median. Multivariate analyses, including the CORRECT REGOSCORE groups, showedan independent 66% reduction in death risk in the group of patients with C2/C1 M-2 ratio ≥median. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum) (0.53, p-value = 0.006). Restricted Cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio rises and when C1 Csum ranged between 2.5 and 5.5 mg/L. PK parameters were not associated with toxicities. Conclusions: M-2 accumulation between C1 and C2 is independently associated with improved OS in mCRC patients treated by REGO. M-2 accumulates and OS is favorable when C1 REGO+M-2+M-5 sum ranged between 2.5 and 5.5 mg/L. These results may lead to develop individual REGO dosage modification strategies based on PK monitoring. Clinical trial information: NCT02699073.
Progression-free survival (PFS) and overall survival (OS) in HER2-ve advanced breast cancer (ABC) patients (pts) according to the molecular subtype in the era of modern agents: Results from the GIM-13 AMBRA study.
Authors: Marina Elena Cazzaniga, Paolo Pronzato, Francesco Schettini, Lucia Del Mastro, Maria Riemma, Massimiliano Alù, Anna Turletti, Monica Giordano, Palma Pugliese, Claudia De Angelis, Ornella Garrone, Paolo Marchetti, Ferdinando Riccardi, Antonio Bernardo, Lorenzo Livi, Alessandra Fabi, Cristiana Taverniti, Sabino De Placido, Giorgio Mustacchi
Journal: Journal of Clinical Oncology (2019)

e12528 Background: Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 &amp; P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test. Results: Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of first-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from first progression was 32.9 24.2 and 15.8 months respectively. Statistical details. Conclusions: Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminal and disappointing for TNBC. Median time from last CHT and Death is quite short and similar.[Table: see text]