tbuckley/cabot-search huggingface dataset:
Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with advanced solid tumors.
Authors: Juanita Suzanne Lopez, Elizabeth Ruth Plummer, Michael-John Devlin, Robert Rulach, Alvaro Henrique Ingles Garces, Noor R Md Haris, Rowan Miller, Donna Crawford, Manolo D'Arcangelo, Caterina Aversa, Alison L. Hannah, Stephanie Anderson, Marc Frederick Engelhardt, Thomas Kaindl, Patrice Larger, Felix Bachmann, Heidi A Lane, Phil McKernan, T.R. Jeffry Evans, Rebecca Sophie Kristeleit
Journal: Journal of Clinical Oncology (2018)

2530 Background: BAL101553 is the prodrug of BAL27862, a small molecule TCC that binds microtubules and promotes tumor cell death by activation of the spindle assembly checkpoint. In a study of BAL101553 administered as 2-h infusions on Days 1, 8 and 15 of a 28-day cycle (NCT01397929, Lopez et al. JCO 34, 2016; abstr 2525), vascular toxicities (troponin increases/ECG changes suggestive of microvascular myocardial injury and hypertension) were observed and appeared to be Cmax related. Nonclinical models indicate that the antiproliferative effects of BAL27862 are AUC driven; this trial was designed to determine whether oral once-daily (QD) administration of BAL101553 reduces Cmax-related toxicity and increases the AUC at the Recommended Phase 2 Dose (RP2D) (NCT02490800, Kristeleit et al. JCO 35, 2017; abstr 2532). Methods: Adult patients with advanced solid tumors received QD oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events (AEs) were assessed by CTCAEv4.03 grade (G); tumor response by RECIST 1.1 every 2 cycles; pharmacokinetics on Day 1 of Cycles 1 and 2. Results: Phase 1 enrollment completed with 26 patients (10M/16F; median age 62 y; median 3 prior chemotherapies) receiving oral BAL101553 at doses of 2–30 mg QD. BAL101553 was generally well tolerated at doses ≤16 mg, with one G3 event of increased alkaline phosphatase not considered clinically significant and G1/G2 events that did not show organ-specific patterns. Dose-limiting toxicities were seen at doses ≥20 mg: G3–4 hyponatremia, G3 hypokalemia and G2 hallucinations (all reversible). Of 19 efficacy-evaluable, 7 patients treated for ≥4 cycles (range 4-10) had stable disease (5/10 at ≥16 mg). BAL27862 exposure (AUC) was dose-related, almost dose-proportional. Cmax levels were below those seen with 2-h infusions at the RP2D and there were no effects on blood pressure. At 16 mg, the BAL27862 Cycle 1/Day 1 Cmax was 120 ng/mL and the estimated weekly exposure was 8400 ng.h/mL. Conclusions: The MTD of daily oral BAL101553 was 16 mg. At this dose, the weekly AUC is ~2-fold higher than that achieved at the RP2D for the weekly 2-h infusion. Vascular side effects were absent. Clinical trial information: NCT02490800.
Predictors of specialized pediatric palliative care involvement and impact on patterns of end-of-life care in children with cancer: A population-based study.
Authors: Sumit Gupta, Rinku Sutradhar, Adam Rapoport, Katherine Nelson, Ying Liu, Christina Vadeboncouer, Shayna M. Zelcer, Alisha Kassam, Jason D Pole, Craig Earle, Joanne Wolfe, Kimberley Widger
Journal: Journal of Clinical Oncology (2017)

10573 Background: Children with cancer are at risk of receiving high-intensity (HI) care at the end-of-life (EOL) and associated high symptom burden. The impact of palliative care (PC) delivered by generalists or of specialized pediatric palliative care (SPPC) on patterns of EOL care is unknown, with previous studies limited by small sample sizes or low response rates. Methods: Using a provincial registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000-2012 and who received care through a pediatric institution with a SPPC team and a clinical PC database. Patients were linked to population-based healthcare data capturing inpatient, outpatient, and emergency visits. Clinical PC databases were used to identify patients receiving SPPC. Remaining patients were categorized as having received either general PC (GPC) or no PC depending on the presence of PC associated physician billing or inpatient codes. We determined predictors of SPPC involvement, and whether either SPPC or GPC was associated with HI-EOL outcomes: ICU admission &lt; 30 days from death, mechanical ventilation &lt; 14 days from death, or in hospital death. Sensitivity analyses excluded treatment-related mortality (TRM) cases. Results: 572 patients met inclusion criteria. Children less likely to receive SPPC services included those with hematologic cancers [odds ratio (OR) 0.33, 95 th confidence interval (CI) 0.30-0.37; p &lt; 0.001)], in the lowest income quintile (OR 0.44, 95CI 0.23-0.81; p = 0.009), and living at increased distance from the treatment center (OR 0.46, 95CI 0.40-0.52; p &lt; 0.0001). In multivariate analysis, SPPC was associated with a 3-fold decrease in the odds of an EOL ICU admission (OR 0.32, 95CI 0.18-0.57), while GPC had no impact. Similar associations were seen with all other HI-EOL indicators. Excluding TRM had little impact. Conclusions: SPPC, but not GPC, is associated with lower intensity care at EOL. Access to such care however remains uneven. In the absence of randomized trials, these results provide the strongest evidence to date supporting the creation of SPPC teams. These results can be used to support PC advocacy and policy efforts.
Association of Time in Range, as Assessed by Continuous Glucose Monitoring, With Diabetic Retinopathy in Type 2 Diabetes
Authors: Jingyi Lu, Xiaojing Ma, Jian Zhou, Lei Zhang, Yifei Mo, Lingwen Ying, Wei Lu, Wei Zhu, Yuqian Bao, Robert A. Vigersky, Weiping Jia
Journal: Diabetes Care (2018)

Continuous glucose monitoring (CGM) has provided new measures of glycemic control that link to diabetes complications. This study investigated the association between the time in range (TIR) assessed by CGM and diabetic retinopathy (DR).A total of 3,262 patients with type 2 diabetes were recruited. TIR was defined as the percentage of time spent within the glucose range of 3.9-10.0 mmol/L during a 24-h period. Measures of glycemic variability (GV) were assessed as well. DR was determined by using fundus photography and graded as 1) non-DR; 2) mild nonproliferative DR (NPDR); 3) moderate NPDR; or 4) vision-threatening DR (VTDR).The overall prevalence of DR was 23.9% (mild NPDR 10.9%, moderate NPDR 6.1%, VTDR 6.9%). Patients with more advanced DR had significantly less TIR and higher measures of GV (all P for trend <0.01). The prevalence of DR on the basis of severity decreased with ascending TIR quartiles (all P for trend <0.001), and the severity of DR was inversely correlated with TIR quartiles (r = -0.147; P < 0.001). Multinomial logistic regression revealed significant associations between TIR and all stages of DR (mild NPDR, P = 0.018; moderate NPDR, P = 0.014; VTDR, P = 0.019) after controlling for age, sex, BMI, diabetes duration, blood pressure, lipid profile, and HbA1c. Further adjustment of GV metrics partially attenuated these associations, although the link between TIR and the presence of any DR remained significant.TIR assessed by CGM is associated with DR in type 2 diabetes.
Phase I study of YM155, selective survivin suppressant in combination with elrotnib in patients with EGFR-mutant advanced non-small cell lung cancer.
Authors: Toshio Shimizu, Kazuto Nishio, Kazuko Sakai, Hidetoshi Hayashi, Kunio Okamoto, Masayuki Takeda, Tsutomu Iwasa, Kaoru Tanaka, Koji Aoyama, Maiko Morishita, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2016)

e20585 Background: Based on the mechanism of action and preclinical evidence of overcoming EGFR-TKI resistance in EGFR mutant non-small cell lung cancer (NSCLC) cells by targeting survivin, a member of the inhibitor of apoptosis (IAP) family, phase I study of YM155 (Y), a small-molecule selective survivin suppressant in combination with erlotinib (E) was conducted in patients with advanced NSCLC. Methods: Patients with previously EGFR-TKI treated refractory NSCLC received fix dose of E (150mg QD) in combination with escalating doses of Y (3.6, 4.8, 6.0 and 8.0 mg/m2/d) administered as a continuous intravenous infusion (CIVI) over 168 hours in 21-days treatment cycles. Biomarker analysis includes changes of expression of survivin in biopsied tumor pre- and post Y administration detected by immunohistochemistry and survivin RT-PCR. Next generation sequencing (NGS), multiplex mutation screening and plasma cytokine analysis have also been conducted. Results: Total of 18 patients received Y at three different dose levels with standard doses of E. The most common adverse reactions judged to be related to Y were urine microalbumin present, whereas grade 3 and 4 toxicities were rare. One patient receiving 4.8 mg/ m2/d Y developed a dose-limiting transient reversible grade 2 serum creatinine elevation. The best overall response was stable disease for 10 (66%) out of 15 evaluable patients. Durable stable diseases > 24 weeks by RECIST criteria were observed in 2 patients (283 days for Y 3.6 mg/m2/d cohort and 264 days for Y 6.0 mg/m2/d cohort). No pharmacokinetic interaction between Y and E was detected and plasma cytokine analysis showed a tendency of lower level of IL-7, IL-9, IL-10 and VEGF in patients who achieved progression free survival > 12 weeks. Conclusions: Y up to 8.0 mg/m2/d administered in combination with standard dose of E every 3 weeks cycle exhibited a favorable safety profile. These results suggest that combining the inhibition of survivin with EGFR pathway is an attractive and a potential therapeutic modality in selected patients with previously EGFR-TKI treated refractory NSCLC.
The impact of inclusion in home palliative program and distance to hospital on chemotherapy near end of life.
Authors: Jose Balsalobre-Yago, María José Martínez-Ortiz, Maria Isabel Luengo Alcázar, Pablo Cerezuela Fuentes, Ana Checa-Soriano, Alice Viney, Mónica Martínez-Penella, Jose Luis Alonso Romero, Francisco Ayala
Journal: Journal of Clinical Oncology (2018)

e22001 Background: Chemotherapy (CT) near end of life is considered a marker of inadequate palliative care for cancer patients. The objectives of our work were to determine the influence of palliative care at home and the distance between the residence area and the cancer referral center on the interval between last chemotherapy cycle and death. Methods: A retrospective observational study was conducted in a tertiary care hospital. All cancer patients deceased between January 2013 and April 2014 were included. Clinical, demographical and treatment variables were obtained from medical records. Results: Our population of 901 patients had a mean age of 63 years; male: 585 (65%), females: 316 (35%). Tumor locations: lung, 243 (27%); colorectal, 117 (13%); breast, 93 (10.3%); pancreas, 74 (8.2%). Table 1 shows an analysis of the CT used in all patients, indicating a high proportion of CT use near the end of life (67% in the last 3 months). Average time elapsed between the end of treatment and death was significantly longer in the group of patients included in home palliative care programs (n = 105; 23%) vs. those not included (n = 353; 77%): 42 vs. 25.3 days (p < 0.05). CT was stopped earlier in patients belonging to geographical areas farther from the referral center, with median times between last cycle of CT and death of 14.7 days for patients living near the referral hospital versus 53 days for > 70 km (p = 0.044) and 58 days for > 100 km (p = 0.013). Conclusions: In our population, a high percentage of CT was observed in the final stages of life, including a high use of third and successive lines of treatment. Patients included in home palliative care programs and/or belonging to more distant geographical areas finished active treatment before, thereby suggesting that both factors impact on decision making for patients with advanced cancer. Understanding the factors that determine the use of CT near the end of life may contribute to limit its inadequate indication. Table 1. Analysis of CT use in all patients. N = 901 n (%) Treatment No CT CT 198 (22) 703 (78) Nr of lines of CT 1 2 3 4 or more 441 (49) 198 (22) 135 (15) 127 (14) Nr of drugs in last line of CT 1 2 3 378 (42) 414 (46) 109 (12) CT in the last 3 months 604 (67) CT in the last 4 weeks 405 (45) CT in the last week 63 (7)
Oral Anticancer Therapy Project: Clinical utility of a specific home care nursing program.
Authors: Massimo Cirillo, Luciano Carlucci, Ilaria Pacchetti, Eliana Rulli, Cosimo Sacco, Vittorina Zagonel, Editta Baldini, Fabiola Lorena Rojas Llimpe, Giuseppe Tonini, Silvana Leo, Marialuisa Meacci, Alfredo Tartarone, Giampaolo Tortora, Marta Zaninelli, Vanna Maria Valori, Annamaria Quaranta, Elisabetta Cretella, Gianluigi Lunardi, Carmine Pinto, Stefania Gori
Journal: Journal of Clinical Oncology (2016)

6597 Background: Patients (pts) receiving anticancer oral therapy need a specific training since treatment is a home-based therapy. Published data suggest the benefit of an active monitoring by means of dedicated nurses caring to improve the efficiency and safety of anticancer oral therapy administration. Aim of this study was to evaluate the potentiality of home care nursing program (HCNP) in decreasing the improper accesses into first aid for not severe toxicity or need of information about therapy administration. Methods: This isan Italian, multicentre randomized controlled trial including pts eligible to receive an oral cytotoxic/biological anticancer therapy. Concomitant use of radiotherapy, intravenous or metronomic therapies or administration of previous oral drugs were not allowed. Pts were randomly assigned to receive either a HCNP (A) or standard care (B). In arm A dedicated nurses provided accurate information to the patient; a daily record on which the patients will take note of taken drug dose and symptomatology eventually occurred; a telephone monitoring by means 2 phone interviews during first cycle of therapy and 1 during the second one. Primary outcome was the reduction of improper hospital accesses for grade 1-2 toxicity according to CTC-AE (version 4.03) or clarifications about the treatment plan. The study was registered in the observational studies registry [AIOM_TO-1(ID 637)]. Results: Out of 430 randomized pts, 386 were analysed (188 pts in arm A and 198 in arm B), since 9 pts were excluded for major violation and 35 for never starting treatment.At least one access to hospital was observed in 40 pts in arm A and in 42 pts in arm B (21.3% vs. 21.2%, respectively). No difference was detected in proportion of improper accesses between arm A and arm B (27.5% vs. 23.8%, respectively). Conclusions: Our experience failed to support the role of a specific HCNP for pts taking oral therapy. An improved attention to specific educational practice and accurate information given to all pts can explain these results. Clinical trial information: AIOM_TO-1(ID637).
Differential epithelial and mesenchymal CTC profiling according to non-small cell lung cancer (NSCLC) molecular subtype.
Authors: Colin R. Lindsay, Vincent Faugeroux, Emma Pailler, Maria Virginia Bluthgen, Chloe Pannet, Maud Ngo-camus, Guillaume Bescher, Esperanza Perez, Caroline Caramella, Fanny Billiot, Jordi Remon, David Planchard, Jean-Charles Soria, Benjamin Besse, Françoise Farace
Journal: Journal of Clinical Oncology (2016)

e23093 Background: CTCs may exist as co-operative epithelial and mesenchymal subpopulations or as individual highly plastic cells. Molecular characterisation of NSCLC has revealed it to be a disease of multiple genetic aetiologies. Here we assessed EMT in CTCs from NSCLC molecular subgroups, asking whether their presence confers poor survival. Methods: 125 patients (pts) with treatment-naïve stage IIIb-IV NSCLC were prospectively included for CellSearch analysis. Pts signed informed consent for 1 CellSave tube prior to systemic treatment. Anti-vimentin (vim) antibody was added to the system for EMT examination. Association of CTC number (vim+ and total) with clinical characteristics were assessed using Fisher's/Mann-Whitney tests. Kaplan-Meier method and log-rank tests were used to analyse PFS and OS using univariate/multivariate testing. Results: 51/125 pts (40.8%) were total CTC-positive (+) and 26/125 pts (20.8%) were vim CTC+. Table 1 shows associations between molecular characteristics and total/vim+ CTCs. There was a significant increase of vim+ CTCs in EGFR mutant vs EGFR WT disease (mean 1.24 vs 1.22, p = 0.013), and a reduction of total CTC in ALK-rearranged vs ALK WT disease (mean 1.69 vs 5.82, p = 0.029). No change in total/vim+ CTC existed in pts according to KRAS, squamous histology, or tobacco use. There was a significant reduction of OS in pts who were total CTC+ vs negative (median 294 days vs 400 days; p = 0.012), but no OS difference existed between CTC-vim+ and CTC-vim negative groups (median 294 days vs 276 days, respectively; p = 0.748). Conclusions: The presence of CTCs in pts with advanced NSCLC confers a poorer prognosis than in those with no CTCs. EMT, reflected by presence of CTC-vim+, varies between NSCLC molecular subgroups. EGFR-tested patients (n = 94) KRAS-tested patients (n = 90) ALK-tested patients (n = 90) Total CTC mean (range) Vimentin CTC mean (range) Total CTC mean (range) Vimentin CTC mean (range) Total CTC mean (range) Vimentin CTC mean (range) Wild-type 4.12 (0-78) 1.22 (0-35) 4.44 (0-78) 1.19 (0-24) 5.82 (0-78) 1.33 (0-35) Mutation/ aberration 4.71 (0-28) 1.24 (0-7) 4.36 (0-37) 1.68 (0-35) 1.69 (0-19) 1.08 (0-12) p = 0.212 p = 0.013* p = 0.755 p = 0.081 p = 0.029* p = 0.607
Some immunohistochemical markers of angiogenesis in melanocytic skin neoplasms.
Authors: Inna Arnoldovna Novikova, Natalia A. Maksimova, Elena Petrovna Ulianova, Maria I. Maksimova, Oksana G. Shulgina, Anastasia Grankina, Victoria V. Pozdnyakova, Maria G. Ilchenko
Journal: Journal of Clinical Oncology (2017)

e21067 Background: The purpose of the study was to analyze the expression of angiogenesis-controlling markers (CD31, VEGF) in tissues of melanocytic skin lesions. Methods: The study included 20 patients with benign pigmented lesions and 15 patients with superficial spreading and nodular melanoma. Immunohistochemical study was performed on sections of paraffin blocks for standard morphological studies using murine monoclonal CD31 and VEGF antibodies. UltraVision Quanto Detection System HRP DAB was used for visualization. Angiogenesis in tumors was assessed by intratumoral microvessel density (iMVD) index. Microvessels were stained with anti-CD31 antibody. The number of vessels was determined in each area of sight using objective lens with 40x magnification and AxioVs40 v-4.8.1.0 program. The tumor was considered VEGF-positive if more than 25% of tumor cells showed positive staining, and percentages of these tumor cells were calculated in each case (in %). Results: Quantitative evaluation of iMVD showed that the median number of microvessels in an area of sight in melanoma and nevi was 10.0±0.9 and 4.1±0.4, respectively, results of CD31 expression were statistically significant (р˂0.05). The numbers of CD31-stained vessels in melanoma ranged from 4 to 18 in one area of sight. 14 nevus cases (70%) showed 4 and less vessels, and only giant-cell nevi (6-30%) demonstrated up to 15 vessels in one area of sight. VEGF expression was found in the cytoplasm of melanoma cells in 100% of cases (15), in nevi – in 65% (13). The expression was not found in nevi cells in 35% (7). The number of VEGF-positive cells varied greatly in both melanomas and in nevi – from less than 5% to 50%. The maximal VEGF expression was observed in melanomas – 32.5±2.9%, while in nevi 23.8±2.1% (р˂0.05). Conclusions: The immunohistochemical study demonstrated a high angiogenic potential of melanoma that can be used as an additional criterion for tumor progression and malignant transformation of melanocytic skin neoplasms and thus contribute to the development of novel approaches to the diagnosis of the disease.
過塩素酸ナトリウムを用いたイオン対抽出と分取イオン対HPLCの組合せによる植物性材料からのアルカロイドの単離 III 中国産厚朴
Authors: Moriyasu M, Wang J, Zhang H, Lu G‐B, Ichimaru M, Kato A
Journal: Nature Medicine (1996)
Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL.
Authors: Jae Hong Park, Isabelle Riviere, Xiuyan Wang, Terence Purdon, Michel Sadelain, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2016)

7003 Background: We have previously reported high anti-tumor activity of CD19-targeted 19-28z chimeric antigen receptor (CAR) modified T cells in adult patients (pts) with relapsed or refractory (R/R) B-cell ALL. Herein, we report the result of a focused analysis on the impact of disease (dz) burden at the time of CAR T cell infusion on toxicity and clinical outcome. Methods: Adult pts with R/R B-ALL were enrolled to the phase I clinical trial. All pts underwent bone marrow (BM) biopsy immediately prior to 19-28z CAR T cell infusion, and were divided into two cohorts based on the blast % in BM: minimal dz ( < 5% blasts) vs. morphologic dz ( ≥ 5% blasts). Subsequently, pts received lymphodepleting chemotherapy followed by 19-28z CAR T cell infusion. Results: Of 46 pts treated, 21 pts had minimal dz and 25 pts had morphologic dz at the time of CAR T cell infusion. Baseline dz and treatment characteristics were similar between the two cohorts, except less HSCT in the minimal dz cohort (29 vs. 48%). Complete response (CR) and minimal residual disease-negative CR (MRD-CR) rates were 91% and 71% in the minimal dz cohort, and 75% and 65% in the morphologic dz cohort, respectively. Severe cytokine release syndrome exclusively occurred in pts with morphologic dz (44% vs. 0%) but grade 3/4 neurotoxicity was observed in 14% of pts with minimal dz vs. 40% with morphologic dz. Although overall relapse rates did not differ between the two cohorts, no relapse or death occurred in the minimal dz cohort beyond 12 months. At a median follow-up of 12.0 months (range, 1-45), the estimated 6-month overall survival (OS) rates for all pts in the minimal dz and morphologic dz cohorts were 73% and 57%, respectively. Among the pts who achieved MRD-CR, the estimated 6-month OS rates were 92% for the minimal dz cohort with remissions extending beyond 3 years, and 65% for the morphologic dz cohort. Conclusions: These data confirm the potent anti-tumor efficacy of 19-28z CAR T cells (JCAR015) in adult pts with R/R ALL regardless of pre-treatment dz burden. Pts with minimal dz appear to have more favorable toxicity profile and long-term survival rates. These findings support the use of 19-28z CAR T cells in earlier lines of ALL treatment, such as in a frontline setting. Clinical trial information: NCT01044069.