tbuckley/cabot-search huggingface dataset:
Vismodegib (VISMO), a hedgehog pathway inhibitor (HPI), in advanced basal cell carcinoma (aBCC): STEVIE study primary analysis in 1215 patients (pts).
Authors: Johan Hansson, Axel Hauschild, Rainer Kunstfeld, Jean Jacques Grob, Brigitte Dréno, Laurent Mortier, Paolo Antonio Ascierto, Lisa F. Licitra, Caroline Dutriaux, Luc Thomas, Nicolas Meyer, Bernard Guillot, Reinhard Dummer, Petr Arenberger, Kate Fife, Ana Raimundo, Emi Dika, Natalie Dimier, Ioannis Xynos, Nicole Basset-Seguin
Journal: Journal of Clinical Oncology (2016)

9532 Background: VISMO, a first-in-class HPI, is approved (US and EU) for use in adults with aBCC. STEVIE is an open-label study focusing on safety of VISMO in pts with aBCC in a real-world setting. We present data from the primary analysis. Methods: Adult pts (laBCC, mBCC) received oral VISMO 150 mg QD until progressive disease, unacceptable toxicity, or withdrawal. Primary objective is safety; pts are followed for 12 months after last dose of VISMO. Secondary objectives include efficacy and quality of life. Results: This analysis includes 1215 pts (laBCC, n = 1119; mBCC, n = 96) at 165 sites in 36 countries. Median (range) age was 72.0 (18.0-101.0) yrs. At the time of analysis, 375 (31%) patients remained on study. Median (range) treatment duration was 8.6 (0-44) months. Treatment-emergent AEs (TEAEs) included muscle spasm (66.4%), alopecia (61.5%), dysgeusia (54.6%), decreased weight (40.6%), decreased appetite (24.9%), asthenia (24.0%), nausea (17.9%), and ageusia (17.5%). Serious TEAEs occurred in 289 pts (23.8%). There was no trend of increased TEAEs or grade ≥ 3 TEAEs with increased time on treatment adjusted by pt-yr. Forty-six pts died from grade 5 TEAEs. Seven deaths were considered by investigator (INV) to be related to VISMO (2 myocardial infarction, 1 each of cardiorespiratory arrest, pancreatitis, pulmonary embolism, ischemic stroke, renal failure; all involved confounding factors). Best overall response (RECIST 1.1; INV-assessed) in pts with histologically confirmed measurable baseline disease (laBCC, n = 1077; mBCC, n = 84) included complete response (CR) (33.4% laBCC; 4.8% mBCC) and partial response (35.1% laBCC; 32.1% mBCC). Median duration of response was 23.0 (95% confidence interval [CI]: 20.4, 26.7) and 13.9 (95% CI: 9.23, not estimable) months in pts with laBCC and mBCC, respectively. Median progression-free survival was 23.2 (95% CI: 21.4, 26.0) and 13.1 (95% CI: 12.0, 17.7) months in pts with laBCC and mBCC, respectively. Conclusions: The primary analysis of STEVIE, the largest ever clinical trial in pts with aBCC, confirms the previously observed safety profile and high response rates with VISMO, including many CRs as well as durable responses. Clinical trial information: NCT01367665.
Chemotherapy plus or minus bevacizumab for platinum-sensitive ovarian cancer patients recurring after a bevacizumab containing first line treatment: The randomized phase 3 trial MITO16B-MaNGO OV2B-ENGOT OV17.
Authors: Sandro Pignata, Domenica Lorusso, Florence Joly, Ciro Gallo, Nicoletta Colombo, Cristiana Sessa, Aristotelis Bamias, Carmela Pisano, Frederic Selle, Eleonora Zaccarelli, Giovanni Scambia, Patricia Pautier, Maria Ornella Nicoletto, Ugo De Giorgi, Coraline Dubot, Alessandra Bologna, Michele Orditura, Isabelle Laure Ray-Coquard, Francesco Perrone, Gennaro Daniele
Journal: Journal of Clinical Oncology (2018)

5506 Background: Bevacizumab (BEV) is approved in recurrent ovarian cancer (rOC) for patients not previously treated with the drug. Our study aimed at evaluating whether the addition of BEV to a platinum-based chemotherapy prolongs progression-free survival (PFS) for rOC patients who had already received it during first line. Methods: FIGO stage IIIB-IV rOC patients relapsing at least 6 months after last dose of platinum, who had received BEV during first-line treatment, ECOG PS≤2, were randomized to 6 cycles of platinum-based doublets (carboplatin/paclitaxel or carboplatin/gemcitabine or carboplatin/PLD) with or without BEV administered concomitant with chemotherapy and as maintenance until disease progression. The primary endpoint is PFS. With 90% power in detecting a 0.67 HR, with 2-sided α error 0.05, 265 events were needed. All efficacy analyses are done on an intention-to-treat basis. PFS and OS curves are estimated by Kaplan-Meier method, and compared with a two-sided log-rank test. Toxicity is graded according to NCI-CTCAE v 4.0. Results: 405 pts were enrolled. Median age was 61; 64% of patients had progressed ≥12 months after last dose of platinum and 72% of patients after completion of first-line BEV maintenance. With a median follow-up of 20.3 months, 304 PFS events and 147 deaths were recorded. Median PFS was 8.8 months and 11.8 months without and with BEV, respectively (HR 0.51, 95%CI: 0.41-0.64, p < 0.001). Median OS was 27.1 months and 26.7 months without and with BEV, respectively (HR 1.00, 95%CI: 0.73-1.39, p = 0.98). Severe (≥G3) hypertension (27.5% vs 9.7%, p < 0.001) and proteinuria (4% vs 0, p = 0.007) were more frequent with BEV. Conclusion: This study shows that for rOC patients previously treated with BEV in first line relapsing ≥6 months after last platinum, rechallenge with BEV in combination with platinum-based doublets is associated with a significantly prolonged PFS, with no unexpected toxicity.Supported by Roche. Clinical trial information: NCT01802749.
An initial geriatric evaluation in older patients with urological cancer to improve the non-oncological side of follow.
Authors: Silvio Monfardini
Journal: Journal of Clinical Oncology (2016)

e21537 Background: In older patients (pts) with Urological Cancer after primary Surgery (S) or Radiotherapy (RT) a Comprehensive Geriatric Assessment (CGA) with a following observation of the healthcare pathways could be of value to understand what is lacking in dealing with age-related issues during the oncological follow up practice in elderly pts. . Methods: From November 2011 to March 2015, to all pts aged 70+ years (y), treated with RT or S at the 7 participating RT and Urology Units in the Milano City, was offered a CGA and phone calls follow up of 2 specially trained evaluators at 6 and12monhs. The information on CGA and phone follow up was not available to the caring physicians. Results: CGA was performed in 459 pts. Prostate cancer was observed in 291 pts (median age 75 y), bladder cancer in 126 (median age 77 y) and kidney cancer in 37 (median age 77 y). According to Balducci’s definition, among prostate cancer pts 40% were Fit, 47% Vulnerable and 13% Frail. In bladder cancer pts 21% were Fit, 42% Vulnerable and 37% Frail. In renal cancer pts 22% were Fit, 43% Vulnerable and 35% Frail. The phone follow up was possible in 415 pts (90.4%). The percentage of pts followed by a specialist for a severe comorbidity was: 60% for cardiac diseases, 40% for diabetes/other metabolic disorders, 35% for hypertension, 35% for respiratory diseases. Of 66 pts with ADL and/or IADL deficit only 7 (11%), were referred to a rehabilitation service. Only 1 case received a Geriatric consultation. Conclusions: Vulnerable and Frail were over 75% of both renal and bladder cancer pts, and 60% of prostate cancer pts. During the follow up only a minority of pts was seen by a specialist in case of severe comorbidities. Only few pts with functional deficits received rehabilitation. A Geriatric consultation was almost unexistent. To achieve a multidisciplinary follow up for older pts with urological neoplasia, an initial CGA could allow appropriate interventions
Use of multiple antigens stimulating cellular therapy to treat patients with hepatocellular carcinoma.
Authors: Yanyan Han
Journal: Journal of Clinical Oncology (2016)

e14530 Background: Hepatocellular carcinoma (HCC) is one of the most common tumors in China, and frequently occurs with chronic hepatitis B virus (HBV) infection. To investigate whether adoptive cell therapy induces tumor specific immune responses in HCC patients and further brings clinical benefits, Multiple Antigens Stimulating Cellular Therapy (MASCT) was applied in addition to conventional therapies. Methods: ActivatedT cells that were prepared from the autologous peripheral blood mononuclear cells (PBMCs). Cells were stimulated and amplified with dendritic cells (DCs) pulsed by multiple tumor antigen peptides, including tumor associated antigen peptides and HBV antigen peptides. All patients received treatment of MASCT every 1-3 months. The immune responses were examined during the treatment. Results: The resulting amplified cells were almost exclusively CD3+ T cells, with a major percentage being CD3+CD8+ cells and a minor proportion being CD3+CD4+ and CD3+CD56+ cells. These T cells have restored immune functions and HLA-restricted specific cytotoxicity against HCC cells. After repeating treatment of MASCT, the frequency of regulatory T cells in the patients was significantly decreased, and the proliferation and function of tumor antigen specific T cells were enhanced. The specific immune responses against each kind of tumor antigens were gradually increased in patients during the treatment of MASCT. In a retrospective study, the disease control rate (DCR) in one year was raised to 80% in stage B HCC patients receiving MASCT combined with conventional therapies. Conclusions: Our study has demonstrated that MASCT is a well tolerate immunotherapy. Specific T cell responses against tumor antigens can be strongly induced in vivo. Our study also indicated that repeated MASCT treatment improves both the immunologic function and disease control of patients with HCC.
Abstract P102: Longitudinal and Secular Decrease in Total Cholesterol Levels in All Birth Cohorts. The Tromsø Study 1979-2008
Authors: Laila A Hopstock, Kaare H Bønaa, Anne E Eggen, Sameline Grimsgaard, Bjarne K Jacobsen, Maja-Lisa Løchen, Ellisiv B Mathiesen, Inger Njølstad, Tom Wilsgaard
Journal: Circulation (2016)

Introduction: Elevated blood cholesterol is a modifiable risk factor for cardiovascular disease (CVD). Surveillance of cholesterol levels is needed to study disease burden, consider priorities for CVD prevention and intervention, and understand the effect of diet, lifestyle and medication use. Previous studies show a cholesterol level decline in recent decades, but lack data to follow individuals from different birth cohorts from early and middle adulthood to older age. Hypothesis: To assess secular and longitudinal trends in total cholesterol levels. Methods: We investigated changes in age-specific cholesterol levels by repeated measurements in 37,968 women and men born 1905-1977 examined up to five times between 1979 and 2008 in the population-based Tromsø Study. Results: Mean total cholesterol decreased from 1979 to 2008 in both genders in all age groups. The decrease in age group 40-49 years was 1.2 mmol/l in women and 1.0 mmol/l in men. Both the 80th percentile and the 20th percentile of the population cholesterol distribution decreased. In birth cohorts born 1940-77, mean total cholesterol levels increased with age up to 2001 and decreased thereafter to 2007. Among those born 1910-39, the cholesterol decrease was evident after 1994-95. The longitudinal trends in those born 1940-77 were not influenced by use of lipid-lowering drugs, while the decrease with age in birth cohorts born 1910-39 was slightly weaker among never users of lipid-lowering drugs compared to the total sample. Conclusions: A longitudinal decrease in mean cholesterol levels was observed from 1994-95 or from 2001 depending on birth cohort. A secular decrease was observed from 1979-80 in all age groups. The findings points to a mass population effect rather than a treatment effect of high-risk individuals alone.
Abstract 12737: Cardiac Early Diastolic Dys-Synchronyis Related to Left Ventricular Remodeling and Function in Hypertension
Authors: Xing Sheng Yang, Jing Ping Sun, Alex Pui-Wai Lee, Ting-Yan Xu, Dian Wang, Xiao-yan Wang, Yan Li, Fang Fang, Cheuk-Man Yu, Ji-Guang Wang
Journal: Circulation (2013)

Background: Cardiac synchronization is important in maintaining myocardial performance. The mechanism of dys-synchronization in ailing to failing myocardium is unclear. The aim of this study is to ...
Evaluation of the effect of dabrafenib on QTc interval in patients with BRAF V600–mutant tumors.
Authors: Noelia Nebot, HT Arkenau, Jeffrey R. Infante, Jason Claud Chandler, Andrew Weickhardt, Jason D. Lickliter, John Sarantopoulos, Michael S. Gordon, Annie St-Pierre, Lihua Tang, Bijoyesh Mookerjee, Stanley W Carson, Kenneth F. Grossmann
Journal: Journal of Clinical Oncology (2016)

e14119 Background: Dabrafenib (DAB) is a BRAF inhibitor approved at a dose of 150 mg twice daily (BID) for treating unresectable or metastatic BRAF V600E/K–mutant melanoma with or without trametinib. Here, the effect of repeated oral supratherapeutic dosing of DAB on QTc interval was assessed in patients (pts) with BRAF V600–mutant tumors. Methods: This was a phase 1, multicenter, 2-part study in pts with BRAF V600–mutant tumors (NCT01738451). In part 1 (P1), safety and tolerability of DAB 225 or 300 mg BID were assessed to inform the P2 dose. P2, a single-blind study, evaluated the effect of DAB on electrocardiographic (ECG) parameters vs placebo (Pbo). Pts received DAB-matched Pbo on study day (d) −1, a DAB 300-mg single dose on d1, DAB 300 mg BID on d2-7, and DAB 300 mg the morning of d8. Each d −1, d1, and d8 dose was followed by 24-h Holter ECG monitoring and pharmacokinetic (PK) serial blood sample collection. PK/pharmacodynamics (PD) analysis assessed the combined effect of DAB and metabolites on QTc interval. Results: All 12 (DAB 225 or 300 mg BID, n = 6 each) pts (100%) in P1 and 31/32 (97%) in P2 completed the study. Based on P1 safety data, a supratherapeutic dose of DAB 300 mg BID was selected for P2. A mean max double delta QTcF of 2.86 ms (90% CI, −1.36, 7.07) occurred on d8, 10 h postdose. Categorical analysis of max QTcF increases from baseline indicated a lack of Pbo and DAB outliers (increase > 60 ms, QTcF > 500 ms). DAB geometric mean Cmax and AUC(0-inf) on d1 after a single 300 mg dose were approximately 2-fold higher than previously seen for a single 150 mg dose. On d8, Cmax and AUC(0-τ) for 300 mg BID were approximately 2.7-fold higher than previously reported at steady state for 150 mg BID. DAB metabolites showed similar trends. ECG data were collected within the time window observed for Tmax for DAB (d1) and metabolites (hydroxy-DAB: d1; carboxy-DAB, desmethyl-DAB: d8). PK/PD modeling/simulation showed a mean QTc increase of < 5 ms (upper 90 % CI, < 10 ms). Most treatment-related toxicities for supratherapeutic DAB 300 mg BID were consistent with the known therapeutic (DAB 150 mg BID) safety profile. Conclusions: Repeat oral supratherapeutic dosing of DAB 300 mg BID had no clinically relevant effect on QTc interval. No new safety signals were seen. Clinical trial information: NCT01738451.
Abstract 20431: Portopulmonary Hypertension is Marked by Severely Diminished Circulating Bone Morphogenetic Protein 9
Authors: Ivana Nikolic, Lai-Ming Yung, Samuel D Paskin-Flerlage, Rajeev Malhotra, Anthony D Faugno, Carol S Lai, Paul D Upton, Peter ten Dijke, Nicholas W Morrell, Roham T Zamanian, Raymond Chung, C. Gregory Elliott, Richard W Channick, Kari E Roberts, Paul B Yu
Journal: Circulation (2016)

Abstract Background: Defects in bone morphogenetic protein (BMP) signaling contribute to the pathogenesis of pulmonary arterial hypertension (PAH). BMP9 is a circulating vascular endothelial quiesc...
Local ablative therapy (LAT) for oligoprogressive, <i>EGFR</i>-mutant, non-small cell lung cancer (NSCLC) after treatment with osimertinib.
Authors: Chul Kim, Nitin Roper, Chuong D. Hoang, Eva Szabo, Maureen Connolly, Emerson Padiernos, Aparna Hemant Kesarwala, Constance Cultraro, Maryam Waris, Shaojian Gao, Seth M. Steinberg, David T. Wong, Javed Khan, Arun Rajan, Udayan Guha
Journal: Journal of Clinical Oncology (2017)

e20545 Background: EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS) in patients with EGFR-mutant NSCLC, but disease progression limits efficacy. Retrospective studies show a survival benefit to LAT in patients with oligoprogressive disease (progression at a limited number of anatomic sites). Methods: This is a prospective study of LAT in patients with oligoprogressive EGFR-mutant NSCLC. Patients with no prior EGFR-TKI therapy (cohort 1) or progression after 1 st /2 nd generation EGFR-TKIs with acquired T790M mutation (cohort 2) receive osimertinib. Upon progression, eligible patients with &lt; = 5 progressing sites undergo LAT and resume osimertinib until disease progression. Patients previously treated with osimertinib qualifying for LAT upon disease progression are also eligible for treatment (cohort 3). Primary endpoint: evaluation of safety and efficacy of reinitiation of osimertinib after LAT (assessed by PFS). Additional goals are assessment of mechanisms of resistance to osimertinib by multi-omics analyses of tumor, blood, and saliva. Results: Between 04/2016 and 01/2017, 15 patients were enrolled (cohort 1: 9, cohort 2: 3, cohort 3: 3). Median age was 57 (range 36-71). Treatment was well tolerated. The most common adverse events (AEs) were rash, diarrhea, thrombocytopenia, and alanine transaminase elevation. Grade 3/4 AEs were observed in 4 (27%) patients. Among evaluable patients, objective response rates prior to LAT in cohorts 1 and 2 were 71% (5/7) and 100% (2/2), respectively, with 6.8 months median PFS (95% CI: 3.4 months-undefined) in cohort 1 and no progressions in cohort 2. To date, 5 patients (33%; cohort 1: 2; cohort 3: 3) had LAT. Two patients with 3 progressing sites underwent a combination of surgery and radiation. Three patients with 1 progressing site underwent surgery alone. Post-LAT PFS and results of molecular analyses will be presented. Conclusions: Patients with EGFR-mutant NSCLC and oligoprogression after EGFR-TKI therapy can be safely treated with LAT. In selected patients, this approach could potentially maximize duration of EGFR-TKI treatment and prevent premature switching to other systemic therapies. Clinical trial information: NCT02759835.
Profiling for microsatellite instability (MSI) and mismatch repair (MMR) among patients with colon cancer in real world settings.
Authors: Tracy Ann Proverbs-Singh, John Marshall, Marian M Varda, Ibrahim Nakhoul, Bhavesh Balar, Jin S. Lee, Philip Agop Philip, Andrew David Norden, Stuart L. Goldberg
Journal: Journal of Clinical Oncology (2018)

e15622 Background: National guidelines (NCCN 2016) recommend profiling for microsatellite instability (MSI) and mismatch repair (MMR) for all patients (pts) with colon cancer. Evaluations may identify pts with familial syndromes requiring surveillance. Profiling may assist in clinical decision making: MSI-High have a significantly better prognosis, stage II pts with defective MMR may not benefit from fluorouracil treatment, pts with defective MMR may harbor BRAF mutations, and advanced stage MSI-High pts may be candidates for immunotherapy. Adherence to testing guidelines is unknown. Methods: The Cota database aggregates detailed diagnostic, clinical, treatment, and outcome information from the electronic health records. Limitations of the database include failure to capture diagnostic tests not scanned into the EHR. Results: 1978 pts with colon cancer diagnosed Jan, 1, 2013 through Dec 31, 2017 from 22 institutions (treated by 173 oncologists) were retrospectively reviewed. 975 (49%) had documentation of immunohistochemical testing for an MMR protein and 343 (17%) had polymerase chain reaction based testing for MSI. (MMR testing by stage: I: 49%; II: 54%; III: 51%; IV: 49%). Testing rates before 2016 for MMR were 47%, which increased to 54% following guideline publication (p = 0.001). Academic centers tested at 67% (400/593) vs 41% (575/1385) in community cancer centers (p < 0.0001). The 18 oncologists evaluating ≥20 pts tested at 52% (422/805) vs 46% (424/925) for physicians with smaller practices. (p = 0.007). Defective MMR were noted in MSH2 5% (45/930), MSH6 5% (46/913), MLH1 16% (137/833), and PMS2 16% (132/821). Testing for BRAF was 14% in the series. Among pts with defective PMS2, 30% were tested for BRAF mutations and 44% were positive (vs 18% testing rate if PMS2 intact with 14% positive). MLH1 pts were BRAF tested 27% with 39% positive. Among the 387 Stage IV pts, 60% were tested for KRAS (37% positive) and 23% for NRAS (5% positive). Conclusions: Testing for MSI/MMR is below guideline recommendations, but is increasing and is higher at academic centers and by physicians with larger colon cancer populations. Given the implications of MSI/MMR educational efforts are needed.
Comparison of three leukapharesis machines for harvest of stem cells for autologous transplantation: A prospective study.
Authors: Rakesh Reddy, Atul Sharma, Sameer Bakhshi, Ajay Gogia, Ranjit Sahoo, Chander Prakash Yadav, Lalit Kumar
Journal: Journal of Clinical Oncology (2016)

8024 Background: Collection efficiency (CE) of an apharesis machine refers to the proportion of cells passing through it that is harvested. A higher collection efficiency reduces the need for repeated apharesis sessions and is a good measure for comparison of individual machines. Methods: Patients who underwent first harvest after G-CSF mobilization between Jan 2014 and Sept 2015 were included in the study. G-CSF was given at 10mcg/kg/day for 4 days and harvest was started from d5. Peripheral blood CD34 (PBCD34) counts were enumerated on d4. The 3 apharesis machines used were Haemonetics MCS+, Fresenius Com.Tec and Cobe Spectra. Standard volume apharesis (2-3 times patient blood volume) with recommended MNC protocols were employed. CE (as%) is calculated as total number of CD34+ cells collected×10-4 divided by D4-PBCD34/µL×blood vol. processed (lt). Oneway ANOVA with post hoc analysis was used to compare CE of individual machines. Simple logistic regression was used to look for peri-apharesis factors which could have influenced CE. Results: Of 141 patients, 94 had multiple myeloma, 16 were NHL, 15 were HL and 16 patients had other malignancies. Comparison of individual machines by CE was depicted in table. CE was significantly influenced by peri-apharesis factors such as circulating CD34+ cells (as assessed by D4-PBCD34 count), TLC and flow rate of the machine. CE had a inverse relation with all these factors. It remained unaffected by volume of blood processed. The mean time taken for harvest completion was higher for Haemonetics (326 min ±64) in comparison to both Fresenius (241 min±35; p<0.001) and Cobe Spectra (239 min±36; p<0.001). Conclusions: In terms of collection efficiency, the performance of Haemonetics MCS+ is better on comparison with both Cobe Spectra and Fresenius Com.Tec, though statistically significant in former. This benefit is offset by prolonged procedure time required for this machine. Machine Haemonetics MCS+ (n=36) Fresenius Com.Tec (n=51) Cobe Spectra (n=54) CE (Mean±SD) 43.3 (±19.1) 37.8 (±14.8) 31.7 (±14.3) Post hoc analysis Haemonetics vs Fresenius Fresenius vs Cobe Spectra Haemonetics vs Cobe Spectra Mean reduction in CE (p value) -5.5 (0.35) -6.1 (0.15) -11.6 (0.003)