tbuckley/cabot-search huggingface dataset:
The impact of obesity on outcomes in metastatic melanoma (MM) patients (pts) treated with dabrafenib and trametinib.
Authors: Jennifer Leigh McQuade, Lauren Elaine Haydu, Silva Frankian, Christine Spencer, Georgina V. Long, Jean Jacques Grob, Stephen R. Lane, Philippe Legenne, Keith Flaherty, Patrick Hwu, Kenneth R. Hess, Michael A. Davies
Journal: Journal of Clinical Oncology (2016)

9566 Background: Obesity is associated with worse outcomes in many malignancies, and metabolic signaling pathways (i.e. IGF1R) promote resistance to MAPK pathway inhibitors in preclinical models. However, the impact of body mass index (BMI) on outcomes in mm pts treated with targeted therapies has not been systematically studied. Methods: We examined the association of BMI at treatment initiation with outcomes in two cohorts of BRAF-mutant mm pts treated with dabrafenib and trametinib (D+T): (1) pts treated in 3 prospective randomized clinical trials (n = 610); and (2) pts treated off-protocol at a single-institution (n = 80). Pts were categorized as underweight (UW; BMI < 18.5), normal (NL; 18.5-24.9), overweight (OW; 25-30), and obese (OB; ≥ 30). UW pts were excluded from comparisons due to low prevalence ( ≤ 3%) and possible cachexia. Kaplan-Meier analysis was used to estimate progression free (PFS) and overall survival (OS). Associations with covariates of interest was determined by Cox proportional hazards regression analysis. Results: In pts treated with D+T on-trial, OB pts had significantly improved PFS (HR 0.73, 95% CI: 0.58-0.95, p = 0.02) and OS (HR 0.63, 95% CI: 0.46-0.86, p = 0.004) compared to NL pts. Differences in PFS (p = 0.039) and OS (p = 0.0018) remained significant on multivariate analysis correcting for multiple prognostic factors (i.e. age, gender, performance status, stage, LDH, prior immunotherapy [IMT]). In D+T off-protocol pts there was a similar HR and a trend towards improved OS in OB compared to NL pts (HR 0.50, 95% CI: 0.2-1.0, p = 0.059), and there were no significant differences in stage, LDH, or prior IMT between OB and NL pts. Conclusions: Obesity is associated with improved outcomes in mm pts treated with D+T targeted therapy. Association of BMI with outcomes is currently being explored in other cohorts of melanoma pts, including mm pts treated with IMT and earlier stages of disease. Biological mechanisms underlying observed associations are also being investigated. Cohort Normal Overweight Obese D+T, On-trial N (%) 222 (36.4) 231 (37.9) 146 (23.9) Median PFS (mo) 9.6 11.0 15.7 Median OS (mo) 19.8 25.6 33.0 D+T, Off-protocol N (%) 18 (22.5) 27 (33.8) 33 (41.3) Median OS (mo) 13.6 10.5 24.3
What improves MD cancer screening recommendations?
Authors: James Austin Talcott, Maureen Bezuhly, Michael P. Osborne
Journal: Journal of Clinical Oncology (2018)

e13547 Background: Guidelines provide guidance but patient (PT) medical factors and preferences alter recommendations. We studied PT factors that alter the correct recommendation (CR) and physician (MD) advice in real-time cancer breast, colorectal, cervical, lung and prostate cancer screening discussions in a 2x2 cluster-randomized trial of MD educational supports. Methods: We enrolled an age- (30-49, 50-69, 70-89 years) and sex-stratified sample of 18 patients (PTs) who underwent a physical examination at 2 urban hospitals by each of 12 primary care MDs. We assigned screening guideline formatting (color-coding [CC]) and academic detailing (AD) to MDs randomly. Immediate post-encounter surveys recorded PT and MD recall of screening discussions. We classified recommendations (CR) conservatively. PSA screening recommendations were classified as incorrect only when against screening, for men too old ( > 75 yrs) or too young (African American [AA] < 40 or non-AA < 50). For other men, either was considered correct. MD-reported serious comorbidity or stated PT choice against screening were also valid reasons against. Results: Of the first 174 participants, 92 (53%) were male. Subjects were diverse (63% white) and highly educated (87% attended, 61% graduated college). Using age and race alone, 49% should not be PSA screened, increasing to 65% by adding comorbidity (1%) and PT choice (15%). By these criteria, MDs advised correctly in 91% of encounters. In univariate analysis, CC (p = 0.08) and shared decision making (SDM) but not AD, PT education and age tended to increase CR. Conclusions: In a highly educated, diverse patient population, including comorbidity and PT choice increased CR against screening by 16%. CC and SDM tended to increase CR. Simple supports and SDM may improve MD guideline recommendations. Clinical trial information: NCT02430948.
A phase I trial of panobinostat with ipilimumab in advanced melanoma.
Authors: Nikhil I. Khushalani, Joseph Markowitz, Zeynep Eroglu, Iulia Giuroiu, Viktoriya Ladanova, Pamela Reiersen, Jeani Rich, Ram Thapa, Michael J. Schell, Eduardo M. Sotomayor, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2017)

9547 Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of effector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, ↑ lipase, ↓ sodium, &amp; ↑ glucose (all n = 1). Three pts had previous anti-PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN &gt; 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study. Supported by grant P50 CA168536, Moffitt Skin Cancer SPORE. Clinical trial information: NCT02032810.
Novel orally bioavailable tubulin inhibitor VERU-111 to suppress ovarian tumor growth and metastasis.
Authors: Guannan Zhao
Journal: Journal of Clinical Oncology (2018)

e17538 Background: Metastatic ovarian cancer is the most lethal gynecological malignancy in women and chemotherapy is one of the standard treatment options.Though several FDA approved anti-tubulin agents, mainly taxanes, are included in the effective management of ovarian cancer, drug resistance to taxanes often develops with resulting disease progression. We recently discovered VERU-111, a new generation of tubulin inhibitor targeting the colchicine binding site, that shows high efficacy against a number of solid tumors. The current study aims to evaluate the preclinical efficacy of VERU-111 in ovarian cancer models. Methods: We determined the efficacy of VERU-111 in vitro using an orthotopic ovarian cancer mouse model. Two weeks after transplantation of SKOV3 cells into the left-side ovaries in NSG female mice, the mice were treated with vehicle or VERU-111 (10 mg/kg) orally 5 times per week for 4 weeks. To test the activity of VERU-111 in SKOV3 and OVCAR3 cells, we examined cell survival ability by performing colony formation assay. Cell migration and invasion were examined using a modified transwell chamber. Results: VERU-111 treatment significantly inhibited SKOV3 ovarian tumor growth and metastasis in major organs (liver and spleen) in vivo (Table 1). Upon VERU-111 treatment for 2 weeks at 10 nM or 30 nM concentration, cell growth in both SKOV3 and OVCAR3 were significantly reduced. Consistently, ovarian cancer cell migration and invasion abilities were substantially inhibited with 20 nM VERU-111 treatment in both SKOV3 and OVCAR3 cells. Conclusions: Our results showed that orally available VERU-111 effectively inhibited tumor growth and metastasis in orthotopic ovarian cancer mouse model without acute toxicity and reduced ovarian cancer cells survival, migration and invasion abilities. VERU-111 is a promising new generation of tubulin inhibitor for ovarian cancer treatment. A Phase 1/2 clinical trial of VERU-111 will begin later this year. Table 1. Catalog Vehicle VERU-111 %Inhibition (vs. control) %Increase (vs. control) Tumor weight 175.8±35.9 mg 24.4±7.2 mg 86.10 Mice weight alternation 1.86±0.65 g 2.46±1.32 g 70.96 Liver metastasized / tested mice 5/5 0/5 Spleen metastasized / tested mice 3/5 0/5
Soluble heregulin, HER3 ligand, to predict the efficacy of anti-HER3 antibody patritumab combination with erlotinib in randomized phase II study, HERALD, for non-small cell lung cancer.
Authors: Kimio Yonesaka, Kenji Hirotani, Joachim Von Pawel, Mircea Dediu, Shuquan Chen, Catherine Copigneaux, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2016)

9071 Background: Patritumab (P) is a fully human anti-HER3 antibody that blocks activation by the ligand, heregulin (HRG), inducing receptor internalization. Preclinical study observed its efficacy in non-small cell lung cancer (NSCLC) with high level of HRG expression (Yonesaka et al, ASCO2014). Phase II randomized, placebo-controlled double-blind study HERALD assessed the efficacy of low or high dose P combination with erlotinib (E) in NSCLC (von Pawel et al, ASCO2014). P + E could not detect PFS improvement compared with placebo (Pbo) + E in ITT population (n = 212). However, P + E significantly improved PFS in subgroup with high level of HRG mRNA. Currently, we examined whether soluble HRG (sHRG) level in serum could correlate with the efficacy of P + E. Methods: Serum was obtained from NSCLC subjects enrolled in HERALD study prior to treatment (n = 194). sHRG level in serum was measured by a validated quantitative immune assay, and blindly assessed about the correlation with survival. The hypothesis is subjects with high level of sHRG demonstrate an improved PFS when treated with P + E compared with Pbo + E. The cut off value was set at primarily third quarter in the blinded sample set. Estimates of the hazard ratio (HR) and the 95% confidence intervals (CIs) of pooled high and low dose P + E were calculated using a stratified Cox’s proportional hazards model. Results: sHRG was detectable in 36% of subjects (0-11772 pg/mL). PFS was significantly improved in the sHRG high subgroup ( > 980 pg/mL, n = 46) when treated with P + E compared with Pbo + E (HR 0.41 [0.18-0.90], p = 0.02). In contrast, the HRG low subgroup ( < 980 pg/ml, n = 148) showed no improvement in PFS (HR 1.05 [0.70-1.57], p = 0.82) with P + E. Further, elevated cutoff value improved HR (Table). Efficacy of P was independently predicted by sHRG compared to tumor HRG mRNA. Conclusions: P + E showed improved PFS in the HRG high subgroup, but not in the HRG low subgroup. Soluble HRG appears to be a predictive biomarker for P + E in NSCLC patients. Clinical trial information: NCT01211483.sHRG cut-off value (pg / mL) N HR for PFS p-value 0 66 0.58 0.08 980 (Q3) 46 0.41 0.02 1622.5 39 0.31 0.01 2000 34 0.28 0.008 3000 30 0.24 0.006 4000 27 0.26 0.01 5000 23 0.40 0.13
Genitourinary disease risks among 5-year ovarian cancer survivors in a population-based cohort study.
Authors: Mia Hashibe, Yuji Chen, Brenna Blackburn, Yuan Wan, Kerry G. Rowe, John Snyder, Vikrant Deshmukh, Michael Newman, Alison M Fraser, Theresa Louise Werner, Ken R Smith, David K. Gaffney, Jennifer Doherty, Patricia A. Ganz
Journal: Journal of Clinical Oncology (2017)

10073 Background: In the US, there are approximately 235,200 ovarian cancer survivors today. Five-year survival for ovarian cancer has increased from 36% for women who were diagnosed in 1975-1977 to 46% for women diagnosed between 2005-2011. Long term follow-up studies among ovarian cancer survivors are uncommon and late effects have not been well characterized in a population-based cohort. Although genitourinary complications during treatment are well known, long term impacts need to be investigated. Methods: A total of 602 first primary invasive ovarian cancer cases diagnosed between 1996-2012 who survived for &gt; 5 years were identified in the Utah Population Database and compared to a general population cohort of women. Genitourinary disease diagnoses were identified through ICD codes from hospital electronic medical records and statewide ambulatory surgery and inpatient data. Cox regression models were used to estimate hazard ratios for disease risks by time since cancer diagnosis with adjustments on matching factors, baseline BMI, baseline Charlson Comorbidity Index (CCI), and race. Results: The overall risk of genitourinary diseases for ovarian cancer patients in comparison to the general population cohort was 1.51 (95%CI = 1.30-1.74) 5-10 years after cancer diagnosis. Approximately 54.6% of ovarian cancer survivors were diagnosed with a genitourinary disease 5-10 years after cancer diagnosis. The most common genitourinary diseases among the ovarian cancer survivors were urinary tract infections (10.1%), acute renal failure (5.5%), and chronic kidney disease (4.4%). The greatest risks were observed for hydronephrosis (HR = 10.65, 95%CI = 3.68-30.80), pelvic peritoneal adhesions (HR = 5.81, 95%CI = 1.11-30.39), cystitis and urethritis (HR = 2.67, 95%CI = 1.21-6.38), and acute renal failure (HR = 2.30, 95%CI = 1.36-3.88). Conclusions: Ovarian cancer survivors experience increased risks of various genitourinary diseases in the 5-10 year period following cancer diagnosis. Understanding the multimorbidity trajectory among ovarian cancer survivors is of vital importance to improve their clinical care after cancer diagnosis and allow for increased attention to these potential late effects.
Obesity at diagnosis and after treatment in breast cancer survivors and risk of neuropathy.
Authors: Jennifer Y. Sheng, Sarah J Skuli, Elissa Thorner Bantug, Jagar Jasem, Nelli Zafman, Carol D. Riley, Jessica Ruck, Karen L. Smith, Claire Frances Snyder, Katherine Clegg Smith, Vered Stearns, Antonio C. Wolff
Journal: Journal of Clinical Oncology (2018)

e22085 Background: Guidelines recommend that breast cancer survivors maintain a healthy body weight as obesity (BMI≥30 kg/m2) predicts worse survival outcomes. We sought to identify patient characteristics, treatment factors and adverse effects associated with obesity in follow up of a cohort of women who had a survivorship transition visit (SV). We hypothesized that those who were obese at diagnosis had higher frequency of therapy-related complications at SV. Methods: Retrospective chart review of stage I-III breast cancer patients who had a SV after initial therapy for early stage breast cancer (ESBC). Data collected at the SV included demographics, tumor features, therapy, anxiety and depression measures and a symptom questionnaire. We collected follow up data on BMI and survival and are collecting measures of anxiety, depression and exercise. Univariate analyses identified variables associated with obesity at diagnosis, SV, and most recent visit, and logistic regression assessed associations between treatment modality and symptoms with obesity. Results: From 2010-2016, 87 women had a SV. At diagnosis, median BMI = 29 (IQR 24-32); 41% were obese. At median follow up of 42.4 months, 81 patients were alive and 47% obese. Compared to baseline, 56% of survivors had an increase in BMI. Women who were normal weight, overweight, and obese at diagnosis increased BMI by 0.74, 1.48, and 0.15 kg/m2, respectively. Compared to currently nonobese survivors, obese survivors were more likely to have had local and systemic therapy (E.g., surgery, radiation, chemo, and endocrine therapy [n = 42], OR = 10.5, 95% CI 1.13-107.18, p = 0.04). 94% of survivors who received chemo (n = 83) had a taxane and neuropathy was observed in 61 patients. When adjusted for diabetes, obesity at diagnosis was associated with peripheral neuropathy (OR = 5.33, 95%CI: 1.41-20.10, p = 0.01). Conclusions: Obesity at diagnosis is common in women with ESBC and BMI commonly increases in follow up. In this cohort, obesity at diagnosis was associated with subsequent neuropathy. If these findings are confirmed, weight control and physical activity interventions following diagnosis may improve cancer and non-cancer outcomes.
Improving safety and adherence of oral chemotherapy.
Authors: George Shahin, Adrian Reyes Bersabe, Clifton Patrick Layman
Journal: Journal of Clinical Oncology (2018)

253 Background: Oral chemotherapy (OC) has gained increasing popularity due to perceived advantages in convenience and toxicity profiles compared to conventional chemotherapy. Based on ASCO/ONS guidelines, we established standard operating procedures (SOPs) and a nurse-led oral chemotherapy clinic to guide the safe administration and monitoring of OC in our outpatient hematology/oncology clinic. Methods: A dedicated oral chemotherapy clinic led by a certified chemotherapy nurse was created to ensure standard metrics identified in the ASCO/ONS guidelines were met with each patient visit. Fifty-seven charts were randomly selected for a 3-month post intervention analysis. Results: The OC nurse identified toxicities in 17/57 (30%) of cases prompting notification of the ordering physician. This led to modifications in supportive medications in 9/17 (53%) of cases. Dose modifications occurred in 6/17 (35%). Informed consent documentation was available in only 36/57 (63%) charts. Necessary lab work was missing in 7/57 (12%) cases, prompting completion prior to OC release. An incorrect OC was dispensed by pharmacy in one case. Each visit took approximately 30 minutes from check-in to release of OC. All patients received OC education specific to their regimen. Conclusions: A dedicated visit with an OC nurse provided a vital means to ensure patient education, safe prescribing, proper dispensing, and monitoring of toxicities. Nursing identified the need for supportive care interventions and dose reductions in over 25% of charts which mitigated potential adverse events. Due to average time required for each patient encounter, we found this process to be unsustainable with increasing needs and limited resources. Thus, we revised our SOP to include a checklist of standard ASCO/ONS metrics. We also decreased the follow-up requirement for patients who did not require further intense monitoring after 6 months. Ongoing efforts will be made to ensure the effectiveness of this program. Future interventions will also capture cost effectiveness to establish a fair compensation model for reimbursement and justification of clinical support required to enforce current administration safety standards.
A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small cell lung cancer with wild type EGFR (OLCSG1202).
Authors: Akihiro Bessho, Nobuaki Ochi, Shoichi Kuyama, Nobukazu Fujimoto, Takahiro Umeno, Kiichiro Ninomiya, Genyo Ikeda, Daijiro Harada, Daizo Kishino, Shinobu Hosokawa, Kenichi Chikamori, Naoyuki Nogami, Shingo Harita, Hiroshi Ueoka, Katsuyuki Hotta, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2017)

e20614 Background: S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur, gimeracil, and oteracil potassium. Two phase III trials in advanced non-small cell lung cancer (NSCLC) showed the non-inferiority of combination of S-1 with carboplatin or cisplatin compared with standard platinum doublet chemotherapy. Although the S-1/platinum is one of the first line combinations for advanced NSCLC, efficacy and safety of the regimen in the elderly remain unknown. Methods: Patients were required to be previously untreated advanced NSCLC with wild-type EGFR, aged 70 or more, PS of 0-2. They received oral S-1 (40 mg/m 2 , twice daily) for 2 weeks and carboplatin (AUC 5 on day 1) every 4 weeks as an induction treatment. After 4 cycles of the induction, S-1 alone (40 mg/m 2 , twice daily for 2 weeks) was administrated every 4 weeks as a maintenance therapy until PD. Primary endpoint was overall response rate (ORR), which was expected more than 20%, and secondary endpoints included disease control rate (DCR), PFS, OS, and toxicity profile. The association between clinical outcomes and gene expressions including thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, orotate phosphoribosyl transferase, VEGF and ERCC1 in tumors was evaluated. Results: Thirty-three patients were enrolled between March 2013 and June 2015. Median age was 78 years old (range: 70 – 89), and 51.5% had a PS of 0. ORR was 30.3% (95% CI: 14.6 – 46.0%) and DCR was 57.6% (95% CI: 40.7 – 74.4%). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%) and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. Median PFS and OS times were 134 days (95% CI: 79 – 173) and 479 days (95% CI: 250 – 571), respectively. Low thymidine phosphorylase expression was associated with DCR (P &lt; 0.01). Conclusions: Carboplatin plus S-1 showed preferable efficacy and tolerable toxicity for elderly with NSCLC. (Clinical trial number: UMIN000009345) Clinical trial information: 9345.
TCT-560 Sympathetic Renal Denervation After Acute Myocardial Infarction Results in Increased Myocardial Salvage in Pigs
Authors: Luigi Emilio Pastormerlo, Marco Ciardetti, Silvia Burchielli, Chrysantos Grigoratos, Giovanni Acquaro, Eleonora Benelli, Sergio Berti, Michele Emdin
Journal: Journal of the American College of Cardiology (2018)
Abstract IA22: Targeting tumor-infiltrating myeloid cells for prostate cancer therapy
Authors: Andrea Alimonti
Journal: Cancer Research (2018)

Abstract Prostate cancer cells are surrounded by a complex tumor microenvironment that controls prostate cancer progression and treatment resistance. We are interested in understanding the liaison between tumor-infiltrating myeloid cells and prostate cancer cells to identify new molecular mechanisms that regulate cancer progression and the emergence of castration-resistant prostate cancer (CRPC). We have previously demonstrated that myeloid-derived suppressor cells (MDSCs) trigger senescence evasion and immunosuppression in primary prostate cancers, eventually promoting tumor progression. These studies have provided the rationale to develop in the clinic novel immune therapies targeting MDSCs for the therapy of metastatic prostate cancer patients. I will present recent results on additional tumor-promoting functions played by MDSCs and tumor-associated macrophages (TAMs) in prostate cancer, and I will discuss new therapeutic strategies that combine the use of immunotherapy with androgen deprivation therapy for the treatment of CRPC Citation Format: Andrea Alimonti. Targeting tumor-infiltrating myeloid cells for prostate cancer therapy [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA22.