tbuckley/cabot-search huggingface dataset:
Influence of deuterium-depleted water as a nutritive factor on the effectiveness of experimental chemotherapy in aging rats.
Authors: Alla I. Shikhlyarova, Galina V. Zhukova, Stepan S. Dzhimak, Mikhail G. Baryshev, Oleg I. Kit, Anna S. Goncharova, Elena A. Shirnina, Tatiana P. Protasova, Anastasia I. Zhadobina, Marina I. Bragina, Ekaterina A. Lukbanova
Journal: Journal of Clinical Oncology (2019)

e14683 Background: The rates of physical and chemical interactions are associated with water isotopic composition. The ability of deuterium-depleted water (DDW) to influence free radical, metabolic and regulatory processes determines the need to change the drinking diet at aging, tumor growth antitumor chemotherapy (CT). Our purpose was to study the influence of DDW on the state of aging female rats, tumor growth and the CT effectiveness. Methods: The study included 37 aging outbred white female rats (250-280 g) with transplanted sarcoma 45 (S-45) receiving chemotherapy with cyclophosphamide (CF). DDW intake (46±2 ppm, 25-30 mL a day) was started 5 weeks before S-45 transplantation. CF was administered intraperitoneally on day 10 at a dose of 50 mg/kg twice with a 5-day interval. We determined tumor volume by Shrek, deuterium concentrations in the blood plasma (NMR spectrometer JEOL JNM-ECA 400MHz) and inner organs (mass spectrometer DELTAplus H/Device, Finnigan, Germany), estrous cycle stages and types of the nonspecific adaptational reactions of organism by Garkavi-Kvakina-Ukolova (1975). Results: DDW administration before the tumor transplantation significantly balanced the stages of the estrous cycle and increased the incidences of the antistress adaptational reactions development by 1.6 times (p &lt; 0.05); external signs of rejuvenation were observed (changes in hair state and motor activity). After S-45 transplantation, its growth prior to CT was suppressed (tumor volume 0.25±0.07 cm 3 vs. 0.47±0.10 cm 3 in controls, p &lt; 0.1). DDW increased the effect of CF by 4.8 times by day 15 (0.88±0.67 cm 3 vs. 4.22±1.43 cm 3 with CF alone, p &lt; 0.05). Concentrations of deuterium in the blood plasma decreased by 33%, in the inner organs (liver, kidney and heart) – by 6-14% (p &lt; 0.05). Conclusions: DDW has an antistress, geroprotective , antitumor and CT-optimizing effect.
Proteogenomic characterization in glioblastoma multiforme.
Authors: Samia Asif, Rawish Fatima, Rebecca Krc, Joesph G. Bennett, Shahzad Raza
Journal: Journal of Clinical Oncology (2019)

e13521 Background: Glioblastoma (GBM) is an aggressive primary brain tumor carrying a dismal prognosis. Understanding molecular architecture of GBM is crucial for development of successful therapies against it. In this study, we performed an integrated proteogenomic analysis to determine a more comprehensive understanding of GBM phenotype. Methods: We performed quantitative proteomics and integrative genomic analysis based on The Cancer Genome Atlas (TCGA) datasets of GBM on 17 consecutive GBM patients. We collected information on driver mutations, oncogenes, major pathway alterations, mutation burden and molecular changes at both gene and protein level as well as clinical, treatment and survival data for the entire group. Results: Significantly mutated genes include TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR alterations by DNA amplification with multiple mutation allele frequencies were seen in 5(29.4%) patients including EGFRvIII expression, L816Q EGFR missense mutation on exon 21 and EGFR fusion (FGFR3-TACC3); all three are potential therapeutic targets of novel agents including EGFRvIII-specific dendritic cell vaccine, EGFR inhibitors and FGFR inhibitors. TP53 mutation was noticed in 30% of patients. TP53 Mutations were noticed in COSMIC hot spot driver gene and accompany IDH1 and ATRX mutations suggesting transformation from low to high-grade glioma. Only 1 patient had a high mutation burden and expired 17 months after initial diagnosis. In contrast, proteomics showed significantly high(n = 9,53%) EGFR expression. 75% of GBMs were MGMT methylated, a predictive marker of response to temozolomide. Twelve of the 17 patients are still alive; median overall survival was 16.5 months. Lowest survival observed was 5 months. Conclusions: This study identifies a distinct biological process that may characterize each glioblastoma differently. Proteogenomic data effectively recognizes potential therapeutic targets of GBM such as Exon 21 missense mutation, previously reported in lung adenocarcinoma with promising response to anti-EGFR antibodies. Incorporation of Whole Genome Sequencing into clinical practice will allow identification of new treatment options for GBM.
Safety of nivolumab and ipilimumab in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Jennifer Maria Johnson, Voichita Bar Ad, Emily Lorber, Dawn Poller, Adam Luginbuhl, Joseph M. Curry, David M. Cognetti, Scott W. Keith, Rita Susan Axelrod, Ralph Zinner, Ulrich Rodeck, Larry Harshyne, Athanassios Argiris
Journal: Journal of Clinical Oncology (2019)

6070 Background: Standard cisplatin-based chemoradiotherapy for LA SCCHN is associated with toxicity and less than desirable survival in high-risk patients (pts). The combination of the anti-PD1 antibody nivolumab (nivo) and the anti-CTLA-4 antibody ipilimumab (ipi) has been effective in melanoma and renal cell carcinoma and is under investigation in other solid tumors including SCCHN. Combining RT and immunotherapy (IO) has a strong preclinical rationale and is being evaluated in the clinic. This pilot trial combines IO and RT to build upon these observations. Methods: We enrolled previously untreated high-risk pts with AJCC 7 th edition stage IVA-IVB SCCHN of the oral cavity, oropharynx (OP), hypopharynx, larynx. HPV+ OP tumors were T4, or N2c or N3 by AJCC 7 th edition criteria. Nivo 3 mg/kg was administered every 2 weeks IV x 17 doses and ipi 1 mg/kg every 6 weeks x 6 doses beginning 2 weeks before IMRT 2 Gy/fraction/day given to total dose 70 Gy. The primary safety endpoint was acute in-field toxicity. Exploratory correlative studies include tumor PD-L1 expression, tumor immune bias, and exosome quantity and composition. The total sample size is 24 pts with 12 enrolled in the first stage and 12 in the expansion cohort. Results: A planned safety analysis was performed in the first 12 pts (8 OP; 1 hypopharynx; 3 larynx). No acute grade (G) 4 or dose-limiting toxicities were seen. Acute G 3 in-field toxicity occurred during RT in 50% of pts: dysphagia (4 pts), mucositis (3), odynophagia (2), hoarseness (1), dermatitis (1). 50% of pts had immune-related toxicity at any time. 3 pts discontinued treatment at &gt; 3 months post RT: 1 for an immune-related cause (G 3 colitis that resolved with steroids), and 2 for non-immune-related causes (1 G 5 bleeding due to carotid rupture secondary to an in-field ulcer at 4 months post RT in a pt with complete response and 1 G 3 OP ulcer resolving with hyperbaric oxygen). 1 pt with a laryngeal primary developed a solitary lung metastasis vs new primary 6 months post RT. 10 of 12 pts are alive with no evidence of disease (follow up 7.2-18.4 months). Conclusions: Preliminary results with this non-platinum-containing RT plus IO regimen are encouraging. Longer follow-up is needed for assessment of late effects and efficacy. Enrollment is ongoing in the expansion cohort. This study is supported by BMS. Clinical trial information: NCT03162731.
Developing an adolescent and young adult (AYA) cancer program in an Italian adult high-volume cancer center.
Authors: Alexia Bertuzzi, Andrea Marrari, Vittorio Quagliuolo, Ferdinando Cananzi, Umberto Cariboni, Cristina Specchia, Renato Bragato, Luca Balzarini, Marta Scorsetti, Pierina Navarria, Licia Siracusano, Emanuela Mencaglia, Elena Vicenzi, Antonino Spinelli, Armando Santoro
Journal: Journal of Clinical Oncology (2019)

e18034 Background: Given the lack of survival improvement and the several unmet clinical/psychosocial issues, programs for AYA (15 to 39 yo) are underway, involving local resources and organizations. Conventionally the healthcare system address inadequately the needs of AYAs. Humanitas Research Hospital is a high volume Cancer Center for adult patients with long lasting expertise in rare cancers based on a multidisciplinary approach. Methods: We conducted a retrospective evaluation of the number of patients followed in our Institute from 2010 to 2017 to assess our potential as an AYA referral center. In February 2017 we started a dedicated program, focused on medical and psychosocial issues of AYA and supported by an interdisciplinary team including medical oncologists, psychologists, surgeons, radiation oncologists, fertility experts, cardiologists, genetic consultants, endocrinologist, palliative care providers, social workers, and liason nurses . Results: From 2010 to 2017 more than 6600 AYA pts were seen in Humanitas. The epidemiology reflects the published data. Since the beginning of the program (February 2017), more than 2000 new AYA pts were referred to our dedicated clinic. Based on a patient-focused model of care, the aims of the first access are the comprehension of the complex pathways to diagnosis often delayed, the access to optimal care including clinical trial, the recognition of the unique psychosocial context, the counselling on key issues for AYA (fertility, cardiology, nutrition, smoking, financial). We created a dedicated physical space where pts, families and caregivers can spend time together, reducing the feeling of isolation. They meet also specialists trained to deal with their needs, to reduce the adverse impact of the diagnosis and to improve the adherence to treatment. Daily activities, such as cooking and photography class, professional writing and acting, are also offered. Conclusions: Humanitas AYA project modified the hospital environment making it more comfortable for our pts and improved the awareness of the healthcare providers to AYA unmet needs. Outcome and research program improvement are long-term endpoints to bridge the clinical gap of AYA pts.
Atezolizumab (atezo) + bevacizumab (bev) versus sunitinib (sun) in pts with untreated metastatic renal cell carcinoma (mRCC) and sarcomatoid (sarc) histology: IMmotion151 subgroup analysis.
Authors: Brian I. Rini, Robert J. Motzer, Thomas Powles, David F. McDermott, Bernard Escudier, Frede Donskov, Robert E. Hawkins, Sergio Bracarda, Jens Bedke, Ugo De Giorgi, Camillo Porta, Alain Ravaud, Francis Parnis, Enrique Grande, Wei Zhang, Mahrukh A. Huseni, Susheela Carroll, Roxana Ioana Sufan, Christina Schiff, Michael B. Atkins
Journal: Journal of Clinical Oncology (2019)

4512 Background: In the Phase 3 IMmotion151 trial, atezo + bev showed improved PFS vs sun in untreated mRCC pts expressing PD-L1. Here we report results of a prespecified subgroup analysis in pts whose tumors have sarc histology, an independent predictor of poor survival. Methods: Pts were randomized to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sun 50 mg po qd for 4w on, 2w off. Coprimary endpoints were reported previously (Motzer ASCO GU 2018). Secondary endpoints included INV-PFS and OS in sarc pts and are shown here with INV-ORR, safety, PRO and biomarker data. Results: 142 randomized pts (16%) from IMmotion151 had tumors with any component of sarc histology; mPFS was 8.3 vs 5.3 mo with atezo + bev vs sun and mOS was NR vs 15.0 mo, respectively (see Table for PD-L1+). ORR was 49% vs 14% and CR rate was 10% vs 3% in the atezo + bev vs sun arms. Grade 3-4 AEs occurred in 27 pts (40%) with atezo + bev and 34 (49%) with sun. Using the MDASI scale, sarc pts reported longer median time to deterioration (TTD) of symptom interference with daily activities with atezo + bev vs sun (11.3 vs 4.9 mo). Prevalence of Angiogenesis High gene expression (GE) signature subset was lower (34% vs 65%) and T-effector High GE subset was higher (54% vs 40%) in sarc vs non-sarc tumors. PD-L1+ disease was more common in sarc vs non-sarc tumors (63% vs 39%). Conclusions: mRCC pts with sarc histology had longer OS and PFS and a higher ORR/CR rate when treated with atezo + bev vs sun, regardless of PD-L1 status. Biomarker data support a biological correlate for the increased responsiveness to atezo + bev in sarc pts. Clinical trial information: NCT02420821. [Table: see text]
Patient and physician preferences for NIH PROMIS patient-reported outcome (PRO) domains in pancreatic ductal adenocarcinoma (PDA).
Authors: Michelle Guan, Gillian Gresham, Arvind Manohar Shinde, Veronica Placencio-Hickok, Jun Gong, Richard Tuli, Andrew Eugene Hendifar
Journal: Journal of Clinical Oncology (2019)

e15721 Background: PDA is associated with high symptom burden. However, treatment and palliation decisions currently weigh on physician interpretation of clinical parameters and may not consider patient values and preferences. The NIH PROMIS tool was created to capture various health domains through PROs. The objective of this study was to identify the most important PROMIS domains to PDA pts and physician providers. Methods: Using the 31 domains in NIH’s PROMIS, we conducted online surveys with PDA pts and PDA physicians from 17 academic centers. These domains are categorized into mental, physical, and social health. Values for the PRO domains were quantified using Maximum Differences Scaling (Sawtooth Software). Results: A total of 116 PDA pts (55% males, 45% females; median age: 68 years, range 42-95) and 33 physicians (78% males, 22% females; median years of experience: 15) completed the surveys. The top five domains identified by pts and providers are listed in the table. Physical functioning (PF), ability to perform activities of daily living (ADLs) and symptom management were among the top domains for both pts and physicians regardless of age, gender, resection status, or years of physician experience. However, social domains such as ability to do things for yourself, family, and friends, and interactions with family/friends were ranked significantly higher by pts versus pain, anxiety, and depression by physicians (p &lt; 0.01). Conclusions: Our findings suggest PDA pts value PF and engaging in work and social activities while physicians focus more on pain, depression, and symptom management. PROs need to become more important endpoints in clinical trials to better inform treatment decisions and develop therapies that address the health priorities of pts. [Table: see text]
Can steroid imbalance in intracrine synthesis of sex hormones in the lung be a pathognomonic factor of lung cancer?
Authors: Valeria A. Bandovkina, Oleg I. Kit, Elena M. Frantsiyants, Tamara G. Ayrapetova, Vladislav M. Legostaev, Oleg M. Babenkov, Anna V. Chubaryan, Maria G. Ilchenko, Elena I. Agarkova
Journal: Journal of Clinical Oncology (2019)

e20020 Background: Local imbalance of the main sex hormones can be detected in various malignancies. Recent studies confirm possible intracrine synthesis of steroid hormones by different tissues of the body, including the skin and lungs. The purpose of the study was to reveal changes in steroid balance in lung cancer (LC) patients of both genders. Methods: Estradiol (E2), testosterone (T) and progesterone (P4) were measured in 10% homogenates of tumors, perifocal tissues (p/t) and intact tissues of the lung by radioimmunoassay using Immunotech kits (Czech). The Е2/Т and Е2/Р4 coefficients were calculated. The study included 33 men and 22 women diagnosed with central and peripheral LC (adenocarcinoma, Т 2-3 N 0-1 M 0 ), mean age 62±3.4 years, all women were menopausal. The comparison group included non-cancer patients (13 men and 12 women) operated on for chronic inflammatory lung diseases. Results: Levels of E2 and T were increased in all studied samples in patients of both genders with central and peripheral LC, while P4 decreased in men and increased in women. It caused an imbalance of the main steroid groups: the E2T ratio in tumors, p/t and in distant tissues of men with central and peripheral LC on average more than 16 times exceeded that in the comparison group, and E2/P4 by 45, 61 and 38 times, respectively. E2/T in tissues of women with central LC was on average 6 times higher, and Е2/Р4 – 9 times higher than in the comparison group. In women with peripheral LC, steroidal imbalance was detected only in tumor samples, and E2/T and E2/P4 were 14 times higher than in the comparison group; samples of p/t and distant lung tissues did not show statistically significant differences. According to statistical data, peripheral adenocarcinomas are more common in women and are clinically characterized by a less aggressive course, compared to central LC. Conclusions: Patients with lung cancer demonstrated a local steroid imbalance with a marked prevalence of estrogens over androgens and progestins.
Efficacy of PD-1 monoclonal antibody SHR-1210 plus apatinib in patients with advanced nonsquamous NSCLC with wild‐type EGFR and ALK.
Authors: Caicun Zhou, Guanghui Gao, Yi Na Wang, Jun Zhao, Gongyan Chen, Zhihua Liu, Kangsheng Gu, Meijuan Huang, Jianxing He, Jianhua Chen, Zhiyong Ma, Ji Feng Feng, Jianhua Shi, Quanren Wang, Ying Yang, Xinmin Yu, Ying Cheng, Yu Yao, Shengxiang Ren
Journal: Journal of Clinical Oncology (2019)

9112 Background: Our preclinical study suggested combination of PD-1 monoclonal antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. This was an open-label, multi-center, phase 1/2 study of intravenous SHR-1210 plus oral apatinib in patients with advanced NSCLC. Here, we reported preliminary efficacy and safety outcomes of SHR-1210 plus apatinib in patients with wild‐type EGFR and ALK. Methods: In dose-escalation phase, advanced non-squamous NSCLC patients (pts) previously treated with at least 2nd line chemotherapy were enrolled to explore 2 dose levels of apatinib (250, 375mg/d) + SHR-1210 (200mg, q2w). 250mg/d of apatinib was selected to be combined with SHR-1210 in phase II trial. Pts previously treated with 1st line platinum-based chemotherapy were enrolled. Primary endpoint was ORR per RECIST 1.1. Archived or fresh tumor tissues and blood samples were taken before the treatment, PD-L1 expression and tumor mutation burden (TMB) were tested and correlated with efficacy. TMB was detected by Oseq-pan cancer panel (including 636 genes and 1.95Mb), and then calculated by in-house algorithm developed by BGI Genomics Co., Ltd. Results: 96 pts with advanced non-squamous NSCLC harboring wild‐type EGFR and ALK were recruited . 23 had ≥2 prior lines of systemic treatment, and 73 had 1 prior line of treatment. Median age was 57, male 79.8%, adenocarcinoma 93.9%, ex-smokers 56.7%. ORR and DCR in 91evaluable pts were 29.7% and 81.3%, respectively. Blood TMB (bTMB) test was available in 80/91 evaluable patients and the cut-point was 1.54 muts/Mb as determined by receiver operating characteristic curve. ORR in pts with high bTMB was 50% (19/38). At data cutoff of 20 Jan 2019, 20/27 responders were still on treatment (table). Across all 96pts, 54(56.2%) grade ≥3 TRAEs. AEs of grade ≥3 occurring in 2 or more pts included hypertension, hand-foot syndrome, gamma-glutamyl transferase increase, proteinuria, abnormal hepatic function and alkaline phosphatase increase. Conclusions: SHR-1210 plus apatinib demonstrated promising anti-tumor activity with acceptable safety in patients with non-squamous NSCLC, especially in those with high bTMB. Prospective study is needed to validate the clinical outcome and bTMB as a predictor of efficacy. Clinical trial information: NCT03083041. [Table: see text]
Decreasing postoperative opioid prescriptions in ambulatory extended recovery patients.
Authors: Nkechi Fearon, Gregory Thomas Chesnut, Nicole Benfante, Melissa Assel, Shirley Mauzoul, Marcia Levine, Vance Broach, Andrew Vickers, James Andrew Eastham, Rebecca Twersky, Brett A Simon, Vincent Paul Laudone
Journal: Journal of Clinical Oncology (2019)

6621 Background: Over-prescription of opioids after surgery contributes to the opioid abuse epidemic. Optimum post-operative opioid dosing is not defined. We evaluated prescribing patterns among different surgical services and created a standardized practice to reduce dispensation of unnecessary opioids. Methods: Opioid-naïve patients over 18 who underwent urologic, gynecologic, or breast surgery between March 2018 and January 2019 were eligible. A 4-month pre-intervention evaluation of number of opioid pills prescribed, number of pills taken, additional refills, and pain-control was obtained by contacting patients 7-10 days post-operatively. Findings were used to standardize prescriptions. Following implementation, patients undergoing surgery for the following 4-months were contacted to assess the impact of standardized opioid prescriptions. Data was compared with the institution’s electronic prescription system. Results: Pre-intervention, 368 eligible urology and gynecology patients (75.6%) responded and were prescribed between 6 and 40 opioid pills. Urology patients received median 28 (20, 30) tablets and 33% reported taking none. Gynecology patients received a median 20 (19, 28) tablets and 41% took none. Of 238 mastectomy patients, 176 (74%) reported taking median 3 and 4.9 of 20 prescribed opioid pills and 39% or 61% took no opioid pills (without vs with reconstruction). Prescriptions were standardized to 8, 7, and 10 tablets for urology, gynecology, and breast services. Post-intervention surveys revealed opioid tablets taken to be unchanged with minimal increase in refill requests. Conclusions: Prior to standardization, a large variation in opioids prescribed was observed. Standardizing opioid prescriptions resulted in fewer opioids dispensed without impacting pain control or refill requests.