tbuckley/cabot-search huggingface dataset:
Association of NGS mutational pattern with immune checkpoint inhibitor clinical benefit in solid tumors.
Authors: Jacob Kaufman, Jill Duffy, Jia Xu, Claudia S. Huettner, Shang Xue, Vanessa Vincenzi Michelini, Stephen J Harvey, Christopher M Guertin, Bradley J Hintze, Neil L Spector, Michael J. Kelley
Journal: Journal of Clinical Oncology (2018)

e24274 Background: Immune checkpoint inhibitors (CPIs) induce prolonged tumor responses in a minority of patients with solid tumors including those with MSI-high, melanoma and NSCLC. Established predictive markers imperfectly identify patients most likely to respond. Multigene NGS testing has become widely available, including throughout the VA healthcare system, and may reveal associations with therapeutic benefit from CPIs. Methods: Patients who had NGS results from the VA Precision Oncology Program (POP) and were treated with a PD-1 or PD-L1 antibody were identified from VA POP and Corporate Data Warehouse databases. Clinical benefit (CB) was defined as having received CPI for ≥ 6 months vs no CB (NCB) completed < 6 mos of CPI. Pathogenic and likely pathogenic mutations of 18 individual genes, 4 composite pathways (MTOR/PI3K, MEK, PARP, CDK), MSI status, and a tumor molecular burden (TMB) algorithm were examined for association with CB using Fisher’s exact test. TMB was calculated based on the number of non-synonymous mutations after removing likely germline variants using 1% as a cutoff in any ethnic group in ExAC database. Results: Among 292 patients there were 22 tumor types (lung adeno 135, lung squamous 39, melanoma 25, unknown primary 19, H&N 15 NSCLC 14, other 45) who received one or more CPI (nivolumab 164, pembrolizumab 108, atezolizumab 12, > 1 CPI 8). 10 pts had > 1 NGS result. CB was seen in 94 and NCB in 113. Non-evaluable patients included 26 continuing CPI < 6 months and 59 treated for < 42 days. Only the presence of a PTEN mutation (PTENmut) was associated with CB: PTENmut 8 of 10 (80%) vs PTENwt 88/206 (43%) (p = 0.025; RR 0.35 (95% CI 0.10-1.21)). All PTENmut were also MSI-low and TMB-low. All 5 lung adeno with PTENmut had CB. Conclusions: In this real-world population of patients with solid tumors, PTEN mutation by NGS was associated with longer duration of treatment with CPIs. Further analysis, including PD-L1 IHC, is ongoing plus planned analysis in an independent validation cohort.
Clostridium difficile infection in acute myeloid leukemia patients.
Authors: Anjali Bal, Amy Morris, Mohammed Athar Naeem, Tanya Thomas, Michael Kenneth Keng
Journal: Journal of Clinical Oncology (2017)

e18503 Background: Clostridium difficile infection (CDI) is the most important cause of nosocomial infectious diarrhea. Studies suggest patients (pts) undergoing acute myeloid leukemia (AML) chemotherapy (ctx) are at high risk of contracting CDI, but clinical and disease characteristics are not described. This study reports CDI rates and disease characteristics in AML pts at University of Virginia (UVA). Methods: A retrospective review of consecutive pt-encounters undergoing AML ctx at UVA from 2011-2016 was conducted. The main endpoint was to determine the rate of CDI within 90 days of ctx initiation, while assessing pt characteristics, comorbidities, risk factors, and disease specific indices associated with CDI. Statistical methods include nonparametric Wilcoxon and Fisher’s exact tests, with significance defined as p-value &lt; 0.05. Results: Of 142 pts, 44 (31%) AML pts had CDI. 7 pts (15.9%) had 1 recurrent CDI episode,;2 pts (4.5%) had more than one. 18 pts (40.9%) underwent CT imaging specifically for CDI, revealing 3 pts (6.8%) with typhilitis and 2 pts (4.5%) with toxic megacolon requiring colectomy. There was no CDI associated mortality. At CDI diagnosis, 33 pts (75%) were neutropenic and 14 pts (31.8%) received prophylactic antibiotics. Median time from ctx was 12 days. Treatment for CDI: 38 pts (86.4%) single agent metronidazole or vancomycin and 6 pts (13.6%) combination. Sixteen (36.3%) CDI pts achieved CR, while 18 (40.9%) pts relapsed from AML. Compared to non-CDI pts, CDI pts were younger (50 v 59), less obese (BMI 26 v 29), poor-risk cytogenetics (26.5% v 14.1%), CKD (6.8% v 0.7%), prior cancer (6.8% v 2.8%). No statistical difference was seen in demographics (gender, race), comorbidities (tobacco use, pulmonary and cardiac disorders), or AML characteristics (bone marrow cellularity and blast, length of stay). Conclusions: The study concludes that the incidence of CDI in AML pts undergoing ctx is greater than hospitalized patients with or without malignancy as reported in the literature. CDI incidence is increased in younger, less obese, history of CKD or cancer, and poor-risk cytogenetics, suggesting potential predictive risk factors for CDI in AML pts. Further prospective studies are needed to confirm these potential CDI risk factors.
The effects of erythropoiesis-stimulating agents on the management of chemotherapy-induced anemia and tumor growth in diffuse large B-cell lymphoma patients.
Authors: Ho Sup Lee, Da Jung Kim, Lee Chun Park, Jee-yeong Jeong, Jae-Cheol Jo, Young Kwang Chae
Journal: Journal of Clinical Oncology (2018)

e19538 Background: Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (EPO) and novel erythropoiesis stimulating protein (NESP), may alleviate anemia in diffuse large B-cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously-administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy-related anemia in DLBCL patients. Methods: We examined EPOR expression in germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab-mediated complement-dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically-confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels < 10.0 g/dL after a maximum of 3 R-CHOP cycles o and received ≥4 doses of fixed-dose NESP (360 µg) once every 3 weeks. The primary endpoint was hematopoietic response (a hemoglobin increase of ≥2 g/dL from baseline or a hemoglobin increase to ≥12 g/dL). Results: EPOR mRNA was detected in all GCB-DLBCL cell lines, but little/none was detected in ABC-DLBCL cell lines. GCB-DLBCL and ABC-DLBCL cell proliferation was unaffected by EPO or NESP. Rituximab-mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dL; the overall mean change in hemoglobin was 1.59±1.3 g/dL (16 weeks). Forty-eight percent of enrolled patients achieved a hematopoietic response. Conclusions: In conclusion, our preclinical studies showed that the use of ESAs did not affect the growth of DLBCL cells. Additionally, in the clinical study, increased hemoglobin levels were observed without any significant toxicity. In real practice, the appropriate use of ESAs can be helpful for patients with CAA (hemoglobin levels of 8-10 g/dL) who have histologically-confirmed DLBCL and were treated with R-CHOP. Clinical trial information: NCT02890602.
The importance of body composition and physical function on overall survival (OS) in non-small cell lung cancer (NSCLC) patients receiving platinum based chemotherapy (PBCT).
Authors: Emily Kinsey, Elizabeth Ajazi, Xiaofei F. Wang, Mary Ann Johnston, Jeffrey Crawford
Journal: Journal of Clinical Oncology (2018)

e21088 Background: Body composition is an integral component of cachexia, which impacts function and treatment outcomes in patients with NSCLC. Our aim was to evaluate weight loss, lean body mass (LBM), and stair climb power (SCP) to determine if baseline or changes during treatment were prognostic for survival in lung cancer patients receiving chemotherapy. Methods: Power 1 and 2 were Phase III trials of NSCLC patients initiating PBCT to assess the efficacy of enobosarm for prevention and treatment of cachexia/muscle loss. We performed a secondary analysis of the placebo group (n = 322) using Cox regression models, after adjusting for other known risk factors, to determine if baseline weight, baseline LBM, or baseline SCP were prognostic for OS and if percent change of these variables after 4 cycles of PBCT was prognostic for survival past day 84. Results: In multivariate analyses after adjustment for stage, ECOG performance status (PS), gender, prior-treatment weight loss, age and tumor response (only for the day 84 analysis), the following variables were found to be significantly associated with survival (p < 0.05): SCP at baseline, LBM percent change during treatment, SCP percent change during treatment, and weight change during treatment. (See table) Conclusions: In patients with advanced NSCLC receiving PBCT, baseline SCP is a prognostic factor for survival after day 0 after adjusting other known risk factors; % change at day 84 in weight, LBM and SCP relative to baseline during treatment were prognostic for survival after day 84, even after adjusting for tumor response. Clinical trials of interventions to improve body composition and physical function in patients with advanced NSCLC are warranted, with survival as an endpoint. Clinical trial information: NCT01355484. HR 95% CI P value Baseline measure and survival after day 0 Weight baseline* 0.75 0.516-1.084 0.1246 LBM Baseline* 0.84 0.526-1.339 0.4616 SCP Baseline* 0.58 0.4-0.829 0.0030 % change at day 84 and survival after day 84 Weight % change# 0.69 0.548-0.859 0.0010 LBM % change# 0.68 0.528-0.865 0.0019 SCP % change# 0.83 0.697-0.987 0.0352
Impact of adjuvant chemotherapy on outcomes in stage IB non-small cell lung cancer.
Authors: Gaurav Goyal, Lata Nawal, K. M. Islam, Peter T. Silberstein, Apar Kishor Ganti
Journal: Journal of Clinical Oncology (2016)

e20002 Background: Adjuvant chemotherapy (ACT) has an established role in stage II and IIIA non-small cell lung cancer (NSCLC) to prevent disease recurrence. However, the role of ACT in stage IB NSCLC remains controversial. Two major meta-analyses demonstrated a non-significant improvement in overall survival (OS) with ACT use in this stage. We aim to assess the impact of ACT use on survival in stage IB NSCLC patients. Methods: This is a retrospective study of patients diagnosed with stage IB NSCLC from 2003 to 2012 in the National Cancer Data Base (NCDB). A Multivariate analysis was performed to compare surgery and ACT using Cox-proportional hazard method. A subgroup analysis of elderly patients (defined as > 70 years) was performed to assess impact of ACT use on OS in this age group. Results: A total of 71,160 patients were included in this analysis. Of these, 71% underwent surgery alone, and 14% received adjuvant chemotherapy. About 8% patients did not receive any therapy and the rest received other unspecified forms of treatment. On multivariate analysis, patients who received ACT had reduced risk of overall mortality as compared to patients who underwent surgery alone (HR 0.71, 95% CI, 0.69-0.73). Other factors that were associated with improved survival included female gender (HR 0.71, 95% CI, 0.69-0.73) and treatment at an academic center (HR-0.94; 95% CI, 0.92, 0.97). On the other hand, increasing age, uninsured or Medicare/Medicaid status, annual income <$38,000 and presence of comorbidities predicted for worse OS. A similar benefit with ACT use was seen on a subset analysis of 29,844 patients > 70 years (HR 0.79, P<0.0001). However, this age group had worse mortality as compared to patients aged ≤ 70 years (HR 1.44, P<0.0001; Table 1). Conclusions: Although ACT improves OS in stage IB NSCLC, including older patients (>70 years), only a small proportion of patients received adjuvant chemotherapy. Further investigations are needed to define indications for optimal ACT use. Impact of adjuvant chemotherapy (ACT) on stage IB NSCLC. Variables HR (95% CI) P-value Treatment type 1.00 Surgery only 0.78 (0.75, 0.80) <.0001 ACT Age ≤ 70 1.00 >70 1.44 (1.40, 1.48) <.0001 Subgroup age >70 years Treatment type Surgery only 1.00 ACT 0.79 (0.75, 0.83) <.0001
Prospection, Perseverance, and Insight in Sequential Behavior
Authors: Nils Kolling, Jacqueline Scholl, Adam Chekroud, Hailey A. Trier, Matthew F.S. Rushworth
Journal: Neuron (2018)

Real-world decisions have benefits occurring only later and dependent on additional decisions taken in the interim. We investigated this in a novel decision-making task in humans (n = 76) while measuring brain activity with fMRI (n = 24). Modeling revealed that participants computed the prospective value of decisions: they planned their future behavior taking into account how their decisions might affect which states they would encounter and how they themselves might respond in these states. They considered their own likely future behavioral biases (e.g., failure to adapt to changes in prospective value) and avoided situations in which they might be prone to such biases. Three neural networks in adjacent medial frontal regions were linked to distinct components of prospective decision making: activity in dorsal anterior cingulate cortex, area 8 m/9, and perigenual anterior cingulate cortex reflected prospective value, anticipated changes in prospective value, and the degree to which prospective value influenced decisions.
Overall survival (OS) of acute promyelocytic leukemia (APL) treated in academic (AC) versus non academic (NAC) centers.
Authors: Smith Giri, Kathan Mehta, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2016)

e18142 Background: Prior studies have shown better OS of cancer patients treated at AC as compared to NAC because of availability of expertise, adequately trained support staff and access to multidisciplinary care and better resources. We tested if academic status of the facility influences outcomes among patients with APL. Methods: We utilized National Cancer Database (NCDB) to extract patient-level data of patients with APL diagnosed between 1998 and 2011. Hospital facilities were classified to be either AC (academic/research program) or NAC (community cancer program, comprehensive community cancer program, and other, per NCDB classification). Only patients who had all of the first course treatment at the reporting facility were included in the study. Subjects with known data on age, sex, race, education, income, insurance, Charlson co-morbidity score, use and timing of chemotherapy, and follow up information were included. Multivariate analysis was done using logistic regression for 30-day mortality and Cox regression for OS. Results: Of 3385 patients with APL, 1831 (54%) underwent treatment at AC. Patients treated at AC differed from NAC in mean age (47 vs 49 years; p < 0.001), race (81% vs 87% whites, p < 0.001), education (p < 0.001) and insurance (p < 0.001) but were similar in terms of income (p = 0.18) and co-morbidity score (p = 0.79). A significantly better outcome was seen in AC compared to NAC in terms of 30-day mortality (22% vs 25%, p = 0.03), 1 year (83% vs 78%; p < 0.001) and 5 year OS (73% vs 70%; p < 0.001). Kaplan Meier Survival curves were significantly better for patients treated at AC as compared NAC (log rank test p value 0.01). OS was significantly worse in NAC as compared to AC (hazard ratio, HR 1.17; 95% CI 1.02-1.37; p = 0.03) after adjusting for covariates. Conclusions: Patients with APL treated at AC versus NAC have better OS. Understanding the underlying reasons may help to reduce the difference. Category HR (95% CI) P value Teaching status AC 1 NAC 1.17 (1.02-1.37) 0.03 Age (continuous) 1.03 (1.02-1.04) < 0.001 Gender Male 1 Female 0.80 (0.69-0.93) 0.003 Race White 1 Black 1.15 (.91-1.45) 0.2 Others 0.92 (0.63-1.33) 0.7 Charlson Index 0 1 1 1.76 (1.48-2.08) < 0.001 2 2.19 (1.75-2.77) < 0.001
Hormonal balance in preserved ovaries after combined treatment for cervical cancer.
Authors: Polina Kruze, Oleg Ivanovich Kit, Galina Andreevna Nerodo, Vera Nikitina, Anna A. Cherkasova, Ekaterina V. Verenikina, Olga Selezneva, Yuriy A. Poryvaev, Natalia V. Chernikova, Tatiyana Georgievna Chalabova, Ivan Nikitin
Journal: Journal of Clinical Oncology (2016)

e17028 Background: Treatment of patients of reproductive age with early cervical cancer stages supposes removal of intraoperatively preserved ovaries from irradiation zone to prevent radiation castration. The purpose of the study was to analyze duration of gonadal function after combined treatment. Methods: 176 women of reproductive age (20-45 years) with Ib stage cervical cancer (squamous cell carcinoma) underwent modified surgery allowing restoring of the ovaries into the small pelvis after radiation therapy and imitation of the ovarian ligament in order to prevent postovariectomy syndrome and radiation castration. At the moment of the result assessment, age of patients ranged from 25 to 56 years, with follow-up from 1 to 11 years. Levels of steroid and gonadotropic hormones were determined in blood plasma by the radio-immunological method during the period corresponding with the follicular phase. The results were compared to the data in healthy women of similar ages. Results: Patients under 45 years (n = 130, 74%) showed stable hormonal indices typical of the age; average levels of the follicle stimulating hormone and estradiol (E2) were 3.8 IU/L and 261 pmol/L, respectively. 46-50-year-old patients (n = 30, 17%): hormonal level in 16 women (9%) was similar to that in perimenopause – moderately increased FSH (10.3 IU/L) and normal estradiol (270 pmol/L) levels. In 14 women (8%), low estradiol content (110 pmol/L) was accompanied by a higher FSH level (28.5 IU/L), however still lower than postmenopausal one (43.25 IU/L), i.e., hormonal profile and ovarian characteristics were typical of follicular atresia-type menopause. Significant increase in FSH level with the median of 41.2 IU/L was observed in patients > 50 years that was an obvious postmenopausal criterion. Conclusions: FSH and estradiol undergo classical changes from levels typical of the reproductive age to premenopausal and then postmenopausal ones. Temporary removal of the ovaries from irradiation zone by our technique allows their normal function according to the patient’s age.
TCT-583 Final 5-Year Results in Unselected Patients Implanted With a Thin-Strut, Platinum-Chromium, Everolimus-Eluting Stent: The PROMUS Element Plus US Post-Approval Study
Authors: David Kandzari, Nima Amjadi Nima Amjadi, Christopher Caputo, Steven Rowe, Henry Chen, Jerome Williams, Hoshedar Tamboli, Thomas Christen, Dominic Allocco, Ian Meredith
Journal: Journal of the American College of Cardiology (2018)
Phase 1 open-label trial to evaluate the safety and immunogenicity of PAN-301-1, a novel nanoparticle therapeutic vaccine, in patients with biochemically relapsed prostate cancer.
Authors: Luke T. Nordquist, Neal D. Shore, James J. Elist, Jamie C. Oliver, William Gannon, Amir H. Shahlaee, Steven A. Fuller, Hossein A. Ghanbari
Journal: Journal of Clinical Oncology (2018)

e15166 Background: PAN-301-1 is a first-in-class therapeutic vaccine candidate targeting human aspartyl (asparaginyl) β-hydroxylase ((HAAH), or aspartate β-hydroxylase (ASPH)). HAAH is an enzyme which demonstrates functionality in fetal development, but is not normally detectable in adult tissues. HAAH is overexpressed and translated to the cell surface in nearly all cancers and is associated with cell growth, motility and invasiveness. PAN-301-1, consisting of inactivated λ-bacteriophage (nanoparticles) that express 200-300 copies of part of the HAAH molecule on the viral head, aims to overcome self-tolerance by this altered antigenic presentation and provide an immunostimulatory effect via phage DNA CpG motifs which activate the MHC class II pathway. Methods: PAN-301-1 was administered intradermally every 21 days in patients with biochemical (PSA) relapsed prostate cancer, using a traditional 3+3 dose-escalation (dose levels of 2E10, 1E11 and 3E11 particles, protein range: 3-40 µg) schema to establish the MTD or R2PD and to determine the DLTs associated with the vaccine. Each patient received ≥ 3 doses of vaccine. Secondary endpoints included safety and immunogenicity parameters as well as a clinical endpoint of assessing serum PSA kinetics. Results: A total of twelve patients received up to 18 doses of PAN-301-1 [median = 10 (3-18) doses/subject] over the 15 month duration of the study. All patients received a minimum of 3 immunizations at the highest dose. The vaccine was well tolerated with minimal adverse events and no DLTs observed at any of the three vaccine dose levels. All subjects experienced dose-dependent HAAH-specific immune responses, including antigen-specific antibody levels in immunoassays and HAAH-specific B-cell and T-cell responses. Of the patients treated at least 3 months, 75 % achieved a decline in PSA levels or a reduction in PSA doubling rate. Conclusions: PAN-301-1 is safe when administered intradermally at doses up to 3E11 particles, induces antigen-specific humoral and cellular immune responses and has provided preliminary indications of efficacy in the reduction of PSA or PSA doubling time. Clinical trial information: NCT03120832.
Recovery after long-term recurrent laryngeal nerve paralysis: Liberation surgical technique.
Authors: Radan Radoslav Dzodic, Nada Santrac, Ivan Markovic, Merima Goran, Marko Buta, Predrag Stankovic
Journal: Journal of Clinical Oncology (2018)

e18111 Background: Recurrent laryngeal nerve (RLN) injury is a major complication in thyroid surgery. It occurs more frequent during surgery of thyroid cancer and large goiters. The aim of this study was to show usefulness of RLN liberation technique for recovery after long-term RLN paralysis. Methods: From 2000 to 2017, we have operated on 19 patients with RLN paresis/paralysis on laryngoscopy. One patient, with large goiter, had RLN distended over the enlarged lobe and consequent paralysis. RLN was liberated from the lobe, back to the tracheoesophageal groove. In other 18 patients liberation was performed in a redo surgery 2 months to 16 years after RLN injury. This original technique consists of removing misplaced ligations, with nerve preservation. In two patients that had bilateral RLN paralysis, we performed a two-step surgery: 2 and 6 months after injury. Patient’s recovery was assessed by laryngoscopy and qualitative scoring scale (QSS) at 4 time points: preoperatively, in 1st, 6th and 12th postoperative month. Results: Indications for surgery were: thyroid cancer in 12, RLN repair in six, large goiter in one patient. 15 patients had score 4 on QSS. Three patients, who had liberation 6 months, 3 years and 16 years after the injury, had score 5 on QSS and restored vocal cord mobility, as well as the patient with surgery due to large goiter. Conclusions: RLN paralysis does not always have to be considered permanent. Some surgical techniques, like nerve liberations, along with phonorehabilitation, can be successfully used for recovery of RLN function after paralysis. It is even possible to achieve complete vocal cord mobility many years after RLN paralysis.