tbuckley/cabot-search huggingface dataset:
P05.50 Hypofractionated stereotactic radiation therapy (HSRT) in skull base meningiomas
Authors: C Franzese, P Navarria, E Clerici, T Comito, F Pessina, L Bello, G Reggiori, S Tomatis, M Scorsetti
Journal: Neuro-Oncology (2018)

Skull base meningiomas, represent a subgroup of tumors in which a complete surgical removal is rarely achieved. Stereotactic radiotherapy, either as hypofractionated stereotactic radiotherapy (HSRT) or single dose radiosurgery, has emerged as a valuable first option in selected patients, or after incomplete surgical resection. Radiosurgery is used for small lesions away from critical structures. Limitations are represented from large meningioma, close to critical structures for the high risk of late toxicity and radionecrosis. To date few date are published about HSRT. Patients with large skull base meningioma has been treated with HSRT in our Institution. The aim of this evaluation has been to assess the impact of HSRT in term of local toxicity, patients symptoms relief and local control rate. This prospective observational study includes patients with MRI diagnosis of skull base meningioma. Patients underwent HSRT in case of one or more of the following: (1) large skull base meningioma, (2) proximity of critical structures, (3) growing residual tumor after surgery, (4) symptomatic patients (with stable and impairing symptoms since more than 3 months and requiring medications for their control), (5) contraindication to surgical resection. All patients were treated with a total dose of 30 Gy in 5 fractions. Treatments were optimized for Volumetric Modulated Arc therapy. Relief from symptoms, local control (LC), overall survival (OS) and toxicity rates were analyzed. Fifty-five patients were included in the study and treated with a dose of 30 Gy in 5 fractions with volumetric modulated arc therapy (RapidArc). Thirty-six patients were symptomatic before treatment. Tumors were located in anterior skull base in 8/55 cases, in middle skull base in 25/55 and in posterior skull base in 22/55. HSRT was performed as first treatment in 36 (65%) patients, in 19 (35%) patients it followed a previous partial resection. Median follow up was 48 months. Clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Out of the 36 symptomatic patients, partial remission occurred in 18 (50%) patients and complete remission in 18 (50%). All asymptomatic patients retained their status after treatment. No severe neurologic toxicity grade III-IV was recorded. No increase of meningioma in the same site of treatment occurred; 32 (62%) patients had stable disease and 18 (38%) patients had tumor reduction. The mean tumor volume after treatment was 10.8 ± 17.8 cm3 compared with 13.0 ± 19.1 cm3 before treatment (p = 0.02). The mean actuarial OS was 72 months. The 1- and 2-years OS was 92.9%. In our experience, HSRT with VMAT given at ablative doses has proven to be feasible with limited morbidity. Local control and durability of results suggest for a routine application of this approach in properly selected cases.
Abstract 14818: Impact of Hospital and Socio-demographic Factors on Utilization of Drug-eluting Stents in Medicare Patients: Bringing Clarity to Disparity
Authors: Tushar A Tuliani, Maithili H Shenoy, Milind Parikh, Diane Levine, Mauricio G Cohen, Cindy Grines, Anthony Hilliard
Journal: Circulation (2014)

Introduction: Studies perusing role of hospital & sociodemographic factors in disparities in drug eluting stent (DES) usage have shown insurance status to be a major predictor. Hypothesis: Do hospital & sociodemographic factors impact DES utilization in patients with Medicare? Methods: We linked data from the 2011 Medicare Inpatient Discharges (Top 100 DRGs), 2011 Medicare Hospital Referral Region (HRR) Report (to determine racial composition of each HRR) and American Hospital Association (to determine bedsize, location, ownership & teaching status). We analyzed stent DRG codes 249 (Bare Metal Stent without major complications or comorbidities [MCC]), 246 and 247 (DES with and without MCC respectively). HRRs were classified as African American (AA), Hispanic (H), White (W) and combined AA & H dominant areas. Using hospital zipcode household median income was determined from American Community Survey. Univariate & multivariate logistic regression were conducted to determine odds ratios for utilization of D...
Mutational load in tumors of African-American non-small cell lung cancer (NSCLC) patients.
Authors: Ann G. Schwartz, Greg Dyson, Manish K. Thakur, Chrissy Lusk, Angie Wenzlaff, Sneh Lata, Susan Land, Gerold Bepler, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2016)

8533 Background: Lung cancer is more common in African Americans (AA) and is associated with worse prognosis. Mutational load has been identified as a possible predictive marker for clinical benefit from anti-PD-1 drugs in NSCLC patients by Rizvi, et al (Science 2015), where the median number of non-synonymous mutations was 200. We assessed mutational load in tumors of AA patients and correlated it with clinical and demographic characteristics. Methods: Whole exome sequencing of both normal and tumor DNA utilizing the Illumina HiSeq 2500 instrument and the Illumina Exome Enrichment kit in a 12plex design was conducted on tumor tissues of 48 AA patients. Read mapping was done using Novoalign; variants were called using GATK and annotated using SnpEff. Variants included here were covered at a minimum depth of 50x in both normal and tumor samples. Results: The median age at diagnosis was 60 years; 54% were males, 94% were former or current smokers, 56% were stage I, 17% were stage II, 21% were stage III and 6% were stage IV. 71% of cases had a diagnosis of COPD. The median number of exonic mutations was 736 (range of 3–2249), while the median number of non-synonymous mutations was 340 (range of 0-947). Nonsynonymous mutational load (high vs. low, dichotomized at the median) was not associated with COPD status, after adjustment for age, pack years, family history of lung cancer and stage. However, stage was associated with nonsynonymous mutational load; specifically, the covariate-adjusted odds of a high mutational load for those diagnosed with later stage cancer (III/IV) were almost six times the odds of a high mutational load among those diagnosed with earlier stage cancer (I/II) (OR (95%CI) = 5.98 (1.42, 32.75), p = 0.022). Conclusions: Mutational load in tumors of AA NSCLC patients is higher than published data. Sources of variation may be attributable to both technical (calling algorithms, quality filters) and biological/clinical (race, stage) factors. Mutational load was associated with stage at diagnosis. Additional exome sequencing efforts are underway to evaluate mutational load by treatment response and driver mutation status, and to evaluate associations with outcome.
Combined Celiac Ganglia and Plexus Neurolysis Shortens Survival, Without Benefit, vs Plexus Neurolysis Alone
Authors: Michael J. Levy, Ferga C. Gleeson, Mark D. Topazian, Larissa L. Fujii-Lau, Felicity T. Enders, Joseph J. Larson, Kristin Mara, Barham K. Abu Dayyeh, Steven R. Alberts, Christopher L. Hallemeier, Prasad G. Iyer, Michael L. Kendrick, William D. Mauck, Randall K. Pearson, Bret T. Petersen, Elizabeth Rajan, Naoki Takahashi, Santhi S. Vege, Kenneth K. Wang, Suresh T. Chari
Journal: Clinical Gastroenterology and Hepatology (2018)
ASN003, a highly selective BRAF and PI3K inhibitor: Preclinical and phase 1 clinical data in patients with advanced solid tumors.
Authors: Drew W. Rasco, Ryan J. Sullivan, Nehal J. Lakhani, Sanjeeva Reddy, Niranjan Sathyanarayana Rao, Louis J. Denis, Anthony W. Tolcher, Keith Flaherty
Journal: Journal of Clinical Oncology (2017)

e14102 Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major signaling pathways involved in tumorigenesis. Components of these two pathways are frequently mutated in a broad range of tumors. ASN003 is a novel and highly selective small-molecule inhibitor of the RAS-RAF-MEK and PI3K pathways. Methods: The activity of ASN003 was determined using PI3K and BRAF enzymes, and efficacy was studied in human tumor xenograft models in mice. ASN003 is currently being investigated in patients with solid tumors in a Phase 1 trial using an accelerated dose titration design. In Part A, safety and tolerability of ASN003 is being studied in patients with advanced solid tumors. In Part B, safety, tolerability and preliminary efficacy of ASN003 will be evaluated in melanoma, CRC and NSCLC patients with a BRAF, PIK3CA or PTEN mutation. Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: ASN003 showed potent and highly selective inhibition of BRAF and PI3K-α and -δ, and low affinity for PI3K-ß. ASN003 showed strong antiproliferative activity in cell lines and caused significant tumor growth inhibition in xenograft models harboring BRAF and PIK3CA or PTEN mutations. ASN003 showed antiproliferative activity in B-RAF and MEK inhibitor resistant cell lines. ASN003 had a strong antitumor activity in a BRAF V600 mutant melanoma PDX model resistant to BRAF inhibitors, vemurafenib and dabrafenib. In humans, to date, ASN003 was well tolerated at 10 and 20 mg QD. Adverse events were mild and peak plasma level of 120 nM at 10 mg QD was achieved with a half-life of &gt; 12 h. Dose escalation is ongoing. Conclusions: ASN003 is a unique small molecule, with highly selective and potent inhibition of BRAF, PI3-α and -δ kinases. ASN003 has strong antitumor activity in various xenograft tumor models harboring both BRAF and PIK3CA/PTEN mutations, and in a BRAF inhibitor resistant melanoma PDX model. To date, ASN003 was well tolerated and achieved good systemic exposure. Updated and detailed clinical, PK and PD results will be presented. Clinical trial information: NCT02961283.
Clinical and immune effects of cetuximab and weekly low dose carboplatin and paclitaxel in head and neck cancer patients with poor performance status.
Authors: Marcelo Raul Bonomi, Brett Klamer, Tamjeed Ahmed, Safoa Ado, Mitra Kooshki, Jishu Das, Guy Brock, Triozzi Pierre
Journal: Journal of Clinical Oncology (2018)

e18005 Background: Patients with recurrent/ metastatic head and neck squamous cell carcinoma (HNSCC) with poor performance status (PS) have limited treatment options. Immune mechanisms are implicated in the antitumor activity of cetuximab. Low-dose chemotherapy can increase anti-tumor immune responses. Soluble program cell death 1 (sPD-L1) has shown to be a marker of immune exhaustion. Antitumor immune responses are regulated by microRNA (miR). In this study, the clinical and immune effects (sPD-L1 and miR levels) of cetuximab and low-dose chemotherapy were examined in patients with HNSCC with poor PS. Methods: Patients with recurrent/metastatic HNSCCC with an ECOG PS of 2 or 3 were treated with weekly cetuximab (400 mg/m2 followed by 250 mg/m2), carboplatin (AUC 1), and paclitaxel (25 mg/m2). sPD-L1 and seven immune-modulatory miRs (125b, 146a, 155, 181, 20a, 223 and 335) were measured in plasma before treatment, at week five, and at the time of tumor progression. Results: A total of 26 patients (M:18/F:8), 17 with a PS 2 and 9 with a PS 3, were enrolled and evaluable for response. Age: 62.5 (50-89). Six patients did manifest cetuximab hypersensitivity (23%). Dose-limiting hematologic toxicity was not observed. Partial response (PR) were observed in 14 (54%), stable disease (SD) in 3 (11%), and progressive disease (PD), in 9 (35%) patients. Median survival was 5.5 months (PR:9.9. SD:5.3, PD:3.9). Median survival was 6 months for PS 2 and 3.1 for PS 3 pts. Pre-treatment low plasma levels of sPD-L1 and high levels of miRs 20a and 335 showed a trend toward better overall survival (OS) (P = 0.17 and 0.16, Log-Rank Test). OS was not associated with miRs and SPD-L1 plasma levels at week five and/or at the time of disease progression. Conclusions: Weekly cetuximab and low-dose chemotherapy is active and well tolerated in HNSCC patients with poor PS. A larger cohort of patients is needed to assess the role of immune modulatory miRs and sPD-L1 as potential biomarkers.
Association of thrombocytosis with disease specific survival in women with uterine papillary serous carcinoma.
Authors: Margot Gardin, Dennis Yi-Shin Kuo, Abdissa Negassa, Xianhong Xie, Nicole Suzanne Nevadunsky
Journal: Journal of Clinical Oncology (2018)

e17561 Background: Thrombocytosis has been reported to be associated with decreased survival in many cancers including uterine and ovarian cancer. The purpose of this study was to evaluate the association between thrombocytosis and survival in a highly racially/ethnically diverse population of women with uterine papillary serous carcinoma. Methods: After IRB approval, the records of 324 women diagnosed with uterine papillary serous cancer from January 1999 until January 2016, were evaluated for demographic factors, dates of diagnosis and death, cancer staging, and hematologic parameters including platelets. Values were obtained within one month prior to the date of cancer staging. Thrombocytosis was defined as platelet levels ≥ 400,000 k/ul. Cox Proportional Hazard model was used to identify factors associated with disease specific survival . Results: Of 323 identified patients, 31(10%) had thrombocytosis at the time of diagnosis. Patients with thrombocytosis were younger, more likely to have stage 4 disease, and were less likely to be on statin or aspirin therapy (p < 0.05). Median follow-up time for the entire cohort was 2.73 years (range: 0.03 - 17.06). Kaplan Meier survival estimates demonstrated that thrombocytosis was associated with decreased overall survival compared to patients with normal platelet levels (log rank 0.04). By univariate Cox regression thrombocytosis was associated with an increased hazard of death (1.68, 1.01-2.8, p = 0.046), however in multivariable modeling stratified by stage only statin therapy was significantly associated with decreased hazard of death (0.59, 0.34-1.00 p = 0.05). Conclusions: In our racially/ethnically diverse population of women with uterine papillary serous cancer thrombocytosis was not independently associated with overall disease specific survival. Use of statin therapy was the only variable significantly associated with improved disease specific survival.
Phase 2 trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): Clinical outcomes and biomarker analyses.
Authors: Robin Kate Kelley, Emily Mitchell, Spencer Behr, Jimmy Hwang, Bridget Keenan, Sarah E Umetsu, John Dozier Gordan, Andrew H. Ko, Pelin Cinar, Chloe Evelyn Atreya, Katherine Van Loon, Thomas Weber, Zoe Ngo, Zoe E. Quandt, Chienying Liu, Alan P. Venook, Lawrence Fong
Journal: Journal of Clinical Oncology (2018)

4087 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. The combination of CPI plus the myeloid cytokine GM-CSF was safe with prolonged overall survival (OS) compared to CPI monotherapy in melanoma. This phase 2 trial evaluates the safety, efficacy, and biomarkers of PEM in combination with 2 cycles of low dose induction GM-CSF in ABC (NCT02703714). Methods: Design: Simon's 2-stage. Key eligibility: ABC after ≥ 1 standard therapy, no prior CPI, bilirubin ≤ 1.5xULN. Treatment: PEM 200 mg IV Q3 weeks plus GM-CSF 250 µg SC days 1-14 Q3 weeks for 2 cycles. Endpoints: 1◦: Overall response rate (ORR) by RECIST 1.1 with H0 5% vs. H1 20%. Key 2◦: Safety, progression-free survival at 6 months (PFS6), OS, tumor PD-L1 expression. Exploratory: CA 19-9 levels, tumor microsatellite (in)stability (MSI, MSS), tumor mutation burden (TMB), tumor and peripheral immune cell profiling. Results: Accrual has completed with 27 patients enrolled 5/2016-9/2017: Stage 1/2 9/18; F/M 13/14; median age 61; intra-/extra-hepatic 74%/26%; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6); MSI/MSS/unknown 1/19/7; TMB high+int./low/unknown 5/11/11. Adverse events (AE): Related ≥ grade (Gr)3 AE in 2 (7%) (1 each immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 fever); irAE requiring steroids in 3 (11%); endocrine irAE in 8 (30%). Disposition: 20 pts discontinued for PD, 1 for Gr2 irAE neuropathy/arthralgia, 1 for unrelated AE; 5 remain on treatment. Median cycles: 6 cycles (range 2-28+). ORR: Confirmed partial response (cPR) in 5 (19%) (95% CI: 3-34%) (1 MSI, 4 MSS); cPR or stable disease (SD) ≥ 6 months in 9 (33%). PFS6: 35% (95% CI: 15-54%); median OS: not reached. Endocrine irAE, CA 19-9 changes ≥ 50%, hepatitis C virus (HCV), and TMB were associated with efficacy in univariate analyses. PD-L1+ in ≥ 1% cells was present in 3/10 (30%) pre-treatment samples but was not associated with ORR or PFS6; additional PD-L1 results are pending. Conclusions: PEM plus induction GM-CSF is safe and well-tolerated in ABC. Prolonged responses and PFS in MSS ABC along with candidate biomarkers warrant further study in larger sample. Clinical trial information: NCT02703714).
Predictive value of hENT1 immunohistochemistry for gemcitabine-treated pancreatic cancer is antibody dependent.
Authors: Dimas Yusuf, Arthur Lui, Zainab Abdelaziz, Jennifer L. Spratlin, John Robert Mackey
Journal: Journal of Clinical Oncology (2017)

e15746 Background: Pancreatic cancer (PC) continues to have poor outcomes, and biomarkers to guide individualized therapy are needed. Gemcitabine (GEM), a pyrimidine nucleoside, requires plasma membrane transporter proteins to enter cells, and deficiency of the human equilibrative nucleoside transporter 1 (hENT1) protein confers high-level GEM resistance in pre-clinical models. Furthermore, abundance of hENT in PC cells, as determined by immunohistochemistry (IHC), has been variably reported to be associated with improved survival in people with PC treated with GEM. The antibodies (Abs) used for IHC differ in targeted epitope, method of generation, and species of origin. The purpose of this review is to evaluate the contribution of anti-hENT1 Ab choice in finding a link between hENT1 expression and outcomes. Methods: We reviewed the published literature investigating relationships between hENT1 IHC tumor expression and survival in people with PC treated with GEM. Results: Eighteen studies were identified, using five distinct Abs (Table 1). We identified apparent differences in predictive value among Abs (Chi square test p = 0.065). All seven studies using the 10D7G2 Ab reported that high hENT1 expression is associated with significantly better outcomes in GEM-treated patients. Studies that used other anti-hENT1 Abs, in particular SP120 and 11337-1-AP, had lower rates of success. Pooled HRs and additional metrics will be presented. Conclusions: There is significant heterogeneity among studies evaluating the link between hENT1 expression and outcomes. hENT1 IHC with the 10D7G2 Ab is a strong and reproducible predictive marker for improved survival in people with PC treated with GEM. [Table: see text]
P05.92 Brain invasion in meningiomas previously classified as WHO grade I has limited impact on outcome
Authors: A Biczok, B Suchorska, R Egensperger, J Tonn, C Schichor
Journal: Neuro-Oncology (2018)

For meningiomas, the 2016 revision of the WHO classification of tumors of the central nervous system introduced brain invasion per se as a sufficient condition to classify as grade II. We analyzed whether meningiomas previously graded as WHO grade I differ in prognosis according to the feature of brain invasion. All consecutive patients having been operated between 1/2009 and 03/2016 upon a meningioma being diagnosed as WHO grade I according to the previous (2007) WHO classification system were included. The reference point of the study was the date of surgery. Date of last follow up was 11/2017. Study endpoint was the date of tumor progression. Prognostic factors were obtained from multivariate proportional hazards models. 949 adult patients were included. The median follow-up was 43 months (range: 3–78 months). Gross total resection (GTR) was achieved in 719 (75.8%) patients, adjuvant radiotherapy was applied in 91 (9.9%) patients. Brain invasion was diagnosed by histology in 24 (2.5%) patients. Patients with/without brain invasion did not differ in terms of age and extent of resection. Patients with histologically proven brain invasion received more often adjuvant radiotherapy (p=0.008). 88 patients experienced tumor recurrence/ progression, overall survival was not reached in the majority of patients. The overall median PFS for patients with (without) brain invasion was 22 (23) months (p=0.48). In univariate and multivariate models subtotal resection and history of malignancy gained unfavorable prognostic influence for PFS (p<0.001). Brain invasion and radiotherapy were not associated with PFS. Among meningiomas classified as grade I according to the WHO 2007 grading system, histological proven brain invasion is a rare event. Extent of resection and history of malignancy was the most powerful prognostic factor. The sole factor of brain invasion seems to be of limited impact for prognosis and may not per se justify the application of adjuvant radiotherapy.
Temporal trends in overall survival and disease-specific survival among patients with advanced renal cell carcinoma during the targeted therapy era: A SEER-Medicare analysis.
Authors: Nicholas J. Vogelzang, James E. Signorovitch, Elyse Swallow, Miranda Peeples, Valerie Koo, Jose Ricardo Perez, Sameer Ghate, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2016)

e16096 Background: Over the past decade, targeted therapies (TT) replaced cytokines as the standard of care for patients with advanced renal cell carcinoma (aRCC). From 2005 to 2012, 7 TTs were approved as treatments for aRCC. This study assessed temporal trends in overall survival (OS) and disease-specific survival (DSS) among patients with aRCC during the TT era. Methods: Adult patients who first initiated a TT after RCC diagnosis were identified from the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database between January 1, 2006 (first Medicare Part D data availability) and December 31, 2012 (data cut-off). Patients had at least 6 months of continuous health plan enrollment prior to initiation of first TT (index date) and a known cause of death (if deceased). Index dates were used to stratify patients into early (2006-2009) and late (2010-2012) TT era cohorts. OS and DSS were defined as the time from index date to death from any cause and death from RCC, respectively. Patients were censored at end of health plan enrollment or end of data; in the DSS analysis, patients who died from a non-RCC cause were censored at the date of death. OS and DSS were compared between cohorts using Kaplan-Meier (KM) analysis and Cox proportional hazards models that adjusted for demographic and disease characteristics. Results: The early and late TT era cohorts included 604 and 641 patients, respectively. Baseline characteristics were similar across cohorts. In the unadjusted analyses, the late TT era cohort was associated with significantly longer OS and DSS relative to the early TT era cohort (median OS: 23.4 vs. 16.7 months; median DSS: 30.1 vs. 22.3 months, both p < 0.001). Similarly, in the adjusted analyses, both OS and DSS were significantly longer among patients in the late TT era cohort than those in the early TT era cohort (OS: hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.63-0.87; DSS: HR = 0.71, 95% CI: 0.59-0.86). Conclusions: This study using SEER-Medicare data showed improvement in OS and DSS from the early (2006-2009) to late (2010-2012) TT era among aRCC patients who used TT. These findings may suggest progress in the management of aRCC.