bluuebunny/crossref_metadata_2025_split huggingface dataset:
A validation study of graded prognostic assessment index for lung cancer patients with brain metastases.
Authors: Du Lingling , Alva Venur Vyshak , Dahiya Saurabh , Garje Rohan , Osei-Boateng Kwabena , Elson Paul , Suh John H. , Chao Samuel T. , Ahluwalia Manmeet Singh 
Published: March 2020

2070 Background: The Graded Prognostic Assessment (GPA) is a commonly used index based on 5 prior randomized trials performed by the RTOG (Protocols 7916, 8528, 8905, 9104, and 9508). The purpose of this study was to validate GPA index in a recent cohort of lung cancer patients with brain metastases (LBM) at a larger tertiary care center. Methods: Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database was used to identify LBM treated in the recent era (2000-12). A proportional hazards model was used to assess overall survival (OS), measured from the date of diagnosis of brain metastases to death or last follow-up. Results: 490 LBM (250 males) median age 61 years (range 35-86) were included. Histology included small cell (64, 13%) adenocarcinoma (289, 59%), squamous (53, 11%), large cell (26, 5%) and unknown (55, 11%). The median number of brain metastases was 1 (range, 1-47). Karnofsky Performance Scale (KPS) was 90-100 in 187 (41%), 70-80 in 238 (52%) and <70 in 33 (7%). Extracranial Metastases was present in 327 patients (67%). OS was 14.1 months (95% C.I. 12.3-15.7). GPA for lung cancer is derived from KPS, the number of brain mets, the presence/absence of extracranial metastases, and age. GPA was 0-1.0 in 83 patients, 1.5-2 in 211, 2.5-3 in 135 and 3.5-4 in 18 patients. Although overall GPA was prognostic for survival (p<.0001), not all of the factors used to derive it were significant (Table). Factors noted to be prognostic for survival included primary controlled (p=<.0001), squamous cell histology (p=.0001), age (p=.0002), KPS (p=.0002). The new index divided the patients into unfavorable, intermediate, favorable that was prognostic for survival in this cohort (p<.0001). Conclusions: New index developed based on a revised set of independent prognostic factors (primary controlled, squamous cell histology, age and performance status) is proposed. [Table: see text]
Tumor perfusion during bevacizumab and irinotecan in recurrent glioblastoma: A multimodal approach.
Authors: Eoli Marica , Di Stefano Anna Luisa , Aquino Domenico , Scotti Alessandro , Anghileri Elena , Cuppini Lucia , Prodi Elena , Finocchiaro Gaetano , Bruzzone Maria Grazia 
Published: March 2020

2074 Background: Angiogenesis is a requirement for progression of glioblastoma (GBM) and vascular endothelial growth factor (VEGF) is a mediator of neo-angiogenesis in this tumor. Bevacizumab (Bev), an antibody directed to VEGF, was recently used to treat GBM. However in vivo modifications induced by treatment are still not clearly understood. Aim of this study is to analyze tumor changes induced by Irinotecan (Ir) and Bev, using two different methodologies: relative CBV variation (rCBV) and Difference Perfusion Maps (DPMs). Methods: 42 recurrent GBM patients underwent Bev (10 mg/kg) and Ir (125 or 340 mg/m2) treatment every 2 weeks and were followed up with a radiological protocol, including Dynamic Susceptibility Contrast MRI every 8 weeks. Radiological responses were assessed based on RANO criteria (Wen et al, 2012). Two methods were used to assess perfusion changes. In method A, relative CBV variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. In method B, relative CBV variations with respect to baseline values were calculated into the evolving tumour region by means of a voxel-by-voxel difference. DPMs were created showing where rCBV significantly increased, decreased or remained unchanged. Results: After a median follow-up of 33.5 months median overall survival (OS) was 35.0 weeks and median progression free survival (PFS) was 20.0 weeks. Method A showed a significant decrease of rCBV for patients with stable disease or partial response after 8 weeks of treatment (p = 0.01) while progressing patients maintained elevated levels of rCBV (p = 0.38). Method B, based on DPMs, showed that patients presenting rCBV increase higher than 25° percentile (corresponding to rCBV increase higher than 18% of tumor volume) had a significantly longer PFS (p = 0.045) and OS (p = 0.016). Conclusions: Using DPM we observed that early increase in global perfusion is related to better survival. This may suggest that Bev, when effective, reduces blood-brain barrier permeability with a higher contrast retention in vessels. If confirmed by further studies this measure could be useful in identifying responders to Bev.
Recurrent glioblastoma: Stratification of patient survival using tumor volume before and after antiangiogenic treatment.
Authors: Huang Raymond , Rahman Rifaquat , Hamdan Alhafidz , Kane Caroline , Chen Christina , Norden Andrew David , Reardon David A. , Mukundan Srinivasan , Wen Patrick Y. 
Published: March 2020

2075 Background: Although antiangiogenic therapies can induce a dramatic clinical and imaging response in patients with recurrent glioblastoma, their benefit on overall survival is less pronounced. We assessed whether tumor volume based on magnetic resonance imaging (MRI) before and after treatment with bevacizumab can stratify patients in terms of progression-free survival (PFS) and overall survival (OS). Methods: Baseline and post-treatment MRI scans of 93 patients with recurrent glioblastoma treated with bevacizumab were evaluated for volume of the enhancing tumor, as well as volume of the T2/FLAIR hyperintensity. The Cox proportional hazards model was used in univariate and multivariate settings to identify volume parameters prognostic and predictive for PFS and OS. Results: Our results show that baseline enhancing tumor volume were predictive of PFS (p = 0.047) and OS (p = 0.011). Specifically, patients with pretreatment enhancing tumor volume less than 18 cm3 have a median OS of 45 weeks, while patients with tumor volume greater than 18 cm3 have a median OS of 26 weeks. In addition, enhancing tumor volume 3 to 6 weeks after treatment, as well as percentage change in volume, are independent predictors of PFS and OS. Neither T2/FLAIR volume nor percentage change in T2/FLAIR volume was associated with survival. Conclusions: These results indicate that measurement of enhancing tumor volume can help identify patients more likely to benefit from bevacizumab therapy.
The prognostic value of cognition in patients with glioblastoma multiforme.
Authors: Flechl Birgit , Sax Cornelia , Ackerl Michael , Crevenna Richard , Gaiger Alexander , Dieckmann Karin , Widhalm Georg , Marosi Christine 
Published: March 2020

2078 Background: In patients with glioblastoma multiforme (GBM) progressive disease leads sooner or later to cognitive decline. In this study we evaluated if two cognitive assessments performed early in the treatment course have a prognostic significance for predicting progression free survival (PFS). Methods: We assessed the cognition of 35 patients with GBM using the program NeuroCogFX with four subscales: working memory, attention, verbal and figural memory and verbal fluency. Baseline evaluation was done at initiation of radiotherapy (11-57 days after diagnosis) and second evaluation three months later (82-117 days after baseline). Results in subscales were categorized in “declined”, “stable” and “improved”. Tumor progression was based on MRI scans. Results: The patients (12 women, 23 men) were in median 54 years old (21-75 years). The majority (61%) showed stable cognitive results, 22% improved and 14% decreased in the summary scale of cognition. The median PFS was 11 months (2.6-27.4 months). An improvement of attention correlated significantly with longer PFS (p = 0.015) whereas the other three cognitive subscales were not associated with PFS. Conclusions: The present study shows evidence, that an increase or decrease of attention scales measured within the first 5 months of disease has prognostic value for PFS.
Descriptive epidemiology of meningiomas in the United States.
Authors: Villano John L. , Anderson Stephen Todd , Dolecek Therese A. 
Published: March 2020

2099 Background: Although meningioma is the most common tumor in the central nervous system (CNS), the incidence, epidemiology, and clinical outcomes have historically been poorly defined. Our analysis follows the implementation of Public Law 107–260, the Benign Brain Tumor Cancer Registries Act mandating collection of non-malignant meningiomas. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on cases diagnosed during 2004-2009 with meningioma (ICD-O-3 histology codes 9530-9534 & 9537-9539) in brain or CNS primary site (C70.0-72.9, 75.1-75.3 ) were analyzed. Population-based statistics were generated using SEER*Stat 8.0.1 software. Results: A total of 35,302 cases (34,718 non-malignant; 584 malignant) were available providing a rate of 7.18/100,000, with meningioma, NOS (9530/0) the most common histology. Rates increased with age (0.13/100,000, 0-19 years; 37.78/100,000, 75+ years). The annual percentage change in incidence rates showed a statistically significant increase of 2.57% over 2004-2009. Significant increases were also observed for males, females, whites, blacks, non-Hispanics, and older age groups. The gender ratio M:F was 0.35 in the 0-49 age group and 0.48 in the 50+ age. Primary site location included cerebral meninges (83%) with almost 5% in the spinal meninges. 51% of cases were diagnosed pathologically versus imaging. However, diagnosis among 85% of spinal cases was surgically based. Older age and females were less likely to have a surgical diagnosis. 3.4% received radiation therapy (RT) with 97% receiving RT following surgery. For grade III or malignant cases, 22% received RT, and in grade 1 and 2 nearly 97% of cases did not receive RT, with older age groups less likely to receive RT. Overall survival was high, except for grade 3 or malignant cases where 5 year relative survival was 61.7%. Conclusions: Our analysis following Public Law 107–260 demonstrates an increasing incidence of meningiomas and provides new information, including a decrease in the gender difference with age. Clinical diagnosis is common and higher in women and older adults. Use of RT is low, even in malignant meningiomas, and employed following surgery. These observations were similar for white and black cases.
Diffuse intrinsic pontine gliomas (DIPG) in adolescents can have differing presentations but similar outcomes compared to those of middle childhood.
Authors: Warren Katherine E. , Jacoby Elad , Fangusaro Jason R. 
Published: March 2020

2101 Background: DIPG are invasive, treatment-resistant, brainstem tumors that generally affect children in middle childhood. The triad of cranial neuropathies, long tract signs, and ataxia are characteristic presenting signs; most patients have a short history of symptoms. Median survival is less than one year, but young children (<3 years) and adults with DIPG may have a better prognosis. Other positive clinical prognostic factors include longer duration of symptoms and absence of cranial neuropathies. We assessed the presentation and outcome of adolescents with DIPG. Methods: Patients were enrolled on an IRB-approved protocol. Clinical data for patients age>10 years and <20 years with a diagnosis of DIPG who were evaluated and treated at the authors’ institutions were reviewed. Results: A total of 46 patients were identified. M:F was 0.77:1. Median age at diagnosis was 13 (range 10-20) yrs. Frequent presenting symptoms included headache (39 %), dizziness (25%), diplopia (27%) and cranial neuropathies (27%). Two were diagnosed as incidental findings. The interval between onset of symptoms and diagnosis ranged from 2 days-5 years, and only 9 of 41 patients (22%) reported symptom duration of less than 2 weeks. The majority (39/42) received radiation therapy, with or without adjuvant chemotherapy. Of patients for whom data is available, 8/22 (36%) did not improve or worsened during radiation therapy and 17 of 27 (63%) remained on steroids at the end of radiation. Two patients are alive with stable disease and 1 is actively receiving initial treatment. Of the patients with progressive disease for whom data is available (n=32), median time to progression was 8 mo (range 2 mo-2.5 yrs). Conclusions: Presenting symptoms of DIPG in adolescents commonly include headache, dizziness and diplopia for several weeks-months. Although the vast majority are treated with radiation therapy, clinical benefit was not observed in a significant number of patients. Overall outcome is similar to those patients diagnosed in middle childhood rather than the adult population.
A phase I study of the safety and pharmacokinetics of DNIB0600A, an anti-NaPi2b antibody-drug-conjugate (ADC), in patients (pts) with non− small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (OC).
Authors: Gordon Michael S. , Gerber David E. , Infante Jeffrey R. , Xu Jian , Shames David S. , Choi Younjeong , Kahn Robert S. , Lin Kedan , Wood Katie , Maslyar Daniel J. , Burris Howard A. 
Published: March 2020

2507 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.
Predictive value of phase I trials for safety and final approved dose in later trials: Analysis of 33,845 patients.
Authors: Fontes Jardim Denis Leonardo , Hess Kenneth R. , LoRusso Patricia , Kurzrock Razelle , Hong David S. 
Published: March 2020

2509 Background: Phase I trials (Ph1) use data efficiently from a small number of patients (pts) to define a maximum tolerated dose (MTD) and the safety profile of new agents. It is unclear how well these trials perform in predicting the future approved dose of agents and in assuring the safety of pts in later trials. Here we compared data obtained from Ph1 and registration trials of the respective agents. Methods: We searched the US Food and Drug Administration (FDA) website for drugs approved in non-pediatric cancers between Jan. 1990 and Oct. 2012. Recommended phase II dose (R2PD), dose-limiting toxicities (DLTs) and grade (G) 3 and 4 adverse events from Ph1 were compared with doses and safety in later trials listed on updated package inserts. Proportions from independent groups were compared using the chi-squared test. Multiple logistic regression analysis adjusted these comparisons for potentially confounding factors. Results: A total of 78 Ph1 (3,499 pts) and 88 later trials (33,845 pts) were included. In 60% (n=50) of 84 matched trials in the dose comparison analysis, the dose from the later trial was the RP2D (often derived from the MTD) from a Ph1. In a multivariable analysis, Ph1 of oral drugs were more predictive of the final approved dose (78% adopting the RP2D oral vs. 43% IV drugs, p=0.011). Other Ph1 characteristics (number of pts, dose levels and tumor type) had no influence on the odds of adopting the RP2D. 55% of phase I DLTs were among the 4 most frequent high-grade events in later trials, with a higher frequency for DLTs of cytotoxic agents (p=0.061). Of the 525 clinically significant toxicities in later trials, 70% (n=369) were described in Ph1. There was a clear relationship (p=0.0032) between increasing the number of pts in the Ph1 (up to 60) and the ability to describe future clinically relevant side effects. Among 28,597 pts in later trials with available data the death rate that was possibly related to drug was 1.48%. Conclusions: Dosing based on Ph1 was associated with a low toxicity-related death rate on later trials. The ability to predict clinically significant toxicities correlates with the number of pts on the initial Ph1. However, the final dose in later trials was the exact RP2D of the Ph1 in only 60% of cases.
Integrated genomics and avatar mouse models for personalized cancer treatment.
Authors: Garralda Elena , Paz Keren , López-Casas Pedro P. , Jones Siân , Katz Amanda , Kann Lisa M. , López-Ríos Fernando , Sarno Francesca , Al-Shahrour Fatima , Vasquez David , Bruckheimer Elizabeth , Angiuoli Samuel V. , Diaz Luis A. , Valencia Alfonso , Velculescu Victor E. , Sidransky David , Hidalgo Manuel 
Published: March 2020

2511 Background: Every cancer has its unique set of molecular changes and the knowledge of such alterations is enabling an individualized approach to cancer treatment. The great intellectual challenge lies in linking confirmed mutations to protein function. Methods: Using massive parallel sequencing we performed whole exome sequencing analysis of 30 patients (pts) with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Avatar models generated by direct engraftment of tumor samples from the patients into immunocompromised mice were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses has been obtained for 28 pts. Tumor specific mutations (Muts) and copy number variations were identified ranging from 5 to 952 and 0 to 956 respectively. All samples profiled contained relevant genomic alterations. Some of the most relevant actionable alterations were: CHEK1, FGFR2, IGF1R, MET, BRCA1, XPC, NOTCH, CREB3LB, GNA11, SMAD4, NF1, PTPRC, PI3KA, DDR2 and EGFR. An Avatar model was generated for 15 patients. In occasions actionable alterations such as muts in NF1, PTPRC, PI3KA and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and accordingly treatment of the pts with these drugs was not effective. So far 13 pts have received a personalized treatment: two, as expected based on the avatar model, did not response; 5 resulted in durable partial remissions. Eight pts are currently on treatment with at least disease stabilization. Bench testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in patients with no actionable mutations. Conclusions: The use of full genomic analysis for cancer care is promising but presents important challenges that will need to be solved for broad clinical application. Avatar models are a powerful investigational platform for therapeutic decision making and help to guide cancer treatment in the clinic. While limitations still exist, this strategy should be tested in prospective randomized clinical trials.
A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors.
Authors: Sandler Alan , Taylor Matthew Hiram , Urba Walter John , Omuro Antonio Marcilio Padula , Anderson Barry Douglas , Hansen Daniel , Fisher Brenda , Claeys Alisa J , Greathouse Amy , McLean Sean , Karmali Rashida A. 
Published: March 2020

2518 Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m2/day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m2) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m2 renal carcinoma (1, 12 cycles); ii) 219 mg/m2-small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m2-1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m2/day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.