bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimal body mass index cutoff point for predicting survival of colorectal cancer in Asian population: A National Health Information Database Analysis.
Authors: Song Nan , Shin Aesun , Huang Dan , Kim Minjung , Park Ji Won
Published: May 2019

e13098

Background: A U-shaped relationship between body mass index (BMI) and colorectal cancer mortality has been revealed. However, an optimal BMI range for predicting survival in Asian colorectal cancer patients is unknown. We established the most appropriate cut-off point of BMI for better survival in Asian colorectal cancer patients. Methods: Two cohorts of colorectal cancer patients were included in this study; 5,815 from the Seoul National University Hospital, Korea for development cohort and 54,043 colorectal cancer patients from the Korean National Health Information Database for validation cohort. To determine the optimal cut-off point of BMI at diagnosis, the systematic dichotomization based on log-rank test was performed by the method of Contal and O’Quigley. We evaluated the association between BMI at diagnosis and overall survival (OS) using the Cox proportional hazard model. Results: During a median follow-up of 5.7 years for hospital-based development cohort and 4.3 years for nation-wide validation cohort, 1,180 (20.3%) deaths and 10,244 (19.0%) deaths occurred, respectively. The optimal cut-off point of BMI at diagnosis was identified at 20.2 kg/m2 (log-rank statistic = 96.69, Q-statistic = 3.07, P< 0.01) for differentiating between the poorer and better OS in development cohort. When compared to the patients with BMI < 20.2 kg/m2, the patients with BMI ≥20.2 kg/m2 were significantly associated with the better OS in the Cox proportional hazard regression analysis (HR = 0.62, 95% CI = 0.54-0.72, P= 1.1×10-10). The association was validated in the nation-wide cohort showing the better OS in the patients with BMI ≥20.2 kg/m2. (HR = 0.64, 95% CI = 0.60-0.67, P< 0.01). Conclusions: We suggest the use of a BMI value of 20.2 kg/m2 to predict survival in Asian colorectal cancer patients.
Epidemiology and survival of lung cancer in a Latin American cohort.
Authors: Ruiz Rossana , Galvez Nino Marco , Morante Cruz Zaida , Valencia Fernando , Pacheco Cristian , Aliaga Llerena Karina Mayra , Olivera Mivael , Valdivieso Natalia , Amorin Edgar , Mas Luis
Published: May 2019

e13101

Background: Lung cancer epidemiology and survival data is lacking in LA. This information is relevant for understanding regional cancer burden and for designing targeted interventions for cancer control. Methods: Retrospective analysis of lung cancer cases diagnosed at Instituto Nacional de Enfermedades Neoplasicas (INEN) from 2010 to 2014. Data was manually curated from clinical files. Results: 1384 patients were included. Median age at diagnosis was 64 years old (range 20-92) and 51.6% were females. The histologic type was adenocarcinoma, NOS carcinoma, squamous cell carcinoma and small-cell carcinoma in 72.3%, 12.8%, 9.4% and 3.5% of the cases, respectively. The adenocarcinoma/squamous cell carcinoma ratio was 7.7. Among NSCLC cases, most patients presented with advanced disease. Stage III (9.2%) and IV (85.5%) were the most frequent. With a median follow-up of 71.5 months, median overall survival (OS) was 9.2, 7.7 and 8.1 months for adenocarcinoma, NOS carcinoma and squamous carcinoma, respectively. Five-year OS for stage III was 6% and for stage 4, 4%. Detailed results are shown in the table. Conclusions: The epidemiological profile of lung cancer in Peruvian patients is different from that of other countries with a younger age at diagnosis, a preponderance of females over males and an unexpectedly high frequency of adenocarcinomas. This may be in concordance with the low prevalence of tobacco smoking and the high prevalence of EGFR mutations reported for our population as well as with particular exogenous exposures such as biomass fumes from inhouse cooking. The molecular characterization of this cohort of patients is ongoing. [Table: see text]
Burden and etiologies of 30-day readmission after bone marrow transplant: Insights from National Readmission Database.
Authors: Premnath Naveen , Sud Karan , Pondaiah Sathish Kumar , Gupta Arjun
Published: May 2019

e13106

Background: With more centers getting accredited as a bone marrow transplant (BMT) unit, attention has shifted to healthcare care quality metrics such as readmissions. Previous studies have shown high rates of 30-day readmission to be associated with worse long term survival. Except a few single center studies there is no viable data for readmissions for patients undergoing BMT. Methods: This is a retrospective cohort study using the National Readmission Database (NRD) for 2014. All adults with index admission for BMT (autologous and allogenic) were included. Exclusion criteria was age < 18 years, mortality during index admission and inter-hospital transfers. ICD 9 codes were used to identify diagnoses and procedures. Results: A total of 3,972 admissions for BMT were identified. Among these 2,462 underwent autologous (AU) and 1,510 underwent allogenic (AL) transplant, respectively. 30-day readmission rate was 8.6% in AU and 8.2% in AL group. The mean age was 55.9 years and 47.8 years in the AU and AL group, respectively. About 40.5% were females in the AU group and 44.4% in the AL group. Major co-morbidities included Smoking (22.7% in AU and 19.1% in AL), diabetes (13.8% in AU and 12.4% in AL), chronic kidney disease (10% in AU and 4.3% in AL) and prior irradiation (5.7% in AU and 4.5% in AL). Mean length of stay during the index admission was 18 days in AU and 26 days in AL group. Principle diagnosis for undergoing transplant was found as multiple myeloma (59.2% in AU) and AML (25.2% in AL). Major etiologies for readmission were neutropenia (26.9% in AU and 15.8% in AL) followed by Infectious etiologies 26% in AU and 20.4% in AL group, nausea and vomiting 4.3% in AU and 3.2% in AL group. Dehydration accounted for 5.7% in AU group and mucositis 5.7% in AL group. Conclusions: There is a significant readmission rate in this study population. 30-day readmissions in this population are primarily due to neutropenia and infectious etiologies including sepsis and pneumonia. Nausea, vomiting and dehydration played a major role in both categories and remain a major targetable group. We believe there is a dire need for major studies to further evaluate risk factors and predictors for readmission and their impact on overall survival. [Table: see text]
Large cell neuroendocrine carcinoma of the lung: A population-based study.
Authors: Kinslow Connor J , May Michael S. , Wang Tony J. C. , Cheng Simon
Published: May 2019

e13122

Background: In 2015, the World Health Organization dissolved the category of non-small cell lung cancer (NSCLC) that was previously known as “large cell carcinoma” into adeno- or squamous cell carcinomas, with the exception of large cell neuroendocrine carcinoma (LCNEC), which is now grouped with other neuroendocrine carcinomas of the lung. There is limited data on the epidemiology and best treatment practices for this malignancy, and studies comparing prognosis with SCLC and NSCLC have been conflicting. Methods: We reviewed the epidemiology of LCNEC using data from the Surveillance, Epidemiology and End Results Program from 2010 – 2015. Demographical features and overall survival were compared with SCLC and NSCLC. Trends in incidence and mortality rates were observed from 2004 – 2015. Results: We analyzed 195,148 cases of lung cancer, including 1,681 (0.9%) cases of LCNEC. Age-adjusted incidence of LCNEC was 0.31 per 100,000 people and had increased by 50% over the period studied. This increased incidence was primarily the result of increased incidence of stage IV disease. LCNEC was more likely to present with brain metastasis at diagnosis (19.2%) than either SCLC (16.7%, p = .01) or NSCLC (13.0%, p < .001). Survival patterns for LCNEC mirrored NSCLC in stage I – III disease and SCLC in stage IV disease. After adjusting for other clinical and demographic variables, survival for LCNEC was not different than SCLC but worse than NSCLC (HR = 0.88 for NSCLC vs. LCNEC, p < .001). Survival rates for LCNEC and SCLC did not significantly change over the time period studied, whereas survival rates for NSCLC significantly improved. Consistent with our findings of increased incidence of LCNEC with no change in survival patterns, age-adjusted incidence-based mortality increased by two-fold over the time period studied. Conclusions: LCNEC generally has a worse prognosis than NSCLC and better than SCLC. LCNEC presents with brain metastases more frequently than SCLC. Incidence of LCNEC is consistently increasing in the U.S. Despite this, it remains poorly studied and prognosis for LCNEC has not improved with time. LCNEC has, therefore, become an increasing cause of lung cancer mortality in the American population.
Validation of a comprehensive cancer genomic profiling assay based on massively parallel DNA sequencing.
Authors: Hong Yuanyuan , Chen Weizhi , Yan Huiting , Yan Linlin , Zeng Xuexia , Song Yipeng
Published: May 2019

e13138

Background: Validation is very important for diagnostic assays, here we describe a validation process of a comprehensive cancer genomic profiling assay based on massively parallel DNA sequencing. This assay can detect base substitutions, short insertions and deletions, copy number alterations, tumor mutation burden (TMB) and microsatellite instability (MSI) across 543 cancer-related genes from tumor specimens or plasma. Methods: Analytical validation was conducted with 20 cell line pools whose mutation were verified by digital droplet PCR (ddPCR). Clinical validation was conducted with Proficiency Test samples and clinical samples whose mutation were verified by ddPCR. Sensitivity, positive predictive value (PPV) and precision of tumor specimens and plasma were assessed across the reportable range of the assay. For measurement of TMB， NGS libraries of a cohort of tumor samples were tested by whole exosome panel (WES) and this assay respectively. And clinical tumor tissue samples whose MSI status were identified by fluorescent PCR-capillary electrophoresis were also tested by this assay. Results: The SNV/Indel LOD95 was 0.6% for hot-spot variants, and 1.3% for panel-wised variants of tumor tissue samples with high specificity (PPV >99%). The SNV/Indel LOD95 was 0.4% for hot-spot variants, and 1.1% for panel-wised variants of plasma samples (cfDNA≥15ng), with PPV >99%. LOD95 of CNV was 2.2-2.3, with PPV>99%. Precision of CNV was higher than 95%, precision of SNV/Indel was higher than 97%. Concordance between TMB results tested by WES and this assay was 0.94. MSI results identified by this assay was the same as fluorescent PCR-capillary electrophoresis method. Conclusions: In summary, we present the analytical and clinical validation of a comprehensive NGS-based diagnostic assay for comprehensive tumor genomic profiling.
Performance and validation of a tumor mutation profiling, based on artificial intelligence annotation, to assist oncology decision making.
Authors: Mitne Neto Miguel , Fornari Alexandre Ricardo , Moreira Luciana Peniche , Burger Matheus , Oku Andre , Pereira Luciana Guilhermino , Stabellini Raquel , Valim Gabriela Rampazzo , Eulalio Otavio Jose , Colleoni Gisele Wally , Santoro Ilka Lopes , Pintão Maria Carolina , Stiepcich Monica Maria Agata , Felipe-Silva Aloisio Souza , Ramalho Rodrigo Fernandes , Marco Antonio David Santos , Fraga Ana Maria , Ferreira Elisa Napolitano
Published: May 2019

e13148

Background: Tumor mutation profiling has become a key component for orienteering the treatment of oncologic patients. A crucial step for this is the correct identification and classification of pathogenic and actionable variants. In the present work we aimed at the development and validation of a tumor mutation profiling panel, based on NGS, which uses artificial intelligence for variant annotation. Methods: We designed a hybrid capture panel, containing 366 genes to evaluate somatic SNVs, INDELs and CNVs, and to calculate TMB, using a customized bioinformatics pipeline. MSI status was determined by fragment analysis using capillary electrophoresis. Analytical performance was determined using reference cell lines. FFPE samples from 70 tumors were accessed and 53 were sequenced. Variant annotation was performed by IBM Watson for Genomics (WfG) platform. Assay performance on clinical samples was defined based on orthogonal assays using Agilent CGH+SNParray 400K (for CNVs only) and Foundation One test (Foundation Medicine) (F1). Results: Breast, colon and lung were the most common tumor origins. Fifty-three samples were successfully sequenced, while 41 of them could also be analyzed by F1 test. A summary of the assay performance is presented in Table 1. Our pipeline detected 1219 variants and 290 (23%) were classified as Pathogenic, Likely Pathogenic or Actionable, according to WfG. Thirty-five samples (66%) presented a variant that could drive the treatment, with 37.7% of samples being sensitive to targeted therapies, while 22.6% were resistant; additionally, 86% had an indication for a clinical trial. Conclusions: The developed assay presented a good overall sensitivity and allele frequency correlation, with TMB and MSI having the best rates. Comparisons with F1 had reduced values of concordance; however, SNVs and INDELs presented a similar frequency. Differences on CNVs identification may rely on distinct thresholds established by the different groups. The high percentage of samples that could benefit from mutational profiling highlights the importance of such approach in the clinical routine. Additionally, the high number of variants features the need for updated information for annotation. [Table: see text]
Enhancing access to genetic cancer risk assessment (GCRA) in Monterrey, Mexico: The beginning of a prevention program.
Authors: Aguilar y Méndez Dione , Weitzel Jeffrey N. , Blazer Kathleen Reilly , Castillo Danielle , Herzog Josef , Marrufo Juan Carlos A. , García-García Marisol , Mesa-Chavez Fernanda , Miaja Melina , Cardona-Huerta Servando , Villarreal-Garza Cynthia
Published: May 2019

e13150

Background: In limited-resource countries like Mexico, GCRA is not routinely provided due to elevated costs, lack of public coverage for testing and prophylactic surgeries, and limited GCRA expertise or awareness among providers and patients. Thus, GCRA services in Mexico are 20 years behind higher income countries, resulting in suboptimal care and limited opportunity for prevention. The Breast Cancer Center TecSalud established formal GCRA services for underserved patients by recruiting a cancer geneticist who provides care at no added expense to patients, building academic collaborations for training and research with City of Hope, and enabling free genetic testing through the Clinical Cancer Genomics Community Research Network, supported in part by the Breast Cancer Research Foundation. Aim: To report the uptake of the GCRA program by patients and relatives at TecSalud from January 2016 - December 2018. Methods: Eligibility includes Mexican women who meet hereditary breast cancer testing criteria and family members of mutation carriers. Risk reduction procedures are covered by Seguro Popular and/or the NGO Fundación Santos y de la Garza Evia. Results: GCRA was offered to 255 patients and 74 at risk relatives, with an increasing reach (proportion of those eligible who access the program). A significant growth of cascade testing and access to risk reduction surgery over time are noted. Conclusions: A growing number of referrals and GCRA visits shows improving reach, possibly due to engagement of the multidisciplinary team and increased patient awareness. The expansion of cascade testing and performance of risk-appropriate surgeries reflects a maturing prevention program. Key determinants of our progress are collaborations that provided us with crucial mentorship, access to genetic assays, as well as the increasing involvement of local leaders, administrators and benefactors for the establishment of vital clinical and research capacity. Multilevel efforts should continue to enhance the delivery of standard of medical care for the most vulnerable and underserved high-risk patients and families. [Table: see text]
Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing in families with BRCA1/2 or MMR gene mutations.
Authors: Pujol Pascal , Alegre Nathalie , vande Perre Pierre , Bignon Yves-Jean , Chiesa Jean , Picot Marie Christine , Galibert Virginie , Bertet Helena , Corsini Carole
Published: May 2019

e13151

Background: Intrafamilial disclosure of hereditary cancer predisposition in BRCA1/2 and mismatch repair gene (MMR) syndromes allows appropriate prevention strategies in at-risk relatives. We previously showed in a nationwide study that the uptake of genetic targeted testing (GTT) in these families by relatives was only 30%. We aimed to identify the medical and psychosocial factors affecting the proband’s intrafamilial disclosure and relatives’ uptake of GTT in BRCA1/2 or MMR syndromes. Methods: We assessed clinical variables, family history and several psychological variables of probands (depression, anxiety, alexithymia, optimism, coping, family relationship, perception of cancer risks and of hereditary transmission risks), together with disclosure and verified uptake of GTT in BRCA1/2 or MMR families. Results: Among relatives eligible for GTT, 68% were informed of the predisposition and 37% underwent GTT, according to proband reports. Intrafamilial disclosure was inversely associated with the degree of kinship (P < 0.01). In multivariable analysis, disclosure increased with time since proband’s genetic diagnosis (P < 0.01) and proband’s feeling of family cohesion (P = 0.01). GTT uptake increased with proband’s depression score (P = 0.02) and decreased with proband’s perception of cancer risks (P = 0.03). BRCA1/2 and MMR groups did not differ in findings concerning family information and GTT uptake. Conclusions: This study identified factors affecting disclosure to relatives and GTT uptake in BRCA1/2 and MMR syndromes and gives new insights to improve probands’ follow-up and intrafamilial sharing of genetic information.
Genetic testing for hereditary breast and ovarian cancer in Indian population: A single institutional study.
Authors: Selvakumar Veda Padma Priya , Garg Shubha , Kaur Jatinder , Kadayaprath Geeta , Rohatgi Nitesh , Walia Meenu , Rangaraju Ranga Rao , Julka Pramod Kumar , Chaturvedi Harit Kumar , Verma Amit
Published: May 2019

e13153

Background: Women with Hereditary breast ovarian cancer have an increased lifetime risk of developing breast, ovarian and other second primary cancers . A number of genes including BRCA 1 & 2 have been implicated in Hereditary Breast Ovarian Cancer. In this background we sought to analyze the genetic pattern of patients who underwent genetic testing as per the NCCN criteria for hereditary breast ovarian cancer syndrome. Methods: All consecutive patients who fit into the NCCN criteria for genetic testing for Hereditary Breast Ovarian Cancer from 2016 to 2018 were referred to our genetic clinic. The data of all the patients who underwent further genetic testing after counselling were collected and analyzed. Results: Out of 155 patients who underwent genetic testing ,131 patients were found eligible for the study.127 were female and 4 were male. There were 27 pathogenic mutations identified while 32 were variants of unknown significance . The remaining 72 were negative for any of the known mutations. 22 were pathogenic for BRCA 1 Mutation , two pathogenic for BRCA 2 and one for TP53 ,PALB2 and ATM each. Out of the 32 VUS, 9 were BRCA 2, 4 in CDH 1, 2 in BRCA1, CHEK2 ,MSH2 and BRIP1 and one each in MLH1, MLH3, ATM, APC, RAD51D, XRCC3, NBN, TP53.Three patients had double VUS reported. BRCA 1 is the most common pathogenic mutation ( 16.79% ) found while BRCA 2 is the most common VUS reported ( 28 %). Conclusions: 20.6 % of eligible patients had pathogenic mutations which is much higher than the western literature. However the VUS rates in Indian population are high 22% owing to a paucity of genetic data of Indian population. Multigene testing helps in identifying other genes asscociated with the Hereditary breast ovarian cancer criteria in addition to BRCA 1 & 2.
BRCA1/2 and multigene panel testing among metastatic breast, pancreas, prostate, and ovarian cancer patients.
Authors: Trivedi Meghna S. , Vo VanAnh L , Jones Tarsha , Silverman Thomas , Chung Wendy , Kukafka Rita , Crew Katherine D.
Published: May 2019

e13160

Background: Given the availability of targeted therapies such as PARP inhibitors, patients with metastatic breast, pancreas, prostate, and ovarian cancer are recommended to have germline genetic testing for hereditary cancer syndromes. Completion of genetic testing among this population is understudied. Methods: We performed a retrospective study of 548 patients with stage 4 breast, pancreas, prostate, and ovarian cancer at diagnosis from January 2013-December 2017 identified in the New York Presbyterian Hospital Tumor Registry at Columbia University Irving Medical Center. Data on socio-demographics, clinical factors, and genetic testing completion and results were collected from the medical record. We conducted descriptive statistics. Results: Our study population had a median age of 66 years (range, 23-97) at diagnosis; 61% female; 50% non-Hispanic white/22% Hispanic/15% non-Hispanic black/5% Asian/7% other; 33% private insurance/16% Medicaid/44% Medicare/7% unknown insurance. Primary cancer was 24% breast, 8% ovary, 61% pancreas, and 7% prostate. Only 38 patients were seen by a genetic counselor (7%) and only 50 (9%) had genetic testing performed. Among those who underwent germline testing, 92% had multigene panel testing (median number of genes tested 13.5, range 2-74). Pathogenic variants were detected in 6 patients (12%), of which 4 had a BRCA1/2 mutation, and 26% had a variant of uncertain significance (VUS). Conclusions: We found that only a small percentage of metastatic breast, pancreas, prostate, and ovarian cancer patients underwent genetic testing. Further research is necessary to identify the barriers to genetic testing uptake in metastatic cancer patients. BRCA1/2 and multigene panel testing has important implications in this patient population not only for treatment decisions, but also to increase cascade testing in unaffected family members who may be at risk for malignancy in the future.
Correlation of negative PD-L1 expression with TMB-H and MSI-H rates.
Authors: Dong Jun , Zhang Xiaoni , Qu Hongyue , Chen Shifu , Zhu Ziyang , Huang Tanxiao , Ye Da-Wei , Bai Long , Cai Xiuyu
Published: May 2019

e13162

Background: PD-L1 protein expression, tumor mutation burden (TMB) and microsatellite instability (MSI) are majorbiomarkers for PD-1/PD-L1 blockade therapy for solid tumors. We designed a study to evaluate the relevance of these biomarkers. Methods: From April 2018 to December 2018, 197 patients with lung cancer, colorectal cancer, andgastric cancer wereprospectivelyenrolled.Foreachpatient, afreshfrozentissuesampleor FFPE sample wascollected. Each sample was dividedinto3parts for next-generation sequencing (NGS), PD-L1 protein expression evaluation and MSI evaluation. The sequencing library was captured using a 605-gene panel and sequenced at~5,000×coverage.Mutationsinthe NGS datawereidentified,andTMB was then calculated. The PD-L1 protein expression was analyzedby immunohistochemistry, and the MSI was evaluated using a multiplex PCR comprising 5 loci(NR27, NR21, NR24, BAT25, and BAT26). Results: 18.78% (37/197) were detected with high PD-L1 expression (positive tumor cells ≥50%); 5.08% (10/197) ofpatientswere diagnosed as MSI-H; 4.06% (8/197) of patients had a TMB-H (TMB > 20 mutations/Mb). Among the 37 PD-L1 positive patients, only one patientwith TMB-Hwas detected, and 3patients were MSI-H. In contrast, among the 14 patients with PD-L1 expression less than 1%, 8patients (57.14%) were detected with TMB-H or MSI-H (3 with TMB-H only, 3 with MSI-H only, and 2 with both). In addition, among all the 10patients with MSI-H, 4patients had TMB-H, indicating that MSI-H may be partly associatedwith high TMB. Conclusions: From our preliminary result, PD-L1 protein expression negative patients tend to have higher rates of TMB-H and MSI-H. For patients with negative PD-L1 expression, it issuggested to evaluate its TMB level and MSI status. This study is ongoing, and more data will be collected to verify these findings.
Treatment of cancer-associated thrombosis after craniotomy.
Authors: Katelnitskaya Oksana V. , Kit Oleg I. , Rostorguev Eduard Evgenevich , Kuznetsova Natalya S. , Porksheyan David H. , Atmachidi Dmitriy P. , Kavitskiy Sergey E. , Guskova Nailya K. , Zakharchenko Viktoria R. , Nozdricheva Anastasia S. , Abakumova Svetlana V. , Selyutina Olesya N. , Tselishcheva Irina V. , Belgova Svetlana V.
Published: May 2019

e13510

Background: The high rates of mortality from venous thromboembolism (VTE) in neurooncological patients determine the relevance of the topic. The risk of VTE in patients with glioma reaches 36% during the treatment period, 16.1% during the first 6 months and increases by 3 times after tumor biopsy. The aim of this study was to evaluate the efficacy and safety of VTE treatment with fondaparinux after surgical interventions for brain tumors. Methods: The study included 32 cancer patients aged from 27 to 76 years (mean 56.5 years) in the acute period of VTE, the first month after craniotomy. Creatinine clearance below 30 ml/min, active bleeding, thrombocytopenia below 50x109/l were exclusion criteria. Glioma was diagnosed in 15 patients (46.9%), metastasis - 9 (28.1%), and meningioma - 8 patients (25%). Radical interventions were performed in 12 (37.5%) cases, palliative - 20 (62.5%). In 81.2% of cases (26 patients) deep vein thrombosis of lower extremities (DVT) was detected, 3 patients (9.4%) had combination with pulmonary embolism. VTE developed in the postoperative period with radiotherapy in 9 cases (32%), dexamethasone - 13 (40.6%). Surgical treatment of DVT was performed in 8 patients (thrombectomy, plication of the femoral vein). Segmental deep vein thrombosis of the lower leg was detected in 14 (43.8%) cases. Results: The efficiency of anticoagulant therapy was assessed by a decrease of thrombinemia markers (fibrinogen, SFMC and D-dimer). After a week of anticoagulant therapy, a significant reduction in the level of D-dimer was observed. However, the decline in fibrinogen and SFMC was statistically insignificant. VTE therapy was performed with fondaparinux in a therapeutic dose from 10 days to 1 month, followed by a transition to oral anticoagulants. There was no hospital mortality. Hematuria developed in one case (3.1%), and was managed conservatively. There were no hemorrhagic complications in the operative intervention zone. Two patients (6.25%) had a recurrence of VTE during the period of radiation therapy. Conclusions: An integrated approach to the treatment of VTE in patients undergoing craniotomy provides a low incidence of recurrent VTE and major bleeding.
High-grade gliomas (HGGs) and immunotherapeutic early-phase clinical trials (ieCTs): A single-center experience.
Authors: Simonelli Matteo , Persico Pasquale , Dipasquale Angelo , Lorenzi Elena , Giordano Laura , Pessina Federico , Navarria Pierina , Scorsetti Marta , Bello Lorenzo , Santoro Armando
Published: May 2019

e13512

Background: Patients with HGGs have historically been excluded from ieCTs due to unavailability of serial bioptic sampling, frequent need of corticosteroids, concerns on activity of immunotherapy in central nervous system, and rapid clinical deterioration. Methods: We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2018. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for age, line of treatment, MGMT methylation and IDH mutational status, was selected for comparison. Clinical parameters including use of steroids, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein, were correlated with survival through an univariate analysis. Results: 5 among 21 ieCTs allowed inclusion of HGG patients. 20 patients were enrolled in our experimental cohort (EC); 17 (85%) glioblastoma, 3 (15%) anaplastic astrocytoma. Median age was 53 years (range 30-71); 12 patients (60%) were men, 8 (40%) women; 13 pts (65%) required steroid therapy, with a median dexamethasone dose of 2 mg (range 1-6). The median number of prior systemic therapies was 1 (range 1-2). 11 patients (55%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 9 (45%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 45% (1 CR + 2 PR + 6 SD) and 30% (1 RP +5 SD), in EC and CC, respectively. 4 patients (20%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 22 months PFS-6 and OS-6 were 53% and 11% (p < .0001), 80% and 42% (p < 0.0001) in EC and CC, respectively. In our small series, none of clinical factors resulted prognostic. Conclusions: Survival outcomes of our HGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical selection factors remains crucial.
Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.
Authors: Peters Katherine B. , Archer Gerald E. , Norberg Pamela , Xie Weihua , Threatt Stevie , Lipp Eric S , Herndon James Emmett , Healy Patrick , Congdon Kendra , Sanchez-Perez Luis , Friedman Henry S. , Desjardins Annick , Vlahovic Gordana , Sampson John H.
Published: May 2019

e13526

Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.
The impact of Epstein-Barr virus status on primary CNS lymphoma survival.
Authors: Prado Isabel P , Barbiero Frank , Baehring Joachim M. , Becker Kevin , Corbin Zachary
Published: May 2019

e13528

Background: Primary CNS lymphoma (PCNSL) incidence is increasing among the elderly and immunocompromised. Especially for these vulnerable populations, a deeper understanding of the prognostic value of tumor biomarkers is necessary to recommend more targeted therapies. Our primary objective is to evaluate the predictive strength of immunohistochemical markers on PCNSL overall survival. Secondary objectives include estimating the impact of these biomarkers on event-free survival. Methods: We retrospectively analyzed PCNSL patients treated at Yale between 2000 and 2018. The primary endpoint is overall survival. Event-free survival, measured by time to relapse or death, is the secondary endpoint. Kaplan-Meier survival curves with log-log confidence intervals were used to estimate survival outcomes. Cox proportional hazards regression models were used to evaluate the statistical significance (at alpha = 0.05) of immunohistochemical markers. Results: One hundred ten subjects were analyzed. Not all biomarkers were available for every subject. The median age of the cohort is 64 years. Sixty-three patients died, and seventy-six experienced an event (progression or death). Surviving patients had a median follow-up of 4.36 years. The median overall survival is 2.63 years (95% confidence interval (CI): 1.13 to 5.98 years). Epstein-Barr virus (EBV) status by immunohistochemistry significantly impacted overall survival. Adjusting for age and immunocompromised status, EBV-positive patients had a higher risk of death than EBV-negative patients (n = 13, hazard ratio (HR) = 33.75, 95% CI: 1.61-708.68). Other significant biomarkers include the GFAP and S100 proteins. The median event-free survival is 1.13 years (95% CI: 0.66 to 2.12 years), and EBV-positive patients had an increased risk of event (HR = 38.23, 95% CI: 2.32-630.88). CD10, BCL2, BCL6, and MUM1 were not significant to predict either survival outcome. Conclusions: We describe a large cohort of PCNSL patients treated at a single institution with comparable survival outcomes to similar research yet conflicting evidence of biomarker significance. Multi-institutional studies may further clarify the prognostic role of immunohistochemistry for improved PCNSL patient survival.
The utility of surgery in butterfly glioblastoma: A case-control study.
Authors: Hall Benjamin James , Maleyko Igor , Brodbelt Andrew , Jenkinson Michael D , Chavredakis Emmanuel
Published: May 2019

e13529

Background: Glioblastoma is the most common primary brain tumour and may rarely infiltrate the corpus callosum. Such ‘butterfly’ glioblastomas (BGBM) are believed to confer a poorer prognosis than their non-callosal counterparts. We aimed to determine the impact of surgery on overall survival (OS) and postoperative morbidity in butterfly glioblastomas. Methods: Retrospective analysis was performed on all case notes of patients histologically diagnosed with GBM from January 2011 to January 2017 at The Walton Centre NHS Foundation Trust, Liverpool. Data was collected under the following headings: demographics, tumour characteristics, surgical data, adjuvant therapy and survival data. A case-matched control group was produced according to age, sex and 1o resection. Univariate analysis was performed. Results: 632 glioblastoma patients were identified. 37 patients were diagnosed with butterfly BGBM, with a median age of 62.7 years and a gender split of 24 males (64.9%) to 13 females (35.1%). Median tumour volume was 31700mm3, with 24 (56%) tumours involving the genu and 13 (22%) the splenium of the callosum. Kaplan-Meier analysis with log-rank testing demonstrated a significant (p = 0.04) decrease in median OS in those with BGBM (100 days (95%CI 57-142)) vs controls (276 days (95%CI 224-327)). Resection of BGBMs resulted in longer median OS than biopsy alone (296 days (95%CI 229-363) vs 81 (66-96)), though this was a non-significant difference (p = 0.36). Multifocal disease occurred significantly more often in BGBM patients (p = 0.01), the exclusion of which from analysis demonstrated a significant survival benefit with resection (427 days (95%CI 207-647)) compared to biopsy (221 days (95%CI 151-291)) (p = 0.04). Postoperative complications did not occur significantly more often in BGBM resections than controls (7/36 (19.4%) vs 5/36 (13.9%) (p = 0.257)). Conclusions: Overall, butterfly glioblastomas confer a worse prognosis than those without callosal involvement. A greater prevalence of multifocal disease is seen in butterfly glioblastoma, warranting further investigation. Resection offers a significant improvement in OS in solitary butterfly glioblastomas without a significant increase in postoperative morbidity, and should therefore be considered an efficacious and safe treatment option.
Impact of next-generation sequencing (NGS) in patients with high grade glioma.
Authors: Kewan Tariq Zuheir , Covut Fahrettin , Thapa Bicky , Spiro Timothy Peter , Haddad Abdo S. , Daw Hamed
Published: May 2019

e13541

Background: Clinical utility of NGS in high grade glioma patients remain debatable. Methods: We reviewed patients who underwent Foundation One NGS between 7/2013 and 10/2018 after high-grade glioma diagnosis at Cleveland Clinic. Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by log-rank test. Cox regression analysis was performed to identify predictors of OS. Results: We identified 153 patients, 130 (85%) had glioblastoma multiforme (GBM) and 23 (15%) had grade III glioma, 51 (33%) were female, and median age at diagnosis was 58 (range: 18 – 92). Sixteen (10%) patients had secondary glioma and 34 (22%) had multilobar involvement. ECOG performance score at diagnosis was 0 or 1, 2, and ≥ 3 for 79 (52%), 54 (35%), and 13 (9%) patients, respectively. Glioma was surgically resected for 112 (73%) patients, 85 (56%) had total and 27 (18%) had subtotal resection, whereas other 41 (27%) patients underwent biopsy only. Radiotherapy, temozolomide, and bevacizumab were given to 132 (86%), 129 (84%), and 67 (44%) patients, respectively. NGS revealed median of 5 mutated genes (range: 0 – 19), commonly mutated genes were TERT (63%), CDKN2AB (60%), EGFR (42%), TP53 (42%), PTEN (38%), and IDH1/2 (20%). Two patients received bevacizumab for KDR amplification, 1 received off-label lapatinib for EGFR amplification, and 3 received off-label everolimus for multiple mutations. Median follow-up was 18 months. Three-year OS and PFS for patients with GBM vs grade III glioma were 29% (95% CI: 22 – 39) vs 78% (95% CI: 63 – 97) and 17% (95% CI: 11 – 25) vs 74% (95% CI: 58 – 94), respectively (p < 0.0001 for both). On univariable analysis, each 10 increase in age, ECOG ≥3 vs < 3, grade IV vs III glioma, surgical resection vs biopsy, radiotherapy, temozolomide, bevacizumab, and IDH / TP53 / EGFR / TERT / PTEN / CDKN2AB / ATRX mutations predicted OS (p < 0.01 for all). On multivariable analysis, ECOG ≥3 vs < 3, grade IV vs III glioma, surgical resection vs biopsy, temozolomide, bevacizumab, PTEN and CDKN2AB mutations have remained to predict OS (p < 0.01 for all). Conclusions: In our cohort, NGS results provided additional prognostic value, however led to change in the management for only 4% of patients with high-grade glioma.
Multi-parametric MRI as supplement to mRANO criteria for response assessment to MDNA55 in adults with recurrent or progressive glioblastoma.
Authors: Roettger Diana , Shaikh Faiq , Bisdas Sotirios , Bexon Martin , Coello Melissa , Merchant Fahar , Merchant Nina
Published: May 2019

e13559

Background: Modified response assessment in neuro-oncology (mRANO) criteria are widely used in GBM but seem insufficient to capture Pseudoprogression (PsP), which occurs due to extensive inflammatory infiltration, increased vascular permeability, tumor necrosis and edema. mRANO criteria recommend volumetric response evaluation using contrast-enhanced T1 subtraction maps for identifying PsP. Our approach incorporates multi-parametric MRI biomarkers to unravel the true PsP from recurrence or distinguish Pseudo Response (PsR) - following anti-VEGF agents - from delayed (immuno)response. Methods: Multiple time-points MRI (18-24h after convection-enhance delivery of the anti-IL4-R agent MDNA55, then at 30-day intervals) was utilized to determine response. Multi-parametric MRI biomarkers analyzed included (1) 3D-FLAIR-T2-based tumor volume assessment reflecting edema, necrosis and tumor infiltration; (2) 3D-gadolinium-enhanced-based tumor volume estimation reflecting active tumor infiltration, neo-angiogenesis and disrupted blood brain barrier; (3) Dynamic susceptibility contrast-based relative cerebral blood volume (rCBV) measurements for estimation of the vascular tumour properties; and (4) Diffusion weighted imaging – Apparent diffusion coefficient measurements that assess interstitial edema, tumor cellularity and ischemic injury. Results: We demonstrate similar imaging phenotypes on conventional FLAIR-T2- and enhanced T1- MR images among different disease states (PsP vs true progression, PsR vs and immuno-response) and describe the perfusion and diffusion MRI biomarkers that improve response staging including PsP masking true progression, PsP masking clinical response, early progression with delayed response, and differentiation between true and PsR. The results are compared with the mRANO-based assessments for concurrence. Conclusions: Incorporating multi-parametric MRI measurements to determine the complex underlying tissue processes enables a better assessment of PsP, PsR and delayed tumour response, and can supplement mRANO-based response assessments in GBM patients undergoing novel immunotherapies.
Lobectomy confers a survival benefit over gross-total resection without lobectomy in cases of primary glioblastoma in non-eloquent area: A retrospective study.
Authors: Kim Euihyun
Published: May 2019

e13561

Background: Following resection, the microscopic remnants of glioblastomas in nearby tissue cause tumor recurrence more often than other tumors. Although surgical oncologists traditionally resect some of the surrounding normal tissue, whether further removal of nearby tissue may improve survival in cases of primary glioblastomas (pGBM) is unknown. In this single-center retrospective study, we assessed whether lobectomy confers a survival benefit over gross-total resection without lobectomy when treating pGBM in the non-eloquent area. Methods: We selected 28 patients who had complete resection of a histopathologically-diagnosed pGBM in the right frontal or temporal lobe, and divided them into two groups according to whether gross-total resection of the tumor involved lobectomy (SupTR group, n = 15) or did not (GTR group, n = 13). Progression-free survival (PFS), overall survival (OS), and Karnofsky Performance Status (KPS) scores were compared statistically between groups (p≤0.05 for significant differences). Results: Median post-operative PFS times (GTR, 9.7 months [95% CI 2.9-16.5]; SupTR, 35.0 months [95% CI 11.1–58.9]; p = 0.082) and mean KPS scores (GTR, 73.4; SupTR, 71.3; p = 0.586) were not significantly different; however, median post-operative OS times were (GTR, 14.4 months [95% CI 12.1–16.7]; SupTR, 35.0 months [95% CI 17.4–52.6]; p = 0.018). In multivariate analysis, the SupTR group was significantly better than the GTR group in terms of both OS (HR 0.249; 95% CI 0.085–0.730; p = 0.011) and PFS (HR 0.362; 95% CI 0.0134–0.982; p = 0.046). Conclusions: In cases of completely resectable, non-eloquent area pGBMs, including lobectomy improved overall survival without negatively impacting patient performance.
Trametinib for aggressive gliomas in adults with neurofibromatosis type 1.
Authors: Romo Carlos G , Slobogean Bronwyn L , Blair Lindsay Karen , Blakeley Jaishri O'Neill
Published: May 2019

e13562

Background: Neurofibromatosis type 1 (NF1) is caused by mutations of the tumor suppressor gene NF1 resulting in decreased levels of neurofibromin and dysregulation of the RAS pathway, including MEK/ERK upregulation. NF1 is characterized by multiple benign and malignant tumors. Central nervous system tumors have an overall standardized incidence ratio of 37.5 in population studies with high rates of aggressive gliomas in adults with NF1. The response to standard glioma therapies is mixed. MEK1/2 inhibitors have shown activity in NF1 driven plexiform neurofibromas and low grade gliomas, however, data is lacking about the optimal dose or sequencing of MEK1/2 inhibitors for adults with NF1 associated aggressive gliomas. We present recent experiences with the MEK1/2 inhibitor trametinib in adults with NF1 and aggressive gliomas. Methods: A retrospective chart review was conducted on all adult patients with NF1 and astrocytoma treated with trametinib at the Johns Hopkins Brain Cancer Program between 2016-2018. Results: Three patients met selection criteria. Two received trametinib as initial therapy (2 mg daily). All developed an acneiform rash; one had transient transaminitis requiring temporary discontinuation and subsequent dose reductions. Clinical benefit was achieved associated with two partial radiographic responses. Conclusions: Astrocytomas in adults with NF1 often have a more aggressive course than suggested by histology. The cases presented here demonstrate clinical benefit from single agent MEK inhibition as well as possible synergistic effects with conventional therapies for gliomas in this patient population. These observations highlight the need for further research in this area. [Table: see text]
Impact of Zika virus infection in human glioblastoma cell lines.
Authors: Fay Andre P.
Published: May 2019

e13563

Background: Glioblastoma (GBM) is the most common central nervous system (CNS) tumor. Despite available therapies survival remains poor, and new treatment strategies are needed. Oncolytic viral therapy is under investigation in GBM. Zika virus (ZV) infection has demonstrated inhibition of neuronal precursor cells proliferation in preclinical studies. This study aims to evaluate the effects of ZV infection on human glioblastoma cell lines survival. Methods: Two GBM cell lines (U138 and U 251) were infected by 2 hours with ZV using the titer of PFU/ml diluted in 1:100, 1:1000, 1: 10000. Cell. We performed tests to evaluate cell viability by MTT and protease active assay, cell migration trough a wound healing assay and cell infiltration using insert culture method. Also the cell lines were tested by cell adhesion capacity, apoptosis (Caspase 3/7), interleukins levels and cell surface markers for CD 14 and CD73.These results were compared to controls. Results: Our study has demonstrated a reduction in cell viability in U138 lineage trough MTT assay. In the U251 lineage and in the others tests for cytotoxicity/viability, ZK did not altered cell viability neither cell migration compared to controls. We showed that ZV caused reduction in cell invasion and resulted in increased rates of apoptosis in both cell lines. We observed that infection of ZV caused increased rates of cell adhesion and CD73 marker. Conclusions: These findings suggest that ZV infection may be associated with increased CD 73 Expression thus increasing cell adhesion and cell infiltration. The ZV may be cause an increase rates of apoptosis and influencing cell cytotoxicity and viability. Further investigations to explore the role of ZV in GBM treatment are warranted.