bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contemporary changes in localized and metastatic prostate cancer incidence by geographic area following decreased PSA screening.
Authors: Yang Daniel X. , Makarov Danil V. , Gross Cary Philip , Yu James B. 
Published: May 2019

1567 Background: In the setting of decreased PSA screening, the incidence of metastatic prostate cancer has been increasing in the United States. This was chronologically proceeded by decreasing localized prostate cancer incidence. While decreased detection of localized disease is hypothesized to increase likelihood of metastatic disease at diagnosis, it is unclear whether the two are geographically connected. Methods: Prostate cancer incidence was obtained from the of Surveillance, Epidemiology, and End Results (SEER) database for men 70 years or older. SEER Summary Stage 2000 was used to classify localized (local) and metastatic (distant) prostate cancers. Changes in incidence rates were calculated by health services areas (HSA), which each represents a relatively self-contained region of hospital care. We chose a priori to examine most recent years 2012-2015 for changes in metastatic disease, and proceeding years 2008-2011 for changes in localized disease. Population-weighted linear regression that was robust to outliers was performed. Results: A total of over 66,600 cases of localized and 6,400 cases of metastatic prostate cancer from 200 HSAs were included for analysis. From 2008 to 2011, localized incidence decreased from 613.6 to 534.2 per 100,000 men overall, and for each HSA on average decreased by 30.3 per 100,000 men for each year. From 2012 to 2015, metastatic incidence increased from 54.7 to 62.1 per 100,000 men overall, and for each HSA on average increased by 2.1 per 100,000 men for each year. Linear regression between HSA-level changes in localized and metastatic disease revealed a correlation coefficient of -0.023 (SE = 0.017, p = 0.16, 95% CI -0.056 to 0.009), representing lack of a statistically significant relationship between decreases in localized disease and later increases in metastatic disease within each health services region. Conclusions: Despite concerns of increasing metastatic prostate cancer incidence coinciding with decreases in PSA screening and localized cancer incidence, we do not observe a statistically significant geographic and temporal relationship between metastatic and localized disease at the HSA level. Our study is limited by short lead time and thus this trend warrants continued surveillance.
Sex-specific mortality trends in adolescents and young adults with cancer from 2007 to 2016.
Authors: Close Allison , Seynnaeve Brittani , Miller Kimberly , Rapkin Louis 
Published: May 2019

1570 Background: Adolescents and young adults (AYA) aged 15-39 years make up approximately 70,000 new oncology cases in the USA. Historically, mortality from cancer has smaller incremental improvements in AYA patients when compared to children and older adults, and not much is known about current sex-specific trends. We assessed overall and sex specific AYA mortality for the last 10 years (2007-2016). Methods: Trends in age-adjusted mortality rates per 100,000 (1972-2016) were obtained from the CDC’s National Center for Health Statistics (NCHS). Average annual percent changes (AAPCs) in relative survival were analyzed using NCI’s JPSurv webtool and mortality AAPCs were quantified using Joinpoint regression analysis. Results: Overall declines in mortality are similar in AYA men and women from 1972-2016, with 54% and 51% decline, respectively. In the most recent 10 years of data (2007 to 2016), combined sex AYA mortality AAPC’s declined by about 0.8% per year, slightly slower than declines in children <15 years (1.3% per year) and adults ages >40 years (1.5% per year). Among AYA males there have been 10 year AAPC mortality declines in leukemia (-1.8%), Hodgkin lymphoma (HL) (-5.1%), Non-Hodgkin lymphoma (NHL) (-4.1%) and melanoma of the skin (-3.4%). For AYA females, 10 year AAPC mortality declines occurred in leukemia (-1.9%), ovarian (-1.5%), HL (-10%), NHL (-4.9%) and melanoma (-2.8%). These declines have been offset by stable or increasing mortality rates for several common AYA cancers, including colorectal cancer (CRC) (1.1%) and bone and joint cancer (0.6%) in AYA males. AYA females have experienced mortality increases for CRC (0.6%), bone and joint cancer (0.5%) and uterine corpus cancer (2.8%). Conclusions: In general, mortality rates for both AYA men and women have declined over the past 10 years due to decreased mortality in hematologic malignancies and melanoma. Despite overall improvement, tumor categories in both AYA males and female such as CRC, bone and joint cancer, and uterine corpus cancers show increasing mortality. These diseases require specific investigations by both pediatric and adult researchers.
Genomic profiling of pulmonary lymphoepithelioma-like carcinoma (PLELC).
Authors: Zhou Chengzhi , Xie Zhanhong , Qin Yinyin , Liu Laiyu , Zhang Hua , Feng Weineng , Xie Xiaohong , Lin Xinqing , Zhang Jiexia , Ouyang Ming , Gu Yingying , Li Bing , Han-Zhang Han , Liu Jing , Mai Suiyi , Chen Shuyin , Zhang Lu 
Published: May 2019

1572 Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p < 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p < 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.
Characterization of genomic alterations in Chinese LCNEC and SCLC via comprehensive genomic profiling.
Authors: Wu Lin , Cao Liming , Chen Likun , Zhu Bo , HU Xiaohua , Gen Lin , Lin Yingcheng , Zhang Sheng , Huang Cheng , Peng Wenying , Jiang Meilin , Mao Xinru , Zhang Tengfei , Ye Junyi , Zhang Lu 
Published: May 2019

1575 Background: LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling. Methods: FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385×. Results: Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p < 0.001, p < 0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p < 0.001, p = 0.014) and carcinoids (p < 0.001, p = 0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, NOTCH1, SPTA1, EPHA3 and KEAP1 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs. We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p = 0.032, p = 0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p < 0.001, p < 0.001) and atypical carcinoid (p = 0.010, p = 0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p < 0.001, p < 0.001) and atypical carcinoid (5.6/Mb, p = 0.003, p = 0.009) than LCNEC and SCLC. Conclusions: We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.
Tumor sequencing with germline genetic testing: Identification of patients with hereditary cancer and precision treatment eligibility.
Authors: Michalski Scott T. , Pineda Alvarez Daniel Esteban , Russell Meaghan , Yang Shan , Sonpavde Guru , Esplin Edward D. 
Published: May 2019

1580 Background: Cancer is a fundamentally genetic disease, as such, somatic and germline mutation analysis is used in the comprehensive assessment of patients with cancer. Studies report that approximately 10% of patient’s tumors have clinically significant variants known to predispose to hereditary cancer, with medical implications for both patients and family members. We retrospectively reviewed a series of patients where providers suspected a somatic variant also existed in the germline and followed up with clinical germline genetic testing. We report the rate of concordance between germline and somatic results and their clinical impact. Methods: Our study used de-identified data from 1043 consecutive patients who underwent somatic genetic testing followed by germline testing with NGS-based hereditary cancer gene panels. Results: Somatic results most frequently prompting germline testing included variants in BRCA2 (290), BRCA1 (174), TP53 (158), ATM (70), MLH1 (65), APC (65), PMS2 (61), MSH6 (58), PTEN (54) and CDH1 (42). In 364/1043 cases (35%) the variant was detected as likely pathogenic or pathogenic (LP/P) in the germline. Genes confirmed as germline variants in 60-100% of cases included: FANCA, AXIN2, RAD50, MUTYH, BLM, PALB2, CHEK2, FANCD2, MITF, SDHB. Variants in: FH, BRCA2, RET, ATM, SDHA, BRIP1, MSH2, BRCA1, BAP1, EGFR and RAD51D confirmed in the germline in 25-60%. Variants were rarely germline for TP53 (3%), APC (3%), PTEN (2%) and none in CDKN2A, NF1 and STK11. In 24 (2%) cases a LP/P germline variant was detected but not reported in the tumor. Conclusions: Approximately ⅓ of patients suspected to have hereditary risk after tumor testing had LP/P germline variants. Notably, some genes had a high probability of variants occurring in the germline, while others were primarily seen in tumors. Interestingly, 6% of the germline variants were not included on the somatic report due to technical and gene content differences in either assays or due to differences of clinical classification between somatic and germline testing. Adding germline results to somatic testing may inform options for precision treatment, prevention, or early detection of, secondary malignancies and guide genetic counseling of family members.
Comprehensive germline multigene panel testing changes clinical care for patients with breast cancer: Untapped clinical utility and PARP inhibitor trial eligibility.
Authors: Beitsch Peter D. , Whitworth Pat W. , Hughes Kevin S. , Patel Rakesh , Baron Paul , Rosen Barry , Grady Ian , Holmes Dennis , Simmons Rache M. , Smith Linda Ann , Compagnoni Gia , Coomer Cynara L. , Brown Eric Allen , Barbosa Karen , Clark Patricia , Gold Linsey P. , Riley Lee B. , Esplin Edward D. , Yang Shan , Nussbaum Robert L. 
Published: May 2019

1583 Background: HBOC testing guidelines were established to identify patients with clinically actionable variants and limit economic burden. We report the impact of germline results on health outcome based on clinical decision making and treatment interventions, regardless of guidelines, in a multi-center registry. Methods: 20 community-based and academic participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel; clinical information was collected. Results: Data on 912 patients has been analyzed to date. 50.5% met NCCN criteria; 49.5% did not. Pathogenic/likely pathogenic (P/LP) germline mutations were found in 8.65% of patients. Of all patients with P/LP findings, 85% had variants in cancer-risk genes with established management recommendations and 80% had germline variants conferring eligibility for clinical trials and precision medicine-based cancer treatments, such as PARP inhibitors. For 62% of patients with P/LP germline mutations, clinicians reported results impacted patients’ health outcome. And for 69%, results impacted the health outcome of patients’ relatives. There was no significant association between BRCAPRO scores and patients having a P/LP finding, whether in BRCA1/2 alone (p = 0.42) or for any cancer gene (p = 0.57). Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p < 0.00001). There was no significant difference in the clinician reported clinical utility of variants of uncertain significance (VUS) compared to negative results (p = 0.467). Conclusions: Comprehensive panel testing of breast cancer patients impacts physician assessed patient outcomes and informs changes in surgical treatment strategy, medical therapies and proactive screening. The data suggest that BRCAPRO calculators are poor predictors of germline presence of P/LP findings. Physicians in this study demonstrate the ability to discern the clinically actionable value of P/LP mutations from non-actionable VUS. Multigene panels impact breast cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance for patients and family members.
Randomized phase IIb clinical trial of continuation or non-continuation with six cycles of temozolomide after the first six cycles of standard first-line treatment in patients with glioblastoma: A Spanish research group in neuro-oncology (GEINO) trial.
Authors: Balana Carmen , Mesia Barroso Carlos , Berron Sonia Del Barco , Pineda Losada Estela , Muñoz-Langa José , Estival Anna , De las Peñas Ramon , Fuster Jose , Gil Gil Miguel J. , Navarro L Miguel , Alonso Miriam , Herrero Ana , Vaz Salgado María Ángeles , Peralta Sergi , Olier Clara , Pérez-Segura Pedro , Covela Rúa Marta , Carrato Cristina , Sanz Carolina , Sepulveda-Sanchez Juan Manuel 
Published: May 2019

2001 Background: The GEINO-14-01 trial (NCT02209948) investigated the role of extending temozolomide (TMZ) for 6 cycles after the standard 6 cycles to improve 6m-PFS, SLP and OS in newly diagnosed glioblastoma (GBM) patients (p). Methods: Between 08/2014 and 11/2018, 166 p were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment for 6 cycles after proving stable disease in the MRI performed before inclusion. Centralized review of histology and determination of MGMT status, if not previously available, were performed before randomizing patients. Two criteria of stratification were used: MGMT status and presence/absence of residual disease on the basal MRI (defined as a residual enhancement larger than 1cm in one). The primary endpoint was differences in 6mPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. Results: Median age was 60.3 (range 29-83), 97p (61%) were methylated, basal MRI showed residual disease in 57p (35.8%). After a median follow up of 14.0 months, with 121 p(76.1%) already progressed and 81p (50.9%) already dead, median PFS is presented. Median (m) PFS is 8.0 months (95%CI: 5.7-10.2). There is no difference in mPFS between arms (adjusted HR = 0.98, 95% CI: 0.82-1.18, P = 0.907). Methylated tumors had longer mPFS (HR=0.57, 95% CI: 0.39-0.83, P=0.004) irrespectively to the study treatment. Conclusions: There is not apparent benefit of continuing TMZ treatment for more than 6 cycles. Data will be actualized for the congress.Supported by a Grant of the ISCIII: PI13/01751. Clinical trial information: NCT02209948.
A phase I study of convection-enhanced delivery of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.
Authors: Souweidane Mark M. , Kramer Kim , Pandit-Taskar Neeta , Zhou Zhiping , Zanzonico Pat , Donzelli Maria , Lyashchenko Serge K. , Haque Sofia , Thakur Sunitha B , Cheung Nai-Kong V. , Larson Steven M. , Dunkel Ira J. 
Published: May 2019

2008 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.
Circulating tumor DNA analysis (ctDNA) for genomic testing in NSCLC patients with isolated CNS progression.
Authors: Aldea Mihaela , Mezquita Laura , Hendriks Lizza , Auclin Edouard , Remon Jordi , Planchard David , Jovelet Cecile , Benitez Jose Carlos , Gazzah Anas , Lavaud Pernelle , Naltet Charles , Lacroix Ludovic , Morris Clive D. , Green Emma , Howarth Karen , Nicotra Claudio , Besse Benjamin 
Published: May 2019

2015 Background: Genomic DNA profiles are mandatory in advanced, treatment naive non-small cell lung cancer (NSCLC) patients (pts) and strongly recommended at progression (PD) on personalized treatment. In pts with PD limited to central nervous system (CNS), tissue biopsy is difficult and the performance of ctDNA is unknown. Methods: Clinical, molecular, imaging data of NSCLC pts included in 2 prospective studies from 01.2016 to 11.2018 at Gustave Roussy were collected. Inclusion criteria were: stage IV disease and any known tissue genomic alteration (GA) EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, TP53. Plasma ctDNA collected at baseline/PD were analyzed by next-generation sequencing (NGS-InVisionFirst™-Lung) in 3 groups: pts with isolated CNS (iCNS), extra-CNS only (noCNS) or both combined (cCNS) disease. iCNS was defined as any PD to CNS, while stable/absent extra-CNS metastases (mts). ctDNA was considered positive if ≥1 GA was found. ctDNA in cerebrospinal fluid (CSF) were also collected. Results: Out of 245 pts with ≥1 ctDNA: 56 had iCNS (66 samples), 97 noCNS (127 samples) and 92 cCNS (107 samples). In this cohort, 60% were female, median age 60 years, 47% smokers; 92% had adenocarcinoma. The median number of mts sites was 3 in noCNS/cCNS groups. Proportions of tissue GA at baseline were (iCNS vs noCNS/cCNS): EGFR (50% vs 44%), ALK (30% vs 11%), BRAF (4% vs 12%), KRAS (5% vs 15%), HER2 (2% vs 5%), ROS1 (5% vs 4%). Tyrosine kinase inhibitors were used in 73% iCNS vs 61% noCNS/cCNS. Local brain treatments were performed in 43% (n = 24) vs 32% (n = 29) and leptomeningeal mts (LM) detected in 34% (n = 19) vs 8% (n = 9), in iCNS and cCNS, respectively. CtDNA was positive (+) in 52% in iCNS vs 84% in noCNS and 92% in cCNS (p < 0.0001). In iCNS, there was a non-significantly higher proportion of + ctDNA in pts with LM vs only brain disease (59 vs 48%, P = 0.44). 12/56 pts of iCNS group had serial ctDNA, being collected also at time of cCNS. In 25% of cases, a negative ctDNA at time of iCNS shifted to + at time of cCNS. In 12 iCNS pts, ctDNA was + in 6 (50%) plasma and in 10 (83%) paired CSF (p = 0.193). Conclusions: Detection of GA by plasma ctDNA is lower in NSCLC pts with isolated CNS PD. Alternative strategies (as CSF analysis) should be explored.