bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole genome and transcriptome analysis and the link between insulin receptor aberration and diabetes in PDAC.
Authors: Lee Michael , Topham James T. , Kalloger Steve , Mendis Shehara Ramyalini , Tsang Erica S. , Karasinska Joanna , Loree Jonathan M. , Schaeffer David F. , Renouf Daniel John 
Published: February 2020

743 Background: Pancreatic ductal adenocarcinoma’s (PDAC) association with diabetes development remains poorly understood. The insulin receptor ( INSR) can divert insulin signaling from metabolic to oncogenic pathway activation through alternative splicing of INSR in several cancer types. Methods: 54 treatment naïve patients with metastatic PDAC underwent fresh tumour biopsy in the BC Cancer Personalized Oncogenomics (POG) and PanGen studies (NCT02155621, NCT02869802) for whole genome (WGA) and transcriptome analysis (RNASeq). Copy status and expression of INSR were correlated with T2DM status, Moffitt subtypes, and overall survival (OS). The findings were then correlated with 92 resected PDAC from the International Cancer Genome Consortium (ICGC). Results: 13/54 (24%) had confirmed T2DM at enrollment, and had poorer OS compared to non-diabetic PDAC patients, independent of Moffitt subtype, HR 3.2 (1.5-6.5), p =0.001. Diabetics were more likely to have hypertension (64 v 11%, p <0.001), dyslipidemia (57 v 16%, p=0.013), and to be older (61.5 v 58 years, p=0.014) and smokers (71.4 v 21.6%, p=0.015). WGA revealed significant enrichment of heterozygous INSR copy loss in T2DM (69%) compared to all other patients (24%; p=0.03) and an enrichment of INSR copy loss for metastatic PDAC relative to resected PDAC in ICGC (35 v 18%, p=0.03). Heterozygous INSR copy loss (n = 17/54) was an independent predictor of worse OS (10.8 v 15.1 months, HR 2.29 (1.20-4.36), p=0.012), and it interacted with diabetes status (p=0.023). Moffitt basal (vs. classical) subtype (n = 17/54, of which 8/17 have INSR copy loss) was also an independent predictor of OS with HR 4.3 (2.1-8.7), p<0.001. Whilst there was no interaction between INSR status and Moffitt subtype on OS (p=0.727), INSR expression is lower in basal subtype, p<0.001. Conclusions: Presence of T2DM in our cohort is an independent predictor of worse OS, consistent with published literature. Alteration in the insulin signalling pathway with heterozygous copy loss of INSR was associated with poorer prognosis, diabetes development and overlapped with Moffitt basal subtype.
Noninvasive comprehensive genomic profiling from plasma ctDNA in pancreatic cancer patients.
Authors: Bitterman Danielle Sara , Price Kristin Sedgwick , Van Seventer Emily E. , Clark Jeffrey William , Allen Jill N. , Blaszkowsky Lawrence Scott , Ryan David P. , Eyler Christine Elissa , Wo Jennifer Yon-Li , Hong Theodore S. , Nipp Ryan David , Roeland Eric , Murphy Janet E. , Corcoran Ryan Bruce , Weekes Colin D. , Parikh Aparna Raj 
Published: February 2020

753 Background: The use of comprehensive genomic profiling (CGP) is increasing in pancreatic ductal adenocarcinoma (PDAC) as knowledge improves regarding molecular drivers of tumorigenesis and effective targeted therapies emerge. However, adequate tissue sampling is often limited. Plasma-based CGP offers a non-invasive approach to assess biomarkers that may impact treatment decisions. Methods: We retrospectively evaluated genomic and clinical data from 97 PDAC patients with circulating tumor DNA (ctDNA) testing from 9/2016-8/2019 (Guardant Health, Inc.). ctDNA analysis included single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 74 genes. ctDNA results were assessed across clinical variables. We evaluated for actionable alterations. Results: A total of 114 samples were obtained from 97 patients for ctDNA testing. ctDNA alterations were detected in 82% (93/114) of all samples, including 90% (18/20) at diagnosis, 88% (59/67) at progression, and 56% (10/18) while on stable therapy. ctDNA alterations were found at each stage of PDAC: in 25% (1/4) of samples with resectable disease, 75% (3/4) with borderline resectable disease, 82% (9/11) with locally advanced disease, and 85% (81/95) with metastatic disease. One or more KRAS alterations were detected in 55% (51/93) of patients with alterations present. The median maximum mutant allele frequency was similar between the cohort of patients with KRAS detected (0.55%) versus not detected (0.70%). 8% (8/97) of patients had potentially actionable alterations (2 activating BRAF SNVs, 1 ERBB2 CNV, 1 ERBB2 activating SNV, 1 KRAS G12C, and 3 indels in Homologous Recombination Deficiency genes). Median turnaround time was 8 days. 51% (49/97) of patients had both plasma-based CGP and tissue-based CGP. Of these patients, tissue-based CGP showed ≥ 1 alterations detected in 82% (40/49), test failure in 14% (7/49), and no alterations detected in 4% (2/49). Conclusions: Plasma-based CGP detected ctDNA alterations in 90% of samples tested at diagnosis and 82% of all samples. Potentially actionable mutations were found in 8% of patients, with prompt processing time allowing for rapid decision making.
Patterns of failure after adjuvant stereotactic body radiation therapy in patients with pancreatic cancer with close or positive margins.
Authors: Patel Ankur , Rodríguez-López Joshua L. , Bahary Nathan , Zureikat Amer H. , Burton Steven A. , Heron Dwight Earl , Olson Adam C. 
Published: February 2020

755 Background: There is no consensus on treatment volumes for stereotactic body radiation (SBRT) in patients with pancreatic cancer (PCa). Herein, we report patterns of failure following adjuvant SBRT for close/positive margins in patients with pancreatic cancer, which may inform appropriate target volume design for SBRT. Methods: An IRB-approved retrospective review of patients with PCa treated with adjuvant SBRT for close/positive margins from 2009-2018 was conducted. Patterns of failure were assessed by review of imaging and were defined as local (LF), regional (RF), local and regional (LRF), or distant (DF). The Kaplan-Meier method was used to calculate long-term failure rates. In-field failures were defined as LFs completely within the PTV (planning target volume). The location of LFs was compared to the RTOG consensus volumes for adjuvant treatment of PCa to determine if conventional radiation volumes would have included the LF. Results: Seventy-six patients were treated with adjuvant SBRT for close (51.3%) or positive (48.7%) margins, with a median follow-up of 17.0 months (interquartile range [IQR] 7.4-28.3 mos.). Adjuvant SBRT was delivered at a median of 2.2 months after surgery (IQR 1.7-3.0 mos.). Most patients (81.6%) received 36 Gy in 3 fractions. The median PTV volume was 17.8 cc (IQR 12.3-25.2 cc). Upon examination of first failure sites, crude rates of isolated LF, isolated RF, isolated LRF, and DF +/- LF or RF were 9.2%, 6.6%, 2.6%, and 56.6% respectively; 2-year rates were 12.4%, 11.5%, 7.0%, and 66.5%, respectively. Thirty-two patients (42.1%) developed a LF at some point during follow-up. Of 28 LFs with available plans and imaging, 21.4% were in-field failures, while the remainder were completely outside (60.1%) or partially outside (17.9%) the PTV. Most LFs outside the PTV (90.9%) would have been encompassed by the RTOG consensus target volumes for postoperative conventional radiation. Conclusions: In patients with PCa who receive adjuvant SBRT for close/positive margins, the majority of LFs are outside the PTV. Future trials involving SBRT or hypofractionated radiation should consider expansion of treatment volumes if feasible.
PD-L1 expression, tumor mutational burden, and microsatellite instability status in 746 pancreas ductal adenocarcinomas.
Authors: Hemmerich Amanda , Edgerly Claire I. , Duncan Daniel , Huang Richard , Danziger Natalie , Frampton Garrett M. , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Lin Douglas I. , Williams Erik , Ali Siraj Mahamed , Reddy Prasanth , Miller Vincent A. , Owens Clarence , Brown Charlotte , Alexander Brian M , Ross Jeffrey S. , Severson Eric Allan , Ramkissoon Shakti H. 
Published: February 2020

757 Background: Pancreas ductal adenocarcinomas (PDA) has a 5-year survival rate of 6% with a need for new therapeutic options. The approval of pembrolizumab for some gastrointestinal cancers shows the potential of immunotherapy (IMT) in PDA. We evaluated the IMT-associated biomarkers of PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 amplification in PDAs. Methods: 746 formalin-fixed paraffin embedded samples were evaluated for PD-L1 IHC using the Dako 22C3 pharmDx assay and scored using tumor proportion score (TPS). The cases had comprehensive genomic profiling (CGP) via DNA sequencing, using a hybrid-capture next-generation sequencing assay (FoundationOne and FoundationOneCDx) for genomic alterations (GAs), TMB, and MSI. Results: PD-L1 was positive (TPS ≥ 1%) in 29% (214/746) and negative in 71% (532/746). 43/214 (20%) of positive cases were high positive (TPS ≥ 50%). TMB (590 cases) had a mean of 3.20, 3.46, and 3.61 mutations/Mb for PD-L1 negative, positive, and high positive groups. 3 hypermutated (TMB ≥ 20) were negative for PD-L1 expression. 3/581 cases were MSI-high with a high TMB score (average 23.53 mutations/Mb). 2 MSI-high cases were negative for PD-L1 and 1 was high positive. PD-L1 amplification was not detected (0/746). Only BCOR was significantly different between PD-L1 high positive and PD-L1 negative tumors (Table). Conclusions: Of 729 PDA cases, 29% were positive (TPS ≥ 1%) for PD-L1 expression while only 6% of all cases showed a high level of PD-L1 expression on tumor cells. TMB high (3/729) and MSI-High (3/729) cases were rare. Only 2 of the TMB high cases were also MSI-high. PD-L1 amplification was not detected. Comparing GAs in PD-L1 high positive vs negative cases was only significantly different for BCOR. Further investigation is needed to see if a combined positive score of PD-L1 expression may identify a subset of patients with PDA who are more likely to respond to IMT. [Table: see text]
Utilization of somatic comprehensive genomic profiling (CGP) to identify patients (pts) with pancreatic cancer (PC) that harbor germline DNA damage repair (DDR) gene alterations.
Authors: Lasowski Matthew , Stachowiak Samantha , Arapi Igli , Dua Kulwinder , Khan Abdul H. , Hall William Adrian , Erickson Beth , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Urrutia Raul , Ritch Paul S. , Kamgar Mandana , Thomas James P. , George Ben 
Published: February 2020

760 Background: Somatic and germline DDR gene alterations in PC have been postulated to positively predict response to DNA damaging cytotoxic agents. Due to the relatively high prevalence of germline DDR gene alterations, germline testing is recommended in all pts with PC. We examined whether somatic CGP can be used to reliably identify PC pts that merit germline testing. Methods: We retrospectively reviewed the electronic medical records of PC pts who underwent both somatic CGP (utilizing the Foundation One assay) and germline testing. DDR gene mutations were categorized as somatic-pathogenic, somatic-variant of uncertain significance (VUS), germline-pathogenic and germline-VUS. For somatic testing, DNA was extracted from formalin fixed paraffin embedded (FFPE) clinical specimens and CGP was done on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Germline genetic testing was performed on submitted blood or saliva samples, utilizing commercial assays; next generation or Sanger sequencing of all coding regions and adjacent intronic nucleotides were performed. Results: Ninety-three pts had somatic CGP data, 51 (55%) pts had both somatic CGP and germline data available. Among the 51 pts with both germline and somatic data available, DDR gene alterations that were somatic-pathogenic, germline-pathogenic, somatic-VUS and germline-VUS were present in 7 (13.7%), 7 (13.7%), 23 (45.1%) and 16 (31.4%) pts, respectively. Of the 7 pts with somatic-pathogenic alterations, 5 (71%) had a concordant germline alteration and of the 7 pts with germline-pathogenic alterations, 5 (71%) had a concordant somatic alteration. Of the 23 pts with somatic-VUSs, 12 (52%) had a concordant germline VUS and of the 16 pts with germline-VUSs, 12 (75%) had a concordant somatic VUS. Conclusions: Both somatic and germline DDR gene alterations are common in PC pts. Despite the relatively high concordance rate between somatic and germline pathogenic DDR gene alterations, somatic CGP will miss approximately one fourth of the germline DDR gene alterations.
Prognostic significance of familial pancreatic cancer after surgery.
Authors: Tezuka Koji , Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ohgi Katsuhisa , Uesaka Katsuhiko 
Published: February 2020

772 Background: Familial pancreatic cancer (FPC) is defined as two first-degree relatives with pancreatic cancer. It is known that the risk of developing pancreatic cancer increases in those who have a family history of pancreatic cancer in first-degree relatives. However, prognostic significance of FPC after surgery is not fully understood. Methods: Patients who underwent pancreatectomy for pancreatic ductal carcinoma between January 2008 and December 2016 were retrospectively reviewed. The prognostic significance of FPC was analyzed. Results: A total of 423 patients underwent pancreatectomy for pancreatic ductal carcinoma. FPC was identified in 32 (7.6%) patients. Recurrence occurred in 72% of all resected cases and in 88% of resected FPC cases. Multivariate analysis revealed FPC (hazard ratio [HR] 1.60; P=0.026), CA19-9 ≥300 U/ml (HR 1.54; P=0.001), lymph node metastasis (HR 2.10; P<0.001), microscopic venous invasion (HR 1.64; P<0.001), nerve plexus invasion (HR 1.39; P=0.010), R1 resection (HR 1.65; P=0.010), and lack of adjuvant chemotherapy (HR 2.27; P<0.001) as independent predictors for recurrence-free survival (RFS). The univariate analysis revealed that FPC is significantly associated with worse overall survival (OS) (P=0.018). The multivariate analysis showed that FPC was not an independent predictor of OS. This cohort was divided into 314 patients (FPC: 18 patients, non-FPC: 296 patients) who received adjuvant chemotherapy (AC group) and 109 patients (FPC: 14 patients, non-FPC: 95 patients) received no adjuvant chemotherapy (no AC group). In AC group, FPC is an independent predictor for RFS (HR 3.03; P<0.001) and OS (HR 2.23; P=0.018). In no AC group, FPC is not a predictor for RFS and OS. Conclusions: This study may show that FPC has a significant impact on RFS and OS after resection in patients who received adjuvant chemotherapy.
Radiotherapy use in the treatment of gastrointestinal cancers in Medicare patients: An analysis of a CMS database.
Authors: Konski Andre A. , Havrilesky Laura Jean , Jewell Elizabeth Lin , Efstathiou Jason A. 
Published: February 2020

800 Background: CMS announced plans to pilot an alternative payment model (APM) utilizing a fixed payment per ICD-10 code for 17 malignancies. CMS released payment data used to calculate the base payments. The purpose of this study was to analyze radiotherapy use in patients with gastrointestinal malignancies to obtain baseline utilization and payment prior to the APM start. Methods: The CMS database, CY2015-2017, contained payment, anatomic site and limited patient data on 517,988 patients, 48,032 of which were identified as gastrointestinal (GI) cancers, (Anal (A) Colorectal (CR), Pancreatic (P), Upper GI (UGI), or Liver(L) cancers) all histologies included. Stata 15, College Station, Texas, was used to perform all statistical analysis. Payments were calculated using only CPT codes for radiotherapy and only include the first 90 days after a treatment planning charge was registered. Results: Anatomic site breakdown was 4940 A, 16,099 CR, 6,970 P, 14,750 UGI and 5,273 L cancers. Patient treatments by year were15,697 in 2015, 16,309 in 2016 and 16,026 in 2017. Use of proton therapy and IMRT increased from 2015-2017 (193 (1.2%) to 302 (1.9%) and 8,107(52%) to 8838 (55%), respectively) whereas use of conventional external beam decreased from 6544 (42%) in 2015 to 5377(34%) in 2017. Of interest, 10,336 (668 A, 3363 CR, 2847 L, 1083 P, and 2375 UGI) of the 48,032 patients receiving radiotherapy were coded as not receiving chemotherapy. Mean professional and technical payments were $28,380.97 (SD $6779.18) for proton beam therapy, $18,186.77 (SD $4534.3) for IMRT, $10,724.88 ($4797.19) for conventional external beam therapy, $13,967.66 (SD $5186.92) for stereotactic, and $19,707 (SD$7393.81) for brachytherapy. Results by anatomic site will be presented. Conclusions: This study provides a baseline for comparison for treatment technique and payment once the APM has been completed. These claims are limited by the lack of available information on specific age, stage or other co-morbidities. Use of proton beam therapy has increased in this population, but remains a small percentage of radiotherapy technique used. 25% of patients receiving radiotherapy were not coded as receiving chemotherapy.
Relevance of real-time teletransmission of physical activity, sleep, and circadian rhythms from gastrointestinal cancer (GIC) patients (pts) during daily routine (IDEAs, IRAS 233972).
Authors: Levi Francis , Komarzynski Sandra , Huang Qi , Young Teresa , Ang Yeng , Fuller Claire , Brettschneider Julia , Finkenstadt-Rand Barbel , Fursse Joanna , White David-Pollard , Innominato Pasquale 
Published: February 2020

801 Background: The relative amount of activity and rest over the 24-hours, as measured by the dichotomy index I < O from actimetry records, is an independent predictor of overall survival and quality of life, and an early warning signal for emergency hospitalisation. The IDEAs study aimed to determine the sleep, physical and circadian pathologies in pts during their daily routine at home, which could lower I < O and be modifiable through personalised interventions. Methods: The rest-activity and surface temperature patterns were monitored in real time using a tele-transmitting chest sensor and a GPRS-platform for one week in 25 pts, with a WHO performance status of 0-1 and metastatic GIC (colorectal, 56%). Each pt completed questionnaires including Chronotype, HADS, and Pittsburgh Sleep Index, filled a precise diary of daily activities, meals and sleep times, and the MD Anderson Symptoms Inventory daily. I < O counts the In-bed activity bouts per min that are below the median activity Out-of-bed. Other pt-specific circadian parameters were estimated with spectral analyses and Hidden Markov models (HMM). I < O predictors were identified through correlation and regression analyses. Results: A poor I < O was found for 13 pts (52%). Self-reported scores for sleep quality or physical fitness showed no significant differences according to I < O. Yet HMM-modelled rest-activity revealed that pts with poor I < O had lower activity out-of-bed (median activity counts per minute, 110 vs 52, p = 0.001) and fractionated sleep (probability of remaining at rest when asleep, 94% vs 90%, p = 0.01). Poor I < O was significantly associated with an abnormal circadian rhythm in chest surface temperature, that was either wrongly timed or suppressed, for 83% of the pts as compared to 25% of those with a good I < O (p = 0.012). Conclusions: Nearly half of the pts displayed altered circadian rest-activity rhythm, with poor sleep and low daytime activity. In most of them, the circadian rhythm in body temperature, which critically regulates sleep, was abnormal. Exploration and specific treatment of sleep and circadian disorders are warranted for improving outcomes in cancer pts. Clinical trial information: 233972.
Family history (FH) of gastrointestinal (GI) cancer and behavioral risks: Analysis of an Internet-based risk assessment tool.
Authors: O'Keefe Ryan M. , Lariviere Michael Joseph , Amaniera Isabella , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Metz James M. , Hill-Kayser Christine E. 
Published: February 2020

807 Background: Certain behaviors are known modifiable risk factors for development of GI cancers. The relationship between family history (FH) of GI cancers and individuals’ behaviors is not well understood, but is important for risk assessment/ counseling. Methods: The OncoLink “Reduce My Risk” tool is a publicly available online survey created in 2009 to provide customized information regarding cancer risk. Details of this survey have been reported; research is IRB-approved. Differences between those with v. without FH of GI cancers were analyzed using chi-square test. Results: 28,001 surveys were submitted. Median age was 26y (18-101), 60% female, 87% lived in North America, 76% White/Non-Hispanic, 64% reported FH of cancer. Individuals with FH of CRC reported eating less red meat (31% v. 34%, p = 0.007), processed grains (55% v. 59%, p < 0.001), or charred meats (14% v. 19%, p < 0.001), but were equally likely to be vegetarian (9% v. 10%, p = 0.059). Those with FH of esophageal cancer were more likely to have GERD (16% v. 9%), smoke > = 1 pack per day (7% vs. 4%) and drink alcohol (63% v. 55%) (p < 0.001 for all). Those with FH of gastric cancer were more likely to have H. Pylori or gastric ulcers (5% v. 3%, p < 0.001), but no difference in the consumption of smoked/salted foods (27% v. 25%, p = 0.20). Those with FH of HCC reported no differences in alcohol consumption (56% v. 55%, p = 0.41) or hepatitis B virus (HBV) vaccination (62% v. 62%, p = 0.66). Those with FH of anal cancer were more likely to have receptive anal intercourse (26% v. 16%, p < 0.001) but showed no differences in human papillomavirus (HPV) vaccination (21% v. 22%, p = 0.91). Those with FH of HCC (15% v. 13%, p = 0.035), gastric (16% v. 13%, p = 0.001), esophageal (17% v. 13%, p < 0.001), and anal (21% vs. 13%, p < 0.001) cancers were more likely to be smokers; those with a FH of CRC were less likely (11% v. 13%, p = 0.006), and those with FH of pancreatic (12% vs. 13%, p = 0.71) or cholangiocarcinoma (15% vs. 13%, p = 0.59) showed no difference. Conclusions: Many individuals with a FH of GI cancers engage in behavioral and other modifiable risk factors that increase risk for GI and other cancers. Future work should explore utility of targeted intervention and screening.