bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA-damage repair deficiency (dDDR) and response to nanoliposomal irinotecan (nal-IRI) in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Rau Sameeha , Espejo Freire Andrea P. , Terrero Gretel , Patel Manisha Jayandra , Rush Benjamin Woodress , Rocha Lima Caio Max Sao Pedro , Hosein Peter Joel 
Published: February 2020

731 Background: Chemotherapy is the standard of care for patients with mPDAC but there are no biomarkers to aid in treatment selection. Nal-IRI with 5-fluorouracil/folinic acid (FUFA) improves survival over FUFA in the second-line treatment of mPDAC. Nal-IRI is a topoisomerase inhibitor and its action produces DNA damage leading to cell death. We hypothesize that tumors with dDDR, a process that is altered in a subset of patients with PDAC, may be more sensitive to the effects of nal-IRI. Methods: Utilizing the IRB-approved pancreas cancer databases at the University of Miami and Wake Forest University, we identified patients with mPDAC treated with nal-IRI and FUFA who had germline and/or somatic mutation testing. We conducted a retrospective chart review to extract demographic and clinical characteristics including treatments received, response, and survival. Results: Among 31 patients identified, the median age was 66y and 47% were female. Nine patients had a DDR mutation; 6 germline and 3 somatic. Median progression-free survival (PFS) in patients with any germline or somatic DDR mutation was 3.2m vs 3.9m for those without (log-rank p = 0.7). When restricted to germline DDR mutations only, the median PFS was not reached with germline dDDR vs 4m for those without (log-rank p = 0.22). Presence of dDDR was associated with a higher clinical benefit rate (CBR = partial response + stable disease); a DDR mutation was present in 36% of patients who showed clinical benefit vs 15% in those without clinical benefit (p = 0.21). Conclusions: DDR mutations appear to define a subset of patients with mPDAC who may be more sensitive to nal-IRI and FUFA. The PFS and CBR were numerically but not statistically superior, especially in patients with germline DDR mutations. Larger data sets and longer follow-up are needed to confirm this trend.
Gray areas and evidence gaps in the management of rectal cancer as revealed by the comparison of recommendations from national and international clinical guidelines.
Authors: Bregni Giacomo , Akin Telli Tugba , Camera Silvia , Baratelli Chiara , Shaza Leila , Deleporte Amélie , Moretti Luigi , Liberale Gabriel , Hendlisz Alain , Sclafani Francesco 
Published: February 2020

74 Background: While the management of nonmetastatic and oligometastatic rectal cancer has rapidly evolved over the last few decades, many grey areas and highly debated topics remain that foster significant variation in clinical practice. We aimed to identify controversial points and evidence gaps in this disease setting by systematically comparing recommendations from national and international clinical guidelines. Methods: Twenty-six clinical questions reflecting practical challenges in the routine management of nonmetastatic and oligometastatic rectal cancer patients were selected. Recommendations from the ESMO, NCCN, JSCCR, Australian and Ontario guidelines were extrapolated and compared using a 4-tier classification system (i.e., identical/very similar, similar, slightly different, different). Overall agreement between guidelines (i.e., substantial/complete disagreement, partial disagreement, partial agreement, substantial/complete agreement) was assessed for each clinical question and compared against the highest level of available evidence according to the Oxford CEBM Levels of Evidence guidelines by using the χ2 statistic test. Results: Guidelines were in substantial/complete agreement, partial agreement, partial disagreement, and substantial/complete disagreement for 8 (30.8%), 2 (7.7%), 7 (26.9%), and 9 (34.6%) clinical questions, respectively. High level of evidence supported clinical recommendations in 2/10 cases (20%) where guidelines were in agreement and in 10/16 cases (62.5%) where guidelines were in disagreement (χ2 = 4.4726, p = 0.034). Agreement was frequently reached for questions regarding diagnosis, staging, and radiology/pathology pro-forma reporting, while disagreement characterised most of the treatment-related topics. Conclusions: Substantial variation exists across national and international clinical guidelines in the recommendations for the management of nonmetastatic and oligometastatic rectal cancer. This variation is only partly explained by the lack of supporting, high-level evidence.
Clinical significance of MUC4 isoforms in pancreatic cancer patients.
Authors: Thompson Christopher M , Cannon Andrew , Kshirsagar Prakash , Bhatia Rakesh , Batra Surinder , Kumar Sushil 
Published: February 2020

742 Background: Pancreatic adenocarcinoma (PC) is a highly aggressive cancer with a 5-year survival rate around 9% with majority of patients diagnosed at advanced stage. Prior studies describe transcriptomic alterations during tumorigenesis, of which novel and progressive expression of mucins are significant. Mucins are large secreted or membrane-tethered glycoproteins that have been shown to be of pathogenic importance in PC. Methods: We explored differential expression and survival outcomes based on mucin expression using TCGA PC patients (n = 150). RNA-Seq. reads were realigned to all known mucin splice variant (SV) sequences. Hazard ratios (HR) were calculated for all SVs (n = 123), and SVs with significant HRs were plotted on Kaplan-Maier survival curves comparing expression about the median. The MUC4 SV (MUC4Δ6) was selected for validation in patient tumor samples (n = 17) due to PC tumor cell-specific expression and in-frame deletion of a single exon. After discovery of significant mucin SVs, we designed a gold-nanoparticle (GNP) assay to specifically detect MUC4Δ6 in circulation from PC patient plasma. Results: In the absence of significant mucin-based survival differences, we expanded our analysis to include mucin SV transcripts. Through hazard and survival analyses, we identified 3 MUC1 SVs with better survival (SV1 HR = .61, p = .033; SV2 HR = .64, p = .05; SV3 HR = .62, p = .04), and one each of MUC4 (HR = 1.93, p = .028) and MUC16 (HR = 1.90, p = .027) with worse prognosis. In a validation cohort, we found 10 samples had a high cellularity (HC) gene signature. Expression of MUC4Δ6 was 4804.7 copies/100,000 GPI copies in the HC population and expressors above the median had a median survival of 397 days compared to1964.5 days (p = .191) in low expressors. Our novel GNP assay detected MUC4∆6 transcripts at minimum concentrations of 100 fM with a synthetic RNA. Uniquely, our assay detects the MUC4∆6 SV but not wild-type variant. Conclusions: We were able to determine that expression of specific mucin SV are prognostic in PC patients. We developed technology to detect MUC4Δ6 transcript in circulation using a novel GNP assay. Future studies will seek to stabilize the nanoparticles and modify them for potential diagnostic purposes in a clinical setting.
CEACAM6 as a candidate biomarker for pelareorep sensitivity in pancreatic adenocarcinoma (PDAC).
Authors: Noonan Anne M. , Yount Jacob , David Jason , Hoang Mindy , Stets Colin W. , Bekaii-Saab Tanios S. , Huang Ying , Frankel Wendy L. , Timmers Cynthia Dawn , Hays John L. , Chen James Lin 
Published: February 2020

746 Background: Pelareorep is a proprietary formulation of live, replication-competent, naturally occurring Reovirus Type 3 Dearing strain. A randomized phase II trial of pelareorep in combination with carboplatin and paclitaxel in first-line treatment of metastatic PDAC (NCT01280058) was performed. Although pelareorep did not improve the primary endpoint of progression-free survival compared to carboplatin and paclitaxel alone, impressive durable responses were seen in the pelareorep arm in some patients (pts). Further, prior studies have noted the immunomodulatory carcinoembryonic antigen-related cell adhesion molecule (CEACAM6/CD66c) as a receptor for specific viral subtypes. We thus speculated that altered CEACAM6 levels may be predictive for pelareorep sensitivity. Methods: Pre-treatment tissue biopsies were collected prior enrolment for all 73 pts on study. Evaluable pts with transcriptomic data was available for only 31 pts. RNA was purified from FFPE tissue and gene expression analysis was performed using SensationPlus FFPE Amplification and WT labelling kit and the Human Transcriptome Array 2.0. CEACAM6 protein expression was determined by immunohistochemistry. Differential gene expression and survival analysis using were performed in R/Bioconductor. Appropriate corrections for multiplicity were performed. Results: When comparing extraordinary responders in the pelareorep treated arm to those with poor outcomes, low levels of CEACAM6 mRNA expression were associated with prolonged PFS in pelareorep-treated pts (adjusted p = 0.05). This effect was not seen in non-pelareorep treated pts. The luminal, but not the cytoplasmic immunohistochemistry score, was highly correlated with mRNA expression levels of CEACAM6, p = 0.001. Modulation of CEACAM6 in vitro and in vivo are underway. Conclusions: CEACAM6 may be a candidate biomarker of sensitivity to pelareorep and, in theory, could improve viral trafficking of this compound in tumor cells. Clinical trial information: NCT01280058 . [Table: see text]
The relationship between perioperative markers of the systemic inflammatory response and postoperative complications in patients undergoing curative resection of colon cancer.
Authors: Knight Katrina , Choong Jia Xun , Roxburgh Campbell SD , Horgan Paul G. , McMillan Donald C. 
Published: February 2020

75 Background: Surgical resection remains the mainstay of treatment for patients with potentially curable colorectal cancer (CRC). However, it can be associated with the development of postoperative complications (POC), which are associated with an increased cancer recurrence risk. Neutrophils are important in innate immunity, especially in the immediate postoperative period as part of the systemic inflammatory response (SIR). We aimed to assess the use of perioperative SIR markers as predictors of POC. Methods: Patients undergoing elective curative CRC surgery at one institution between March 2008 and June 2015 were identified from a prospective database. Demographics and clinicopathological data were extracted from medical records. Logistic regression was used to assess the relationship between perioperative blood counts, clinicopathological variables and POCs. Results: Of 443 cases, most were aged 65 years or older (n = 314, 71%), male (n = 245, 55%), smokers (n = 229, 52%), overweight or obese (n = 263, 59%) and had ASA score of 2 or less (n = 267, 60%). The majority underwent open resection (n = 288, 65%). Preoperative factors associated with the development of POC were: ASA grade > 2 (OR 1.48, 95% CI 0.99-2.18, p = 0.05), smoking history (OR 1.99, 95% CI 1.35 – 2.93, p < 0.001), neutrophil count > 7.5x109/L (OR 3.40, 95% CI 1.82-6.36, p < 0.001) and CRP > 10mg/L (OR 1.70, 95%CI 1.12-2.59, p = 0.013). Postoperative factors associated with the development of POC were open surgery (OR 0.47, 95%CI 0.31-0.72, p < 0.001), neutrophil count > 7.5x109/L (OR 2.67, 95%CI 1.75-4.07, p < 0.001) and CRP > 150mg/L (OR 3.97, 95%CI 2.61-6.02, p < 0.001) on postoperative day 3 (POD3). On multivariate analysis, a preoperative neutrophil count > 7.5x109/L (OR 3.65, 95%CI 1.68-7.90, p < 0.001), a neutrophil count > 7.5 x109/L on POD3 (OR 1.69, 95%CI 1.05-2.72, p = 0.029) and CRP > 150mg/L on POD3 (OR 3.66, 95%CI 2.29-5.87, p < 0.001) were related to POC, independent of smoking, ASA and operative approach. Conclusions: Neutrophil count complements the prognostic value of pre and post-operative CRP to predict POC. Further validation work is required.
Association of SMAD4 loss with response to neoadjuvant chemotherapy with the autophagy inhibitor hydroxychloroquine in patients with pancreatic adenocarcinoma.
Authors: Fei Naomi , Wen Sijin , Rao Pavan , Ramanathan Rajesh , Hogg Melissa E. , Zureikat Amer H. , Lotze Michael T. , Bahary Nathan , Singhi Aatur D. , Zeh Herbert , Boone Brian A. 
Published: February 2020

761 Background: SMAD4, a tumor suppressor gene, is inactivated or deleted in 60-90% of pancreatic adenocarcinomas (PDA). Loss of SMAD4 allows tumor progression by limiting cell cycle arrest and apoptosis and increasing metastases. SMAD4 deficient PDA cells are resistant to radiotherapy by upregulation of autophagy, a cell survival mechanism that allows intracellular recycling of macromolecules and organelles. Hydroxychloroquine (HCQ) is a known autophagy inhibitor, suggesting that HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. Methods: We retrospectively analyzed the SMAD4 status of PDA patients enrolled in two prospective clinical trials evaluating preoperative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ ( NCT01128296 ). More recently, a randomized trial of gemcitabine/nab-paclitaxel +/- HCQ evaluated Evans Grade histopathologic response ( NCT01978184 ). Immunohistochemistry of resected specimens for SMAD4 was previously performed. Patients not treated at the max HCQ dose (n = 5), not resected (n = 2) or with SMAD4 staining unavailable were excluded (n = 10). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log-rank test were used to assess response and survival. Results: 52 patients receiving HCQ with neoadjuvant chemotherapy and 24 patients receiving neoadjuvant chemotherapy alone were studied. Of the HCQ group, 25 patients had SMAD4 loss (48%), compared with 15 control patients (63%, p = 0.32). 76% of HCQ treated patients with SMAD4 loss obtained a histopathologic response ≥2A, compared to only 37% with SMAD4 intact (p = 0.006). In the control group, loss of SMAD4 was associated with a nonsignificant detriment in 3 year OS (25% vs. 78%, p = 0.3) that was less apparent in patients treated with HCQ (46% vs. 47%, p = 0.18). Conclusions: The addition of HCQ to neoadjuvant chemotherapy in PDA may improve treatment response in patients with SMAD4 loss. Further study of the relationship between SMAD4, autophagy and treatment outcomes in PDA is warranted.
Impact of surveillance among patients with resected pancreatic cancer following adjuvant chemotherapy.
Authors: Wong Selina , Gondara Lovedeep , Renouf Daniel John , Lim Howard John , Gill Sharlene 
Published: February 2020

768 Background: Pancreatic adenocarcinoma carries a poor prognosis and high risk of recurrence even after surgery and adjuvant chemotherapy (AC). Guidelines recommend against routine surveillance imaging due to lack of evidence supporting a survival benefit. With current first-line chemotherapy options, it is unclear whether surveillance scans allow for early detection of asymptomatic disease and therefore an opportunity to offer fit patients chemotherapy. We describe the patterns of surveillance in patients followed at a Canadian provincial cancer agency and determine whether routine imaging after AC is associated with receipt of palliative chemotherapy (PC). Methods: A retrospective review was completed to identify patients treated at British Columbia (BC) Cancer centres between January 1, 2010 and December 31, 2016 who had undergone curative intent resection and received at least one cycle of AC. Baseline characteristics, number of scans done after completing AC to recurrence, and PC were collected. Logistic regression analysis was performed. Results: A total of 151 patients followed at BC Cancer were identified. Patients who recurred within 28 days after AC were excluded, leaving 142 patients, of which 115 patients had recurrence. We defined 2 cohorts based on number of scans done between completion of AC and recurrence: those with 0-1 scans were “symptomatic” recurrences (22 patients, median age 68y, 64% female, and 91% node-positive) and those with > 1 scan were “surveillance” recurrences (93 patients, median age 64y, 43% female, and 81% node-positive). Patients who underwent surveillance scans were more likely to receive PC at time of recurrence, though statistical significance was not reached (OR 2.11, 95% CI 0.75-6.58, p = 0.17). Conclusions: Despite guidelines, the majority of patients treated in BC underwent surveillance imaging. Within the limits of our sample size, we demonstrated a trend towards increased likelihood of receiving PC in patients who receive surveillance scans following AC. With efficacious PC options available, studies to determine whether receipt of PC in asymptomatic recurrences detected on imaging translates into improved survival and/or quality of life are warranted.
Timing and location of palliative care consultation in metastatic pancreatic cancer: A retrospective, single-center observational study.
Authors: Patel Timil , Miccio Joseph Anthony , Srikumar Thejal , Prsic Elizabeth Horn , Adelson Kerin B. , Kozhevnikov Dmitry , Patel Komal , Lacy Jill , Cecchini Michael 
Published: February 2020

770 Background: Patients (pts) receiving treatment for metastatic pancreatic cancer (MPC) experience significant symptoms, treatment related side effects and psychosocial burdens. The ASCO guidelines recommend early palliative care consultation (PCC) to improve quality of life and survival. However, limited real-world data is available regarding the timing of PCC, hospice enrollment and location of death (LOD) in pts with MPC. Methods: We conducted a retrospective observational analysis of pts treated with chemotherapy for MPC at the Yale Smilow Cancer Hospital and affiliated community care centers (CCC) from January 2011 to April 2019. Patient demographics, treatment dates, initial PCC, enrollment of hospice at the time of death and LOD were manually abstracted from the electronic medical record. Univariate and multivariable logistic regression analyses were conducted to predict for PCC and death outside the hospital. Results: Of 363 pts identified with MPC who received chemotherapy, 38% (138) had a PCC. 67% (93) of patients’ initial PCC was in the hospital versus 33% (45) in the outpatient setting. The median time from the start of first-line chemotherapy to the first PCC was 5.2 months (interquartile range [IQR] 1.2 – 12.9). The median time from the first PCC to death was 1.5 months (IQR 0.5 – 4.42). At the time of our analysis, 300 pts had died and of those 76% (229) were enrolled on hospice at the time of death while 24% (71) were not. With respect to LOD, 47% (139) of pts died at home with hospice, 31% (94) at an inpatient hospice facility and 22% (67) died in the hospital. Female gender was associated with an increased likelihood of a PCC (HR 1.78, 95% CI 1.07-2.94, P = 0.026). Pts treated at a CCC were less likely to have a PCC (HR 0.21, 95% CI 0.12-0.36, P < 0.001). A PCC was not associated with a higher likelihood of death outside the hospital (HR 1.31, 95% CI 0.75-2.29, P = 0.346). Conclusions: Although most pts with MPC enroll in hospice, PCC is generally underutilized. In fact, many pts receive PCC near the end of life and in the hospital. Further studies are warranted to determine how best to incorporate early PCC to maximize supportive care for pts with MPC.
Prognostic value (PV) of pathologic response (PR) to neoadjuvant chemotherapy (NC) alone in resected pancreatic cancer (PDAC): Initial analysis.
Authors: Picozzi Vincent J. , Mandelson Margaret T. , Lin Bruce Shih-Li , Biehl Thomas R , Alseidi Adnan , Rocha Flavio G. , Helton Scott 
Published: February 2020

771 Background: As neoadjuvant Rx for resected PDAC often includes chemoradiation, the PV of PR includes its impact. We began analysis of the impact of NC alone in this setting. Methods: Patients (pts) were identified from the Virginia Mason Pancreaticobiliary Cancer Database. Inclusion criteria: 1) Dx 1/2010 - 3/2019; 2) Path dx PDAC stage I-III; 3) NC ( any type) as sole neoadjuvant Rx; 4) complete surg path data; 5) longitudinal OS known. Exclusion criteria: 1) neoadjuvant chemoradiation; 2) unknown NC (outside providers only). Histologic response was scored as follows: ( 0=complete response, 1 ≥95% response, 2=50-95% response, 3<50% response). Results: Results for 134 pts are in Table. Median (med) f/u was 33 months (mo). In univariate analysis, all path features examined were statistically significant re med/5-yr OS. In multivariate analysis, risk increased with tumor size (HR 1.9, 95% CI 1.1-3.2) and tumor differentiation (HR 1.8, 95% CI 1.1-3.1 ) independent of other variables. Conclusions: 1) In univariate analysis, all PR features after NC had PV for med/5-yr OS, especially tumor size and histologic response score. NC type was not significant. 2) In multivariate analysis, risk increased with tumor size and tumor differentiation.3) This data needs extension to a bigger pt base/correlation with other variables (Ca 19.9, postop Rx, recurrence pattern etc.) for greater utility ( now underway). 4) This approach may aid postop Rx decision -making in this setting. [Table: see text]
Nonoperative management (NOM) in rectal cancer: Physician perspectives on offering NOM as standard of care.
Authors: Covelli Andrea Marie , Quereshy Fayez A. , Kennedy Erin Diane , Chadi Sami A. , Wright Frances Catriona 
Published: February 2020

79 Background: 20% of rectal cancer patients will have a complete clinical response (cCR) following neoadjuvant chemoradiotherapy. Non-operative management (NOM) with close surveillance can spare patients proctectomy and avoid the sequelae of surgery. Patients are interested in and advocate for NOM, whereas oncologists appear to be reluctant to offer this option. We wished to identify the perceptions and barriers that oncologists face when considering NOM. Methods: This qualitative study explored oncologists’ experiences treating rectal cancer and identified their perceptions and values around NOM. Purposive and snowball sampling identified medical, radiation and surgical oncologists’ who treat a high volume of rectal cancer across Canada. Oncologists varied in length/location of practice and gender. Data were collected via semi-structured interviews. Constant comparative analysis identified key concepts. Results: Data saturation was achieved after 40 interviews: 20 surgeons, 12 radiation and 8 medical oncologists. The dominant theme was “NOM is not ready for prime time’. Most oncologists felt that there is insufficient long-term data around NOM and single center studies appear ‘too good to be true’. Physicians voiced concerns about worsening oncologic outcomes in the setting of regrowth, the challenges in determining a cCR and apprehension around patient compliance to surveillance. Some oncologists felt that NOM is limited to a very select population and voiced reluctance in offering it to younger patients or patients with more advanced disease. There was little consideration to improved functional outcomes with NOM. Overall the majority of participants felt that NOM is ‘ trading the benefit of saving the rectum for the uncertainty of an inferior oncologic outcome’. Conclusions: Oncologists felt that NOM should not be offered as a standard of care option following a cCR. Most felt that there is insufficient data supporting NOM and are concerned around worse oncologic outcomes. Patient views of NOM are critically needed to assess if patients value the same outcomes. Additional research is needed to address barriers should patients wish to consider NOM as a treatment option in the setting of a cCR.