bluuebunny/crossref_metadata_2025_split huggingface dataset:
The incidence of peritoneal carcinomatosis and impact on outcomes in relapsed early T4 colorectal cancer.
Authors: Habib Rosemary , Gebski Val , Micklethwaite Kenneth , McLeod Duncan , Toh James , El-Khoury Toufic , Pathma-Nathan Nimalan , Ctercteko Grahame , Gowrishankar Kavitha , Wilcken Nicholas , Wong Mark , Nagrial Adnan 
Published: February 2020

73 Background: There is limited data regarding the association between peritoneal carcinomatosis (PC) and clinical outcomes in colorectal cancer (CRC). We examined the incidence of PC and explored the relationship to survival (RFS & OS) in CRC. Methods: The demographic and clinical details of patients with stage II/III CRC referred to a tertiary centre in Western Sydney between 2009-2016 were obtained. Associations between clinical outcomes and baseline prognostic factors were investigated using proportional hazards regression models. The effect of prognostic factors on outcome were examined by tumour stage. Results: 495 patients were identified, 281 (57%) with stage II and 214 (43%) with stage III. Median follow-up was 38 months. 330 (67%) had T3 and 165 (33%) had T4 disease. Median age at diagnosis was 72 years (19 -94). 104 (21%) patients relapsed, 24 (23%) had PC and of those, 6 had PC as their only site of metastasis. 10% (n = 5) with T3 developed PC compared with 35% (n = 19) with T4 disease (P = 0.02). Compared with non-PC, PC was associated with poorer median OS (28 Vs 46 m; p = 0.03). Median RFS for T3 was 16 months, T4, 14 months (NS). Median OS for T3 was 34 months Vs T4 28 months (P = 0.45). Of those with PC relapse, the diagnosis of PC was highest in the first two years post-operatively (88%). 9 patients (38%) with PC died due to bowel obstruction Vs 4 (5%) patients with non-PC relapse (P < 0.01). Poorer OS was associated with PC (HR 1.74; p = 0.03), right sided primary (HR 1.602; P = 0.05), T4 stage (HR 1.69; P = 0.03), LVI (HR 1.95; p < 0.01), N stage (HR 1.51; P < 0.01), and number of metastases at baseline (HR 1.25; p = 0.04). On multivariable analysis right sided primary and T4 stage remained significant. Conclusions: Patients with PC relapse have an 18 month shorter median OS than those with non-PC relapse. Further, PC recurrence is more common in patients with T4 compared with T3 CRC and was the only site of metastatic disease in 7% of relapsed patients with T4 CRC. Consideration for peritonectomy and/or HIPEC should be given for patients with PC metastases. For patients with resected early stage T4 CRC, consideration should be given for surveillance laparoscopy.
Real-world outcomes in pancreatic adenocarcinoma (PDAC) and persona types with implications for standard of care (SOC) therapy (Tx).
Authors: Petricoin Emanuel , Pishvaian Michael J. , DeArbeloa Patricia , Barg Daniel , Thach Dzung , Brody Jonathan Robert , Matrisian Lynn McCormick , Chung Vincent , Hendifar Andrew Eugene , Mikhail Sameh , Sohal Davendra , Blais Edik Matthew 
Published: February 2020

735 Background: Molecular profiling (MP) for PDAC has gained increased acceptance and we previously demonstrated that targeting actionable mutations can improve patient (pt) outcomes. However, the correlations of diverse patterns of molecular alterations with outcomes following SOC Tx are largely unknown. Methods: We analyzed longitudinal outcomes of 1355 PDAC pts who underwent MP and received SOC Tx. “Persona” types were established based on the molecular characteristics of each pt using unsupervised clustering, as well as a supervised review defined by our molecular tumor board, following classifications reported in previous studies. Progression-free survival (PFS) for each type was assessed based on the choice of first-line Tx (i.e. FOLFIRINOX [FFX] vs. gemcitabine + nab-paclitaxel [GA]). Statistical comparisons were made against all other types within a specific Tx group. Results: The prognostic/predictive value of the persona types for 1st-line Tx revealed distinct differences in outcomes (Table). As expected, the DDR deficiency type was associated with a significantly improved PFS for pts treated with FFX but not for GA. In addition, pts in the cell cycle type had a worse PFS compared to other persona types for both FFX and GA. Using this platform, we will further subdivide the persona types into molecular subtypes and associate these with pt outcomes. Conclusions: Our analyses demonstrate that specific molecular persona types exist in PDAC pts and can be linked to Tx outcomes. Ultimately, knowing the persona type/subtype early in a pt’s Tx course may help personalize Tx to improve outcomes. [Table: see text]
Gene expression profiling of unresectable pancreatic cancer patients treated with gemcitabine, nab-paclitaxel, metformin, and dietary supplements (DS).
Authors: Chung Vincent , Frankel Paul Henry , Shibata Stephen , Mambetsariev Isa , Yin Holly , Mirzapoiazova Tamara , Mambetsariev Bolot , Kulkarni Prakash , Lim Dean , Li Daneng , Chao Joseph , Fakih Marwan , Bild Andrea , Pillai Raju K. , Adalsteinsson Orn , Hirsh Steven , Salgia Ravi 
Published: February 2020

736 Background: Pancreatic cancer commonly causes weight loss and many patients take supplements to improve nutrition but also for any potential anticancer properties. We conducted a pilot trial evaluating a standardized combination of dietary supplements, metformin and gemcitabine plus nab-paclitaxel chemotherapy. Methods: The supplements were custom designed by a nutritionally trained oncologist. 17 supplements were given as 12 pills and 2 smoothie packets divided twice per day. Patients began metformin on day (D)-6 to evaluate GI tolerance before starting the DS on D-3. On D1, gemcitabine and nab-paclitaxel chemotherapy was administered at standard doses. Serum samples were collected D-6, C1D1, C3D1 and at the end of treatment. RNA was extracted from PBMC samples and a total of 48 samples were analyzed from 19 patients. NanoString Human Immune Profiling and PanCancer Pathways were performed to evaluate changes in gene expression with treatment. Results: The differential expression of genes was small with dietary supplements alone and in combination with chemotherapy. After 2 months of treatment, 17 genes were upregulated while 4 genes were down regulated. At the time of tumor resistance, 33 genes were upregulated while 17 genes were downregulated. We observed downregulation of tumor suppressor gene expression with upregulation in growth factor pathways. Interestingly, SPRY2 mRNA expression was also up regulated which functions as a negative feedback regulator of multiple receptor tyrosine kinases. Conclusions: Increasing number of genes were upregulated with continued treatment. The most common pathway affected was cell cycle and apoptosis. During the initial supplement run-in period from D-6 to C1D1, IL-8 mRNA expression was upregulated the most. IL-8 is a neutrophil chemotactic factor secreted by cells involved in the innate immune response as well as pancreatic cancer cells associated with a pro-inflammatory state. Treatment with gemcitabine and nab-paclitaxel decreased the IL-8 mRNA expression. Additional studies with longer course treatment with supplements alone would be required to explore its impact on differential gene expression.
Translational analysis from SCALOP trial: CCL5 as a prognostic biomarker and a potentially actionable target in locally advanced pancreatic cancer (LAPC).
Authors: Mukherjee Somnath , Lanfredini Simone , Cox Catrin , Thapa Asmita , Hughes Sophie , Bangs Fiona , Willenbrock Frances , Wilhelm-Benartzi Charlotte , Abraham Aswin George , Owens Rob , Sabbagh Ahmad , Maughan Tim , Hurt Chris , O'Neill Eric 
Published: February 2020

740 Background: SCALOP was a multi-centre phase II RCT where 114 patients with LAPC were received 3 cycles of Gemcitabine and Capecitabine (GEMCAP) and those with stable/responding disease (n = 74) were randomised to Gem-RT or Cap-RT. The trial showed superiority of Cap-RT. Baseline blood samples of randomised patients were analysed for 35 circulating biomarkers. In vivo study was undertaken with candidate biomarker (CCL5) to test actionability. Methods: Patient bloods were tested using R&D multiplexed magnetic Luminex assays and IGF-1, TGF-b1 and b-NGF DuoSet ELISA. Orthotropic KrasG12D;P53R172H;PDXcre (KPC) tumors were implanted in Bl6-mice and treated with Gem, CCR5-inhibitor (CCR5i) maraviroc (MV), PD1 inhibitor (PD1i), PD1i+MV alone and in combination with MRI guided small animal Radiotherapy (RT). Immunophenotyping was performed by IHC and Aurora Cytek spectral flow cytometry. Results: Baseline biomarker data was available on 63/74 randomised patients. Of the 35 biomarkers tested, only CCL5 was found to be significantly associated with OS with a median OS of 18.5 (95% CI: 11.76-21.32) vs 11.3 (9.86-15.51) months (low vs high), and HR 1.37 (95% CI:1.04-3.65; p = 0.037) in the Cox multivariable model. Treatment of orthotopic KPC tumors revealed that combination of MV+PD1i+RT resulted in tumour growth inhibition and a switch of tumour macrophages from M2 to M1 accompanied by increase in infiltration of cytotoxic CD8+ Tcells and NK cells. Conclusions: Previous pre-clinical studies reported CCL5-CCR5 axis as a poor prognostic marker and a possible cause of immune-resistance in pancreatic cancer. Herein we have demonstrated in prospectively collected clinical trial blood samples that high circulating CCL5 is associated with poor prognosis in LAPC. CCR5 inhibitor in combination with RT+PD1i may overcome immune-resistance, and should be tested in clinical trials. Clinical trial information: 96169987 .
Pancreatic cancer intratumoral microbiome and characteristics within paired patient samples.
Authors: Noticewala Sonal Suresh , Lin Daniel , Kouzy Ramez , Maitra Anirban , Colbert Lauren Elizabeth , Taniguchi Cullen M. 
Published: February 2020

744 Background: While most studies evaluating the microbiome in gastrointestinal cancers analyze stool, little is known about the microbiota of the peri-tumoral and intra-tumoral environment. Here, we evaluated the intra-tumoral and peri-tumoral (duodenum and normal pancreas) microbiome for paired duodenal, normal pancreas and resected tumor specimens from pancreatic cancer patients. The purpose of this study was to describe the similarities and differences within patient microbiota. Methods: Fifteen specimens from 5 patients with pancreatic cancer were collected during surgical resection. Genomic bacterial DNA was extracted from these specimens and underwent 16S rRNA sequencing. Alpha (Inverse Simpson) and beta diversity were calculated, and relative abundances of individual bacterial species were compared. Sorensen distance was used the evaluate the spread in beta diversity between paired sample types. Results: Of the five patients who underwent resection, the following baseline characteristics were obtained: median age = 65 years (range 55 -80 years), 2/5 patients were treated with gemcitabine/abraxane, 3/5 patients were treated with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX); 4/5 patients received pre-operative radiation. 16s sequencing analysis of the pancreatic tumor showed the dominant genus to be Escherichia/Shigella (10.6%). Bradyrhizobium (10.1 %) was dominant in the normal pancreas . Escherichia/Shigella (14.3%) was abundant in the duodenum. There was a trend towards higher alpha diversity in tumor vs. normal duodenum/ pancreas (p = 0.12). Sorensen distance was statistically different between sample types (p = 0.004), with duodenal samples most consistent (distance = 67.82), and tumor vs. normal pancreas (81.86) and tumor vs. other tumor samples the most heterogeneous (78.5). Conclusions: This pilot data suggests that the pancreatic tumor microbiome is distinct from the normal pancreas and duodenal microbiome, which indicates tumor specific bacteria should be studied. In future studies, intra-tumoral microbiome may be more relevant to associations with outcomes and treatment response than stool or intestinal microbiome studies.
Clinical and molecular profiling of locally advanced compared with metastatic pancreatic adenocarcinoma.
Authors: Picardo Sarah Louise , O'Kane Grainne M. , Fischer Sandra , Zhang Amy , Denroche Robert Edward , Jang Gun Ho , Dodd Anna , Grant Robert C. , Grunwald Barbara , Moura Shari , Elimova Elena , Prince Rebecca M. , Zogopoulos George , Notta Faiyaz , Wilson Julie , Gallinger Steven , Knox Jennifer J. 
Published: February 2020

747 Background: It is unclear whether locally advanced pancreatic cancer (LAPC) should be treated similarly to metastatic pancreatic cancer (MPC). Clinical trials often exclude LAPC. We compare clinical and genomic characteristics of LAPC and MPC. Methods: Patients with LAPC and MPC were enrolled in the COMPASS trial (NCT02750657). Clinical, demographic and survival data was collected (cut off 8/31/19). WGS, RNAseq and modified Moffitt classification was performed. Results: Patients with LAPC (n = 28) and MPC (n = 180) did not differ in terms of age, gender, smoking or diabetes history. Patients with LAPC had lower BMI (p = 0.005) and lower baseline Ca19-9 (p = 0.02) than those with MPC. LAPC/MPC tumors had similar rates of KRAS, p53, CDKN2A and SMAD4 mutations and similar levels of ploidy, indels and neoantigens. There were increases in single nucleotide variants (p = 0.026) and structural variants (p = 0.04) in MPC compared with LAPC. No LAPC tumors were homologous recombination deficient (HRD) or KRAS wild type (WT), compared with 14 (8%) HRD and 16 (9%) KRAS-WT MPC. All LAPC were classical subtype compared with 77% MPC (p = 0.0052). OS data is shown in the table. MPC classical subtype tumors had improved OS compared with basal-like tumors (p = 0.008). Patients with MPC and p53 mutation trended towards worse OS compared with those without p53 mutation (p = 0.07); this was not seen in LAPC. There was a significant correlation between time on chemotherapy and OS in LAPC (p = 0.002) and MPC (p < 0.0001). Conclusions: Patients with LAPC have similar molecular profiles to those with MPC with similar rates of altered drivers. LAPC tumors are more likely to be Moffitt classical subtype and have similar OS to classical subtype MPC. LAPC patients benefit from local therapy; all patients benefit from increased time on chemotherapy. These data suggest that patients with LAPC should be treated similarly to those with classical subtype MPC but should be offered local therapy when possible. Clinical trial information: NCT02750657 . [Table: see text]
The potential of Tenascin C in the tumor-nerve microenvironment to enhance perineural invasion and correlate with locoregional recurrence-related poor prognosis in pancreatic ductal adenocarcinoma.
Authors: Furuhashi Satoru , Sakaguchi Takanori , Muraki Ryuta , Kitajima Ryo , Fukushima Mayu , Takeda Makoto , Morita Yoshifumi , Kikuchi Hirotoshi , Setou Mitsutoshi , TAKEUCHI HIROYA 
Published: February 2020

748 Background: Perineural invasion (PNI) is commonly seen in pancreatic ductal adenocarcinoma (PDAC) and worsens the postoperative prognosis. However, the detail mechanisms of PNI in PDAC remain unclear. Tenascin C (TNC), an extracellular matrix glycoprotein, is abundant in cancer stroma and modulates tumor progression. In this study, we hypothesized that TNC could enhance PNI in PDAC. The aim of this study was to investigate the roles of TNC in the tumor-nerve microenvironment of PDAC. Methods: We immunohistochemically examined TNC expression in 78 resected PDAC specimens. TNC staining intensity in perineural sites at the invasive front was classified as low or high, by comparison with adjacent non-cancerous tissues in the same section. The relationships between TNC expression and clinicopathological features were retrospectively analyzed. Furthermore, interactions between cancer cells and nerves after supplementation with TNC were investigated using in vitro co-culture model with a PDAC cell line and neonatal mouse dorsal root ganglion (DRG). Results: High perineural TNC expression at the invasive front, seen in 30 (38%) patients, was associated with the presence of PNI (p = 0.006), pathological T stage ≥ 3 (p = 0.01), and postoperative locoregional recurrence (p = 0.002). It was independently associated with postoperative, poor recurrence-free survival in multivariate analysis (p = 0.045). In the in vitro co-culture model, TNC supplementation significantly enhanced both neurotropism of PDAC cells and tumor tropism of a DRG. On the other hand, when PDAC cells and a DRG were cultured separately, TNC did not affect cancer cell proliferation or neural outgrowth. Furthermore, the knockdown of Annexin A2, which is known to be a receptor for TNC, cancelled the neurotropism of PDAC cell toward DRGs. Conclusions: Strong perineural TNC expression was a prognostic indicator of locoregional recurrence-related poor prognosis. The neurotropism of PDAC induced by TNC and TNC-Annexin A2 signaling pathway could be the potential therapeutic target for PDAC by regulating PNI.
Molecular genetic changes in solid pseudopapillary neoplasms (SPN) of the pancreas.
Authors: Rodriguez-Matta Elisa M. , Colon-Otero Gerardo , Hemmerich Amanda , Severson Eric Allan 
Published: February 2020

749 Background: Solid Pseudopapillary Neoplasms (SPNs) of the pancreas are rare accounting for 1-2% of all pancreatic tumors. Previous studies had shown that a pathogenic mutation of the CTNNB1 gene is present in over 90% of the SPN tumors with very limited information available on the specific molecular changes present in SPN. Here we report the results of next generation genetic testing of a large series of SPN tumors from the Foundation Medicine database. Methods: Foundation Medicine database from 07/2012 to 04/2019 was reviewed. A total of 31 cases of SPN tumors were identified out of 12,892 cases of pancreatic cancers. Information collected included demographic information on the patients as well as tumor analysis for next generation genetic sequencing of 315 genes associated with cancer with FoundationOne or 324 genes associated with FoundationOneCDx. Microsatellite stability status and tumor mutation burden were determined. Results: Twenty nine out of 31 cases (93%) had a CTNNB1 mutation. Seventy percent of the CTNNB1 mutations were on position 32 (14 cases, 41%) or in position 37 (9 cases, 29%). Other sites of CTNNB1 mutations included position 34 (3 cases, 9.6%), position 2 (2 cases, 6.4%) and position 38 (1 case, 3.2%). Two cases did not have a CTNNB1 mutation, one had a CDKN2A mutation and the other had no detectable mutations. Most cases had additional mutations aside from the CTNNB1, the most common were TP53 (3 cases, 9.6%) and LRP1B (2 cases, 6.4%). Other accompanying mutations were seen just once. Twenty-five percent of these cases had actionable gene mutations, each found in one case including: MSH2, BRCA2, ATM, XRCC3, ATRX, PTEN, ESR1, CDKN2, and PIK3CA. Conclusions: Next generation genetic testing of SPN tumors is of clinical benefit since it identifies actionable mutations in 29% of the cases.
Pancreatic adenosquamous carcinoma: Clinical associations, treatment, and outcomes.
Authors: Hartgers Mindy L. , Bamlet William , Graham Rondell P. , Mahipal Amit , Mounajjed Taofic , Cleary Sean P. , McWilliams Robert R. 
Published: February 2020

751 Background: Pancreatic adenosquamous carcinomas (PASC) are rare malignancies, with limited evidence regarding best treatment options. The Mayo Clinic Pancreatic Cancer SPORE Registry was utilized to compare/contrast outcomes for pancreatic cancers with a squamous component to pancreatic ductal adenocarcinoma (PDAC). Methods: Patients were identified from the SPORE Registry (2000-2019), were reviewed and confirmed by expert pathologists. Demographic and clinical information was ascertained from medical records and risk factor questionnaires. A case control study of patients with PASC vs PDAC was constructed. PASC patients were also followed for outcome and treatment records were extracted. Results: Of 2,584 total patients with pancreatic cancers, 45 cases of PASC and 2,438 with PDAC were identified. There were no differences in age (median 69 vs 67 years, p=0.42), sex (male 64.4vs 56.6%, p= 0.29), BMI (27.41 vs 27.78 kg/m2, P=0.50), or ever-smoking (61.0 vs 55.3%, P=0.47), with a borderline association with reported diabetes (17.8 vs 29.9%, p =0.08). Compared to PDAC, PASCs were more likely to involve the body/tail (48.9 vs 33.2%, p= 0.02) and had poorer overall survival, adjusted for age, gender, and stage (median 7.1 m vs 12.8m, HR 1.89, p=0.0004). Of 9 PASC pts treated with neoadjuvant intent, 4 were surgically resected, median survival was 7 months. Eleven pts underwent upfront surgery, with variable adjuvant treatments. Median OS post- surgery was 18m (range 7-51). Of 14 patients presenting with metastatic disease, median survival was 4.5 m (range 1-22). With regard to systemic chemotherapy, for neoadjuvant or metastatic disease median duration of treatment was 3 months (range 0.5-7m) for Gemcitabine + nab-paclitaxel (N=9) and also 3 months (range 2-6m) for FOLFIRINOX (N-13). Conclusions: The diagnosis of PASC carries an even poorer outcome than pancreatic adenocarcinoma. Tumors are more likely to arise in the distal pancreas, and patients may be less likely to report associated diabetes. Limited antitumor activity was noted with multi-agent chemotherapeutic regimens. Prospective trials will be needed to clarify choice of regimen in the future.
Exceptional responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with refractory pancreatic ductal adenocarcinoma (PDAC) and germline BRCA or RAD51 mutations.
Authors: Terrero Gretel , Pollack Terri , Sussman Daniel A. , Lockhart Albert Craig , Hosein Peter Joel 
Published: February 2020

754 Background: Immune checkpoint inhibitors (ICI’s) have not shown meaningful clinical activity in unselected pts with PDAC. BRCA-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with mutations in BRCA or other homologous recombination repair genes may be sensitive to ICI’s. Methods: Utilizing the IRB-approved PDAC database at the University of Miami, we identified pts with relapsed/refractory PDAC with pathogenic germline mutations who were treated with combination ICI’s (ipi 1mg/kg and nivo 3mg/kg every 21 days followed by nivo 240mg every 2 weeks). Results: Five pts were identified (1 BRCA1, 2 BRCA2, 1 RAD51C and 1 RAD51D). Among the 3 evaluable pts, there was one complete response (CR), one partial response (PR) and one had progressive disease (PD). The pt with a CR had BRCA1; he had resection followed by adjuvant gem/cape and had a biopsy-proven recurrence in the lung and retroperitoneum 1y after the end of adjuvant therapy. He received ipi/nivo at recurrence and achieved a CR, ongoing for 17m on nivo maintenance. The patient with a PR had RAD51C; he was diagnosed with mPDAC and received FOLFIRINOX for 6m, followed by olaparib on a trial for 12m. Upon PD, the disease quickly progressed on 5FU/liposomal irinotecan, gemcitabine/nab-paclitaxel/cisplatin and FOLFIRINOX. He then started ipi/nivo with immediate improvement in pain and tumor markers. A radiological PR was seen after 2 doses and is ongoing for 3m with continued clinical and tumor marker improvement. The 3rd evaluable pt had BRCA2 and had PD with an exponential rise in tumor markers accompanied by clinical deterioration. Response data on the final two pts were pending at the time of submission and will be presented at the meeting. Conclusions: In this biomarker selected cohort, 2 out of 3 evaluable pts with PDAC had impressive responses to ipi/nivo. PDAC has generally been refractory to ICI therapy but this series suggests that this subgroup may be responsive to ICI’s. Further evaluation is warranted.