bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of immune-related risk model for prognosis of hepatocellular carcinoma.
Authors: Li Yue , Xu Ximing
Published: May 2020

e16683

Background: Hepatocellular carcinoma is the most common malignant tumor. Although the treatment of HCC has significantly improved, the 5-year survival rate is still only 18%. There is increasing evidence that tumor immune microenvironment (TIM) plays critical roles during cancer initiation and progression. Based on the comprehensive exploration of the immunogenomic, an immune-related risk model was constructed to predict hepatocellular carcinoma prognosis. Methods: Transcriptomic data of HCC patients were downloaded from the TCGA database, and the differentially expressed immune-related genes (IRGs) (FDR < 0.01, |log2fold change| > 2) were identified. Functional enrichment analysis was performed to explore potential molecular mechanisms of the differentially expressed IRGs. By univariate and multivariate Cox regression analysis, we identified eight prognosis-related IRGs. Based on the expression levels of IRGs, we constructed the immune-related risk model. The Kaplan‐Meier (K‐M) survival curves, ROC curves, univariate and multivariate analysis were used to evaluate the immune-related risk model. According to the risk score, HCC patients were stratified into low and high-risk groups. CIBERSORT was applied to analyze the profiling difference of infiltrating immune cells between the two groups. Results: A total of 113 differentially expressed IRGs were identified, of which nine IRGs were correlated with the prognosis of HCC patients. Functional enrichment analysis showed that these genes were involved in immune response and immune signal pathway. The immune-related risk model consisted of eight IRGs (FABP6, RBP2, MAPT, BIRC5, PLXNA3, CSPG5, IL17D and STC2). The immune risk score was an independent prognostic factor (HR, 2.63 [1.93−3.58]; P = 8.16E−10) and the patients with a high-risk score tended to have a shorter OS than those with a low-risk score. In the TCGA cohort, high-risk patients tended to have an advanced stage. Moreover, we found that the patients in the high-risk group had higher fractions of T follicular cells helper and macrophages M0. The patients with low-risk scores had higher fractions of CD8+ T cells and CD4+ T cells. Conclusions: We have identified the immune-related risk model of hepatocellular carcinoma based on the expression profiles of eight immune-related genes. This model could predict prognosis and reflect the tumor immune microenvironment of HCC patients, which can provide new insights in the individualized treatment of HCC and potential novel targets for immunotherapy.
Sorafenib as an adjuvant therapy for hepatocellular carcinoma with microvascular invasion after radical resection: A prospective multicenter nonrandomized controlled study.
Authors: Xu Li , Tang Yuhao , Li Hua , Zhou Jie , Zhou Zhongguo , Zhang Yaojun , Chen Minshan
Published: May 2020

e16685

Background: Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) is established with poorer outcome and more frequent postoperative recurrence. Sorafenib is the first target drug that successfully prolongs the survival of advanced HCC, but it failed to prolong the survival of HCC after radical resection or ablation in the STORM study. After that, series studies revealed that sorafenib could improve the survival of HCC with MVI after surgery, while most studies with positive results were retrospective ones. Methods: A multicenter, prospective non-randomized, open-label study was performed in pts undergoing radical resection, postoperative pathology confirming HCC with MVI (BCLC A or B stage; T2 or part T3aN0M0). Pts in the treatment group (S group) started sorafenib within 4-6 postoperative weeks at the dose of 400mg per day at most 2 years, and the control group (C group) never received sorafenib. The primary endpoint is recurrence-free survival (RFS) rate at the 2nd postoperative year, and the secondary endpoints include postoperative median time to recurrence (TTR), 1-year postoperative RFS, pts’ overall survival (OS), and safety. This study was approved by Ethical Committee of Sun Yat-sen University Cancer Center, and registered at ClinicalTrials.gov with number NCT02867280. Results: Between 1 June 2015 and 31 August 2019, 154 eligible pts from 3 academic hospitals in China were enrolled (83 in C group and 53 in S group). Baseline demographics were balanced between the two groups. The 2-yr RFS rate was 56.1% in the S group vs. 55.7% in the C group, respectively ( P = 0.955), and the median RFS was 15.5 vs. 16.0 months ( P = 0.827).The recurrence rates at the 1st postoperative year were 38.6% vs. 34.0% ( P = 0.568), and the median TTR was the same as the RFS. There were 31 pts (54.4%) of the S group experienced treatment-related adverse events (AEs). The most common AE was hand-foot syndrome (HFS, 19/57, 10 pts ≥ grade-2). Other AEs included diarrhoea (15/57, 26.4%), alopecia (11/57, 19.3%), hypertension (5/57, 8.8%) and decreased platelet (3/57, 5.3%), and gastric ulcer with bleeding (1/57, 1.8%). Sorafenib was interrupted or discontinued in 7 pts due to AEs. Recruiting of this study was closed according to the results of the planned mid-term analysis, and all pts were followed on schedule to observe the other survival data. Conclusions: Postoperative sorafenib treatment with dose of 400mg once daily was well tolerated, but did not improve the RFS and TTR of Chinese HCC pts with MVI. Clinical trial information: NCT02867280 .
Genome-wide CRISPR/Cas9 library screening to identify PAK1 as a critical driver for lenvatinib resistance in HCC.
Authors: Huang Shanzhou , Zhang Chuanzhao , Hou Baohua
Published: May 2020

e16687

Background: Lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). However, the development of drug resistance of lenvatinib is becoming common. Methods: Here, we performed the first genome-wide CRISPR/Cas9-based screening on lenvatinib-treated HCC cells to identify essential genes for non-mutational mechanisms related to acquired lenvatinib resistance and/or sensitivity in HCC cells. A genome-scale CRISPR knockout (mGeCKOa) library containing 123,411 single guide RNAs (sgRNAs) was used to identify loss-of-function mutations conferring lenvatinib resistance upon HCC cells. CCK8, wound-healing, transwell and flow cytometry assays were used. Subcutaneous xenotransplantation models were used to investigate the role in vivo. Results: By using genome-wide CRISPR/Cas9 library screening, we identify PAK1, a family member of serine/threonine p21-activating kinases, as a critical driver for lenvatinib resistance and the most-effective genetic suppressor of lenvatinib activity. Analysis of the survival of HCC after hepatic resection revealed that low PAK1 expression shortened overall and tumor-free survival (P < 0.001). Further, loss of PAK1 from HCC cell increased the cytotoxicity of lenvatinib in vivo. Lenvatinib treatment activates series of metabolism, including “Glycolysis/ Gluconeogenesis、Cysteine and methionine metabolism、Selenocompound metabolism、Sphingolipid metabolism、Pyruvate metabolism、Metabolic pathways”. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that loss of PAK1 activates the Glycolysis/ Gluconeogenesis and increase the production related metabolites. Concomitantly, activation of PAK1 reduces ROS level and HCC apoptosis upon Lenvatinib treatment. Lenvatinib treatment activates series of metabolism, including “Glycolysis/ Gluconeogenesis”. With RNAi knockdown and CRISPR/Cas9 knockout models, we show that loss of PAK1 activates the Glycolysis/ Gluconeogenesis and increase the production related metabolites. Concomitantly, activation of PAK1 reduces ROS level and HCC apoptosis upon Lenvatinib treatment. Conclusions: In summary, our results demonstrate that targeting PAK1 is an effective approach to overcome lenvatinib drug resistance in HCC.
Long-term survival of combined ablation therapy and tremelimumab with or without durvalumab in advanced hepatocellular carcinoma.
Authors: Monge B. M. Cecilia , Xie Changqing , McVey John , Mabry-Hrones Donna , Duffy Austin , Wood Bradford J. , Greten Tim F.
Published: May 2020

e16689

Background: Immune checkpoint inhibitor therapy has recently been approved for the treatment of patients with Hepatocellular Cancer (HCC). Data on long-term survival is lacking and the predictors of good outcomes are unknown. The combination of locoregional therapies (transarterial chemoembolization or radiofrequency ablation) plus tremelimumab (trem) with or without durvalumab (durva) was studied in patients with advanced HCC. We report the long-term survival and analyze predictors of good response in two trials of immune checkpoint and ablation treatment in advanced HCC. Methods: Adult patients (pts) with pathologically confirmed HCC with advanced or sorafenib refractory disease who satisfied the eligibility criteria were enrolled in the studies (NCT02821754, NCT01853618). They received treatment with trem, 10 mg per kilogram every 4 weeks for six doses followed by 3 monthly infusions (23 pts) or trem 75 mg flat dose every 28 days for four doses and then durva 1500 mg flat dose every 28 days (35 pts). Subtotal radiofrequency or chemoablation was done on day 36. Results: The average overall survival in the 58 pts was 10.1 months (range 0.9 to 74.2 months); 41.6% were alive at 12 months and 5.5 % were alive at 61 months. A select group of patients had exceptional overall survivals up to 67 months. Predictors of improved overall survival included the presence of higher grade immune related (irAEs) (OR 0.235, p = 0.075) and a partial or stable disease response per RECIST. No new late toxic effects were noted during this long term follow up. Conclusions: Impressive overall survival times of up to 68.8 months were observed with ICI and subtotal ablation in patients with advanced HCC; the presence of irAEs and the tumor response per RECIST may be predictive of better overall survivals. To our knowledge this has not been previously reported in the literature. Clinical trial information: NCT02821754,NCT01853618 .
Anorectal neuroendocrine carcinoma (NEC): Patient characteristics and treatment outcomes.
Authors: Ueberroth Benjamin Edward , Liu Alex John , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad Bassam
Published: May 2020

e16702

Background: There are only a few reports examining the treatment patterns for poorly differentiated rectal/anal NEC. In this study, we sought to report treatment and survival outcomes for patients with NEC of the anus and rectum seen at Mayo Clinic. Methods: We identified patients with a primary NEC of the anus or rectum using Mayo Clinic databases (Minnesota, Arizona, Florida) from the year 2000 to present. NEC identified within polyps on colonoscopy was excluded from this study. Patients’ demographics were compiled. Kaplan Meier analyses were performed to evaluate overall survival (OS) for all patients, as well as subgroups with locoregional disease (LRD) and metastatic disease at diagnosis. Progression free survival (PFS) was also evaluated for patients with LRD treated with chemoradiation therapy (CRT). Results: 38 patients with NEC of the anus/rectum were identified with a median age of 55.5 years. 23 patients (61%) had metastatic disease at diagnosis and 15 (39%) had LRD. The most common site of metastasis was the liver (n = 20). Patients with metastatic disease at presentation had significantly shorter OS compared to patients with LRD (median OS 10.4 vs. 18.9 months, p = 0.039; HR 2.46, 95% CI [1.001-6.050]). 34 total patients received chemotherapy (ORR 11.8%), with platinum + etoposide (EP) being the most common first-line chemotherapy (n = 26). 10 of 15 patients with LRD received CRT (9 with EP and 1 with 5-FU) with median PFS of 6.3 months (95% CI 2.3-16.5 months), a 1-year PFS rate of 20%, and median OS of 18.6 months (95% CI 13.5-23.7 months). 2/10 received induction chemotherapy prior to CRT with 6/10 undergoing primary tumor resection (1 prior to CRT and 5 after CRT). Only 3 CRT patients were living at time of analysis (all underwent surgical resection), 2 without any active disease, 1 who achieved complete response with CRT then suffered recurrence and is still undergoing treatment. Conclusions: NEC of the anus and rectum is an aggressive malignancy with most patients experiencing metastatic disease at presentation and poor response to chemotherapy at all stages. Even those with LRD experience a very poor prognosis with OS of 18.9 months from diagnosis. For LRD, most patients underwent CRT with only a short-lived response (median PFS 6.3 months). Those achieving sustained response also underwent surgical resection. Overall, prognosis is poor for all stages and further study on a large scale is warranted to better characterize this rare, aggressive malignancy.
Prolongation of the average survival time in pancreatic cancer (a new measure of effect): Pooled analysis of adjuvant chemotherapy trials.
Authors: Ceballos Barbancho Eduardo , Sánchez Robles Galo
Published: May 2020

e16723

Background: With the aim of improving the prognosis of the disease, in recent years attempts have been made to optimize the adjuvant treatment of pancreatic cancer, having demonstrated the usefulness of chemotherapy in several phase III trials: CONKO-001, JASPAC-01, ESPAC -4 and PRODIGE. Methods: The method to measure the Area Under the Curve (AUC) is universally known. When the curve is not homogeneous, the AUC is calculated using the traditional method of breaking down the total area into a sum of many polygons. We have calculated the AUC through pixel counting using Image J, which is an image processing application, programmed in Java, developed in the National Institutes of Health and free to access. To estimate the consistency between the pixels and the sum of polygons, we have performed several curves with linear edges to measure the AUC through the sums of the polygons, and then by counting pixels with the Image J application. We have verified that the results are similar, so the pixel count can be used to replace the sum of polygons, especially when the curves are not homogeneous. Entering the areas obtained with Image J in the worksheet, made for this purpose, and available for free at evalmed.es, the measures of the effect are automatically obtained: prolongation of the average surival time (PtS), prolongation of the average event free time (PtSLEv) and time lived without an event (PtvSEV). Results: The median follow-up in all studies was 60 months, with the exception of CONKO-001, for which we have data at an average follow-up time of 136 months, however for our comparative purpose we cite the results in the first 60 months. -CONKO-001: PtS was 5.1 months (24.2 observation vs 29.3 gemcitabine). PtSLEv was 9.6 months (13 observation vs 22.6 gemcitabine). PtvSEv was 22.57 months. -JASPAC-01: PtS was 9.04 months (32.4 gemcitabine vs 41.5 gemcitabine + S1). PtSLEv was 9.75 months (21.6 gemcitabine vs 31.4 gemcitabine + S1). PtvSEv was 31.38 months. -ESPAC-4: PtS was 3.2 months (34 gemcitabine vs 37.2 gemcitabine + capecitabine). PtSLEv was 2.7 months (25.6 gemcitabine + 28.3 gemcitabine + capecitabine). PtvSEv was 24.92 months. -PRODIGE: PtS was 6 months (37 gemcitabine vs 43 FOLFIRINOX). PtSLEv was 8.9 months (22.4 gemcitabine vs 31.2 FOLFIRINOX). PtvSEv was 31.23 months. Conclusions: In the adjuvant treatment with chemotherapy in pancreatic cancer, the transit from observation to gemcitabine, and from here to the most intensive schedules, has meant or contributed an important advance for patients in terms of PtS, PtSLEv and PtvSEv.
A real-world comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine to nab-paclitaxel in treatment of advanced stage pancreatic cancer.
Authors: Shaik Abdul Rashid Shaik Abdul Samad , Cohen Steven , Micaily Ida
Published: May 2020

e16728

Background: Pancreatic adenocarcinoma is a dreaded malignancy accounting for 7% of all cancer related deaths in the United States. The two most used chemotherapeutic regimens are a combination of 5- fluorouracil, leucovorin, oxaliplatin and irinotecan (FFX) and a combination of gemcitabine nab paclitaxel (GN). Both improve survival when compared to gemcitabine alone but have not been compared directly. Methods: Retrospective chart review of 83 chemotherapy naïve patients with metastatic cancer of exocrine pancreas who underwent chemotherapy between February 2011 and June 2017. Patients who completed at least one cycle of chemotherapy regimen were included. Characteristics, efficacy and adverse events between the two regimens were compared using appropriate statistical analyses. Results: 83 patients met selection criteria. 39 patients received FFX and 44 received GN. Mean age of FFX and GN patients was 69.7 (SD 8.7) (Median 66) and 72.3 (SD 8.8) (Median 69) yrs respectively (p = 0.100). The proportion of patients with ECOG performance scale ≤1 receiving FFX vs. GN was 50.8% vs. 49.2% and > 2 receiving FFX vs. GN was 33.3% vs 66.7% (p = .286). Of the 23 patients > 75 yrs., 7 received FFX and 16 received GN (p = .086). Median overall survival was 10.1 months (95% CI: 5.4-18.7) in FFX and 7.2 months in GN (95% CI: 5.4-11.3) [p = 0.037]. Median survival based on site of tumor was 10.2 months (95% CI: 6.7-13.8) in head and 10.1 months (95% CI: 4.3-14.7) in body and tail tumors [p = 0.776]. Incidence of vomiting in FFX / GN was 94.1% / 73.7% (p =.027), vomiting requiring hospital admission was 55.9% / 21.1% (p = 0.003). Other events requiring admission included: diarrhea 31.4% / 17.9%; anemia 5.7% / 10.3%; thrombocytopenia 11.4% / 7.7%; febrile neutropenia 28.6% / 12.8% and acute kidney injury 25.7% / 15.4%; no statistically significant differences between groups. Conclusions: Patients treated with FFX had a longer survival in this retrospective review. FFX is associated with an increased incidence of vomiting requiring hospitalization. FFX remains a preferred regimen in treating patients with good performance status regardless of age.
Clinical trials in pancreatic cancer: A comprehensive analysis.
Authors: Katayama Erryk Stephan , Hue Jonathan J. , Bajor David Lawrence , Ocuin Lee Mayer , Ammori John Brian , Hardacre Jeffrey , Winter Jordan Michael
Published: May 2020

e16730

Background: Pancreatic cancer is the most aggressive of common cancers and desperately in need of novel therapies. Unlike many other common cancers, there have been no new paradigm-changing therapies in the past 40 years beyond chemotherapy. The most urgent question in the field then is what is coming down the pike? In this study, we perform the first comprehensive analysis of the current clinical trial landscape in pancreatic cancer to better understand the pipeline of new therapies. Methods: We queried clinicaltrials.gov for registered pancreatic cancer clinical trials. Studies were curated and categorized according to the phase of study, the clinical stage of the study population, the type of the intervention under investigation, and the biologic mechanism targeted by the therapy. This compendium revealed the full landscape of investigational therapeutic trials. Results: As of May 18, 2019, there were 440 total trials testing 600 distinct interventions. 104 of these trials spanned multiple phases, yielding 544 trials across phases. These included 38 trials (8.6%) in phase III testing, 269 (61%) in phase II, and 237 (54%) in phase I. With respect to therapeutic category, 186 (31%) were investigating immunotherapies, 66 (11%) targeted cell signaling pathways, 140 (23%) targeted cell cycle or DNA biology, and 32 (5%) targeted metabolic pathways. Of the 38 phase III trials, only 10 are currently testing novel drugs that are not already FDA approved or routinely used in patients for another indication. Conclusions: A large number of novel therapeutic strategies are currently under investigation. They include a broad range of therapies targeting diverse biologic processes. However, only a small number of novel therapies are in late-stage testing, suggesting that future progress is likely several years away, and dependent on the success of early-stage trials. [Table: see text]
Oncogenic roles of CEACAM6 in pancreatic ductal adenocarcinoma.
Authors: Mahadevan Daruka , Pandey Ritu , Chen Yuliang , Essif Jacob , Al-Khinji Aisha
Published: May 2020

e16744

Background: Carcinoembryonic cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the Ig-superfamily overexpressed in human Pancreatic Ductal Adenocarcinoma (PDA), enriching to the classical activated stroma subtype. CEACAM6 has multifaceted roles in PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report functional correlative studies across PDA cell lines with high vs KO vs low of CEACAM6 and a PDX model with a therapeutic Mab. Methods: RNA-Seq and microarray expression data of PDA cell lines were downloaded from GEO using R (4.3), normalized and log transformed for analysis: CEACAM6 high vs. low were assessed for differential gene expression changes. Correlation of CEACAM6 levels with genes of interest was studied and compared with the CEACAM6 KO proteomic profile of HPAF-II cells. CEACAM6 WT vs. KO cells were profiled for protein kinase (PK) activity (PAMChip) and gene expression changes by RNA-Seq. NSG-CD34+ mice bearing PDX were evaluated with a humanized anti-CEACAM6 Mab for anti-tumor activity. Results: Differential expression analyses between PDA cell lines with low vs KO vs high CEACAM6 resulted in identifying similar markers changing in quantitative proteomics. KRT20, SYTL1, SKIL, CES1P1, MAN1A1 were down-regulated and HMOX1, CPNE2, ABCD1 were up-regulated in CEACAM6 low or KO cell lines. Specific PKs are upregulated in CEACAM6 KO enriching to the TK family (EPH A1, 3, 4, 8 and HCK), AGC family (e.g. AKT, PKA) and cellular apoptosis (e.g. BAD). RNA-Seq of CEACAM6 WT vs KO cells reconfirmed the up-regulation of MMP1, IL2RG, ATP6V0D2 and low expression of KRT20, AGK and MAN1A1 in CEACAM6 KO cells. Pharmacologic inhibition with a humanized anti-CEACAM6 scFv-Fc (IgG4) in PDA PDX of NSG CD34+ mice demonstrated ~55% tumor growth inhibition (TGI) with enhanced survival of > 14 days vs. control. Conclusions: CEACAM6 is expressed exclusively in primates and humans and plays multifaceted oncogenic roles in PDA pathogenesis. When CEACAM6 is disrupted, ECM proteins are altered reshaping the stroma, activating specific PKs and priming apoptosis. The therapeutic anti-CEACAM6 Mab possesses anti-tumor activity with associated cellular apoptosis and increased mouse survival.
Germline ATM mutations on survival in metastatic pancreatic cancer patients.
Authors: Gower Arjan , Gresham Gillian , Haladjian Nanor , Lee John , Ng Camille , Mehta Sejal , Hendifar Andrew Eugene
Published: May 2020

e16746

Background: Ataxia telangiectasia mutated (ATM) protein is a DNA damage repair enzyme and regulates normal cell-cycle mechanisms. Germline ATM mutations are associated with increased risk for developing pancreatic cancer (PC), occurring in approximately 2% of PC patients (pts). The role of germline ATM mutations in PC is not well defined. The objective of this study was to compare survival outcomes in patients with germline ATM mutations compared to somatic ATM mutations in PC. Methods: Tumor genomic profiling was completed in 144 PC patients at a single institution in the US, where pts were included in the analysis if they had either germline ATM mutations or somatic ATM mutations. Clinical outcomes were compared between pts with germline ATM mutations and pts with somatic ATM mutations only. Adjusted Cox regression models were fit to evaluate the impact of ATM mutation on overall survival (OS), calculated from treatment (tx) initiation to death, and progression free survival (PFS) calculated from tx initiation to first progression. Results: From 144 PC pts evaluated, 7 pts (4.9%) had germline ATM mutations, all of whom presented with metastatic disease, and 14 pts (9.7%) with somatic ATM mutations only, of whom 10 presented with metastatic disease and 4 who initially presented with locally advanced PC. The majority of pts (15/21), including all 7 pts with germline ATM mutations and 8 with somatic ATM mutations, were treated with first line gemcitabine and abraxane. Median OS was not reached in patients with germline mutations, and 11 months for patients with somatic mutations. Pts with germline ATM mutations had significantly higher OS (HR: 0.12, 95% CI 0.03-0.62, p = 0.01) and PFS (HR:0.26, 95%CI 0.07-0.91, p = 0.04) compared to patients with somatic ATM mutations only after adjusting for age, sex, and first-line tx. Conclusions: Pts with germline ATM mutations may experience greater survival benefit from tx compared to those with only somatic ATM mutations. Further research into the underlying mechanism is warranted.
Novel targeted and sustained drug delivery therapy for localized pancreatic cancer: Validation in porcine models and minimally invasive surgical feasibility in human cadavers.
Authors: Lashof-Sullivan Margaret , Kim Michael Paul , Tzeng Ching-Wei David , Indolfi Laura
Published: May 2020

e16747

Background: As systemic therapy improves, control of localized pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable tumors, for whom enhanced local downsizing of disease could improve resection rates and survival. PanTher is developing a locally targeted drug delivery product (PTM-101) to treat localized PDAC by directly delivering chemotherapy to the primary tumor. PTM-101 is a bioresorbable polymeric patch containing paclitaxel surgically placed onto the tumor. It biodegrades, resulting in sustained localized release of drug. In murine orthotopic patient-derived xenograft models a 60% increase in OS and inhibition of metastasis was achieved after single treatment. Here we validate and de-risk PTM-101 implantation in standard OR settings in large animals and human cadavers to prepare for a phase 1 study. Methods: We conducted two 30-day studies in porcine models to assess safety, toxicity and biodistribution. Parameters included body weights, hematology, urinalyses, drug levels in the blood and at the implantation site and histomorphologic evaluation. To validate the feasibility of minimally invasive surgical insertion, we conducted a follow-up study in three human cadavers. In each case, PTM-101 was laparoscopically placed directly on the pancreas. Results: We surgically implanted PTM-101 without complications and our approach ensures localized drug delivery with extreme control of drug biodistribution. Importantly, no detectable levels of drug were present in the blood any time during the 30-day treatment, confirming our targeted delivery. PTM-101 was consistently and effectively placed during a minimally invasive surgery without substantial increase in procedure time. PTM-101 conforms fully to pancreatic tissue, allowing for close contact with the intended tissue for drug delivery, and can cover the areas of the pancreas where critical involvements of tumors with vasculature are commonly found. Conclusions: By changing the route of administration to target just the area of interest, PTM-101 can increase the amount of drug reaching the tumor with the aim to enhance therapeutic efficacy. This could open the door to clinically relevant applications in PDAC patients: (i)pre-operatively as neoadjuvant treatment to control progression and downsize locally advanced and borderline anatomy to improve resectability; or (ii)post-resection to reduce the rate of local recurrence.
Cytokines as a prognostic biomarker of overall survival in pancreatic cancer.
Authors: Tan Harold Nathan Choa , Velasco Rogelio Nona , San Juan Michael Ducusin , Cornelio Gerardo H.
Published: May 2020

e16753

Background: Pancreatic cancer is an aggressive malignancy with a dismal 5-year survival rate of only 9%. Novel biomarkers are urgently needed to improve the survival outcomes of patients with this dreaded disease. Cytokines serve a key role in tumor development and metastasis in pancreatic cancer, with each cytokine demonstrating unique functionality in the tumor microenvironment. This meta-analysis examined the role of cytokines in prognosticating overall survival (OS) of pancreatic cancer patients. Methods: Relevant literature were identified via electronic search of PubMed, EMBASE, Google Scholar and Cochrane Library databases up to January 1, 2020. Employing Review Manager 5.3, pooled hazard ratios and 95% confidence intervals were computed. Results: A total of 18 studies comprising 1920 patients were included. Pooled analysis showed worse OS among patients with high T-helper 1 (Th1) cytokines, with a hazard ratio of 1.48 (95% CI 1.27-1.74, p < 0.00001). High T-helper 2 (Th2) cytokines also demonstrated significant association with poor OS, with a hazard ratio of 1.62 (95% CI 1.12–2.34, p = 0.01). In terms of individual cytokines, high IL-6 correlated with inferior OS, with a hazard ratio of 2.73 (95% CI 2.18-3.43, p < 0.00001). Similarly, high IL-12 were linked with worse OS, with a hazard ratio of 1.85 (95% CI 1.26-2.72, p = 0.002). Other individual cytokines were not significantly associated with OS. Conclusions: Cytokines show promise as a prognostic biomarker in pancreatic cancer. Th1 and Th2 cytokines portend worse overall survival outcomes. In particular, high levels of IL-6 and IL-12 can potentially prognosticate patients with poor overall survival. Further prospective studies are encouraged to delineate the role of cytokines in mediating treatment outcomes in this deadly disease.
Myosteatosis to predict postoperative morbidity in pancreatic ductal adenocarcinoma patients receiving neoadjuvant chemotherapy.
Authors: Louie Raphael , Aleixo Gabriel , Deal Allison Mary , Damone Emily , Tremont-Portelli Jaclyn , Nyrop Kirsten A. , Williams Grant Richard , Yeh Jen Jen , Yu Hyeon , Kim Hong Jin , Muss Hyman B.
Published: May 2020

e16754

Background: Myosteatosis (adipose deposits in muscle) can be detected on cross-sectional imaging through variations in Skeletal Muscle Density (SMD). Patients with myosteatosis tend to have lower overall survival, increased chemotherapy toxicity, and shorter progression-free intervals across cancer types. We investigated whether changes in myosteatosis during neoadjuvant chemotherapy can predict postoperative morbidity risk in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: This is a retrospective cohort study from 2014-2019 of patients with biopsy-proven PDAC who completed neoadjuvant chemotherapy and R0/1 resection (R1: margin < 1mm or microscopically positive). We obtained preoperative patient (age at diagnosis, baseline body mass index (BMI), sex, race, comorbidities) and treatment data (neoadjuvant chemotherapy regimen and duration, time from completion of systemic therapy to surgery, type of operation). Primary outcomes were postoperative complications and 90-day readmission. Average SMD was measured using imaging analysis software at the L3 level on axial abdominal CT scans at the time of diagnosis and at completion of neoadjuvant therapy (SliceOmatic TomoVision QC, Can). We defined SMDΔ as the decrease in SMD during neoadjuvant chemotherapy. Descriptive statistics and Student’s t-test were performed with STATA. Results: We identified 44 patients who received neoadjuvant chemotherapy, achieved a R0/1 resection, and had available CT scans for body composition evaluation. The postoperative complication rate was 43% (n = 19) and 90-day readmission rate was 30% (n = 13). Lower SMD at diagnosis was associated with increased postoperative delirium (p < 0.01) and 90-day readmission (p = 0.02). Greater SMDΔ was associated with increased ICU utilization (p < 0.01) and tube feeding upon discharge (p = 0.03). There was no significant association between preoperative BMI or albumin and our primary outcomes. Conclusions: Preoperative SMD and SMDΔ, rather than albumin or BMI, can predict postoperative morbidity in PDAC patients who received neoadjuvant chemotherapy. This study provides the framework for future studies to develop and validate a tool to predict postoperative morbidity risk in these patients.
Radiomic texture analysis correlates with PDAC patient outcomes on SM-88.
Authors: Ocean Allyson J. , Korn Ronald Lee , Kim Semmie , Burkett Andre , Hindosh Ziad , Nolte Zak , Del Priore Giuseppe
Published: May 2020

e16776

Background: SM-88 (racemetyrosine) is a dysfunctional tyrosine derivative; previous studies demonstrated a well-tolerated profile with encouraging efficacy. Recent advances in image analysis using Quantitative Textural Analysis (QTA) have uncovered non-invasive biomarkers that correlate with molecular drivers of cancer and prognostic signatures of response in PDAC. Earlier radiomic data from subjects treated with SM-88 showed a positive correlation between circulating tumor cells and tumor texture at baseline. This study extends those findings to focus on radiomic changes associated with SM-88 doses in a Phase II dose escalation trial (NCT03512756). Methods: Retrospective evaluation of 18 subjects with >1 prior therapy, ECOG PS <2, with no restriction on size, number, or locations of mets, and had baseline (BL) and follow up (FUP) contrast enhanced CTs. Subjects received > 1 cycle of SM-88 at either 460mg (n = 8) or 920mg (n = 10) QD oral doses. CTs were analyzed by the QTA platform (TexRad, Essex, UK) for tumor texture. The largest met of each subject was selected using portal venous phase images. A region of interest was posited on the axial slice with the longest tumor diameter and features automatically generated using voxel resampling to correct for scanner variability across subjects and time points. Results were displayed as histogram frequency curves (HFCs) of pixel densities (Hounsfield Units). First order HFC analysis (mean, StDev, MPP, skewness, kurtosis) at spatial scale filters (SSF) ranging from no filter, to fine, to coarse texture (SSF:0, SSF:2, SSF:6, respectively) were reported. Results: Subjects whose largest lesions showed greater changes in tumor texture at FUP vs. BL were more likely to develop tumor progression (StDev in PD (n = 10) vs SD (n = 7) (1 N/A): -0.07 vs -0.25, p = 0.05). Greater tumor textural changes were associated with poor survival at 180 days (Skewness: Chi-Sq. = 4.81, p = 0.03; HR = 4.1 for above median □Skewssf3). There was a negative change in FUP kurtosis vs BL in the 6 subjects who developed new lesions vs the 12 who did not (mean □kurtosis = -0.67 vs +2.63, p = 0.05). Greater change in tumor texture on FUP vs BL scans was seen in the 460mg vs 920mg group (MPPLD = -0.29, MPPHD = -0.04; p = 0.05) suggesting more tumor stability (less change in texture and better outcomes) was associated with the 920mg dose. Conclusions: Tumor lesions in subjects on 920mg of SM-88 were less likely to show a change in tumor texture and were associated with better outcomes. Using radiomic QTA, less tumor texture variability from baseline may be associated with better outcomes in PDAC subjects.
Predictors of recurrence and implications for overall survival in borderline resectable pancreatic cancer patients treated with total neoadjuvant therapy: A retrospective cohort study.
Authors: Kaplan Jori Lee , Powers Benjamin , Fan Wenyi , Schell Michael J. , Centeno Barbara , Kim Dae Won , Frakes Jessica , Hoffe Sarah E. , Malafa Mokenge Peter , Hodul Pamela Joy , Fleming Jason B. , Carballido Estrella M.
Published: May 2020

e16781

Background: Borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) is a subset of pancreatic cancer with unique prognostic implications. A multimodality, neoadjuvant therapy (NAT) approach has known benefits such as downstaging tumors, reducing the risk of a positive margin, and treating micrometastatic disease. Patient selection and therapy sequencing are controversial owing to the high risk of recurrence. Therefore, we aimed to identify factors predicting recurrence and overall survival (OS) in BR PDAC patients undergoing NAT. Methods: We identified BR PDAC patients treated with NAT followed by surgery at Moffitt Cancer Center between 2008-2015. We evaluated clinical, demographic, and perioperative factors to identify predictors of recurrence and OS. Statistical analyses were performed with univariate and multivariable Cox regression models. Results: 117 patients with BR PDAC who received NAT were evaluated; 53 (45%) were female and 64 (55%) were male. Of those, 91 (78%) received gemcitabine/xeloda/taxotere and the remainder received other gemcitabine or 5FU regimens. 107 (91%) patients received neoadjuvant radiation, mainly 5-day dose painted SBRT. Post- NAT CA 19-9 normalized in 39 (33%) and 11 (9%) additional patients normalized after surgery. Pathologic treatment effect was appreciated in 85 (73%) patients and pathologic complete response (pCR) was seen in 18 (15%). 95 (81%) patients initiated adjuvant therapy. In multivariable analysis, the strongest predictor of recurrence was higher log(10) post-operative CA 19-9 (HR 2.29; 95% CI, 1.40-3.75). Time from initiation of NAT to surgery ≥ 5 months also predicted recurrence (HR 2.08; 95% CI, 1.16-3.72). In OS analysis, 71 patients had recurrence after multimodality treatment; 61 (86%) died and 10 (14%) were alive. In multivariable analysis, the strongest predictors of prolonged OS from recurrence were female gender (HR 0.47; 95% CI, 0.26-0.84) and presence of a treatment effect (HR 0.37; 95% CI, 0.15-0.93). Conclusions: We observed treatment effects and pCR comparable to other institutions, supporting a multimodality approach to BR PDAC. Higher post-operative CA 19-9 and time to surgery ≥ 5 months from initiation of NAT were associated with an increased risk of recurrence. These data suggest that timely receipt of surgery after completion of NAT may impact recurrence and OS in BR PDAC.
BMK_PANC: Search for new predictive/prognosis biomarkers (BKs) in potentially resectable pancreatic adenocarcinoma (PDAC).
Authors: Viudez Antonio , González-Borja Iranzu , Goñi Saioa , Ghanem Ismael , Amat Irene , Arrazubi Virginia , Pérez-Sanz Jairo , Hernandez Irene , Feliu Batlle Jaime , Vera Ruth , Fernández-Irigoyen Joaquin
Published: May 2020

e16782

Background: New BKs are urgently needed in order to improve PDAC patient’s outcome. In this sense, the main aim of this multicenter and prospective project is to find predictive and/or prognostic BKs based on many cytokines that are produced in cancer microenvironment and can nowadays be accurately analyzed. Methods: Patients diagnosed of potentially resectable PDAC with poor prognostic factors and treated with neoadjuvant treatment are being included. Serial analyses (basal, with TC, with surgery and time of relapse/or after 1y of follow-up) of serum levels of 80 cytokines are being done. Results: With a median follow-up of 11,25 months (m) (4,67-38,28) 22 patients (pt) with median of age of 62,5 y-0, most of them men (63.6%) have been included, with radical surgery performed in 14 of them (2 pts with bypass). Seven operated pt received adjuvant treatment and 12 operated pt developed progression of disease. 18 pt have received nab-paclitaxel and gemcitabine as perioperative treatment and 4 received Folfirinox. Perineural and vascular invasion were confirmed after surgery in 45,5% and 27,3% of cases, respectively. Positive nodes were found in 40,9% of them, being the median of positive and resected nodes of 1 (0-14) and 26 respectively. Surgical margins were negative (R0) in 64,3% of cases (35,7% R1). Pathological response was described as partial in 13,6%, with no changes in 31,8% and progression in 13,6%. Globally, PFS and OS were 13,50 m (CI95%: 6,44-20,55) and 17,31 m (CI 95% 8,86-25,76). Significant differences (p = 0,002) were observed in cases in which radical surgery had been performed with PFS of 13,5 m (9,34-17,66) and 3.97 m (0-8,23) for unresectable patients. Regarding the cytokine array, we observed different PFS outcome based on basal MCP3 levels (low: 16,32 m CI 95%: 5,02-27,63; high: 7,52 m CI95%: 6,23-8.81, p = 0,023), basal Oncostatin (high: 7,12 m CI95%: 3,09-11,15, low: not reached; p = 0,007) or basal Eotaxin (low: 7,12 m CI 95%: 5,75-8,50; high: not reached, p = 0,029). A cytokine score was created based on these results, maintained significant differences for PFS (16,32 m CI95%: 5,07-27,57 vs 6,53 m CI95%: 2,75-10,32, p = 0.003). Our cytokine score showed a significant role as independent prognosis factor in multivariate analysis (HR: 0,196 CI95%: 0,042-0,918; p = 0.039). Conclusions: In potentially resectable/borderline PDAC our basal cytokine score seems to be able to discriminate as independent prognosis factor between those patients that will get significant benefit from neoadjuvant treatment from those that will not
Pembrolizumab in combination with the oncolytic virus pelareorep in patients progressing on systemic chemotherapy for advanced pancreatic adenocarcinoma: A phase II study.
Authors: Mahalingam Devalingam , Kalyan Aparna , Kircher Sheetal Mehta , Maurer Victoria , Kocherginsky Masha , Xu Jiahui , Viveiros Pedro Antonio Hermida de , Vagia Elena , Wilkinson Grey A , Coffey Matthew C. , Mulcahy Mary Frances , Benson Al Bowen , Zhang Bin
Published: May 2020

e16789

Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Analysis of tumor tissue from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination pembrolizumab in patients with PDAC would lead to improved response, effective T-cell recognition of tumor antigens and expand peripheral T-cell repertoire. Methods: This investigator-initiated phase II study enrolled PDAC patients who progressed after first-line treatment. Patients received pelareorep at a dose of 4.5x1010TCID50IV on Days 1, 2, 3 & 8of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. Primary objective was overall response rate (ORR) by RECIST v 1.1 criteria. Secondary objectives included evaluation for reovirus replication and immune analysis in peripheral blood and tumor biopsies. The study was designed using Simon’s two-stage design with 90% power and one-sided alpha = 0.025 to compare 10% vs. 35% ORR. A total of ≥2/11 responses were needed to proceed to stage 2. Results: Thirteen patients were enrolled. Disease control was achieved in 30% of the 12 efficacy-evaluable patients. One patient achieved partial response. Three additional patients achieved stable disease. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed a high degree of peripheral repertoire turnover and creation of new T-cell clones during treatment. Immune correlation with efficacy analysis is ongoing. Conclusions: Pelareorep with pembrolizumab showed manageable safety profiles and modest efficacy in an unselected PDAC population. The study will not proceed to stage II, however further evaluation of anti-tumor activity of pelareorep and anti-PD-1 therapy is now planned in biomarker defined patients. Clinical trial information: NCT03723915 .
DNA damage repair (DDR) gene mutations (mut) are predictors of response to platinum-based chemotherapy in advanced pancreatic cancer (PC) patients (pts).
Authors: Verdaguer Helena , Guardiola-Fernandez Magda , Mancuso Francesco M , Acosta Daniel , Buxó Elvira , Hernando Jorge , Diez Marc , Laquente Berta , Baraibar Iosune , Ros Javier , Garcia Alejandro , Matito Judit , Martin Agatha , Sierra Alexandre , Villacampa Guillermo , Molero Cristina , Miquel Josep M , Vivancos Ana , Dienstmann Rodrigo , Macarulla Teresa
Published: May 2020

e16805

Background: Somatic DDR mut have been reported in close to 10% of PC samples. In this study we investigate their predictive value for response to platinum-based chemotherapy. Methods: Case-control study with pts deriving response to oxaliplatin-based treatment (partial or complete response at any line) [n = 30] versus no response (progression in first restaging at 1st line) [n = 18]. An in-house NGS panel test of 420 genes was performed on tumor samples. DDR mut were classified in 2 subgroups: (a) functional BRCA1, BRCA2 or PALB2; and (b) any functional DDR gene mut, including those in (a). Results: 48 pts were included, median ages was 54.5 years (30-74), 29 male, 26 were diagnosed with stage IV, 36 pts (75%) received FOLFIRINOX and 37 received platinum-based chemotherapy as 1st. line treatment. Prevalence of DDR mut are described in the table. Among responders, 3 tumors had BRCA2 mt, 3 BRCA1, 2 ATM, and 1 each with BRCA2 + MSH2, PALB2, PMS2, MUYTH, RECQL4 + MDC1. Among non-responders 1 tumor each had ATM, FANCD2 and BLM. Median progression-free survival (PFS) with oxaliplatin-based chemotherapy in pts with BRCA1, BRCA2 or PALB2 mut tumors was 21.7 months (95% CI 12.3-NA); among those with any DDR mt was 12.3 months (95% CI 9.13-NA); while in pts whose tumors had no DDR mut was 6.4 months (95% CI 3.07-13)(Log-rank P-value = 0.02 comparison subgroup [a] vs. others; P-value = 0.1 subgroup [b] vs. others). Conclusions: The subgroup of pts with PC whit tumors harboring DDR gene mut, particularly functional BRCA1, BRCA2 or PALB2, have higher response rate and longer PFS with oxaplatin-based chemotherapy. [Table: see text]
Efficacy of carboplatin-based chemotherapy regimens in patients with bladder cancer in the neoadjuvant setting.
Authors: Aslam Hafiz , Bukhari Sumera , Nadeem Muhammad , Awwal Talha
Published: May 2020

e17001

Background: There is paucity of evidence regarding efficacy of neoadjuvant chemotherapy regimens in bladder cancer patients. Radical cystectomy has been standard of care for patients with T2-T4, N0, M0 bladder cancer. However, recent trials have shown better survival rates in patients who underwent neo-adjuvant chemotherapy. Our meta-analysis is based on the data from non-randomized clinical trials on the efficacy of carboplatin based regimens. Methods: We conducted a systematic search of Medline (Pubmed) and Cochrane (from inception through May, 2018). Only published single arm clinical trials, abstracts of single arm clinical trials and data from one randomized trial on efficacy of neoadjuvant Carboplatin based therapies in patients with bladder cancer were included in our meta-analysis. Total of > 70 studies were identified. Studies which were duplicate, included adjuvant therapy, systematic reviews or meta-analysis, trials not based on neoadjuvant therapy were excluded. A random effect model was used to calculate pooled proportions. Studies based on ITT protocol were analyzed separately as well as studies based on per protocol analysis. Comprehensive Meta-Analysis software version 3.0 was used. Results: The pooled proportion of pCR (pathologic complete response) calculated from trials based on ITT analysis was 0.23 (95% CI 0.19 to 0.28, P= 0.000). Tests for statistical heterogeneity was non-significant heterogeneity p-value = 0.79 (I2 = 0 %). The pooled proportion of pCR calculated from trials based on per-protocol analysis was 0.29 (95% CI 0.19 to 0.42, P= 0.002). Tests for statistical heterogeneity show nonsignificant heterogeneity p-value = 0.95 (I2 = 0 %). The pooled proportion of ORR (objective response rate) calculated from trials based on per-protocol analysis was 0.69 (95% CI 0.57 to 0.78, P= 0.001). Tests for statistical heterogeneity showed heterogeneity p-value = 0.203 (I2 = 37.3). The pooled proportion of cCR (clinical Complete response) calculated from trials based on per-protocol analysis was 0.25 (95% CI 0.18 to 0.34, P= 0.000). Tests for statistical heterogeneity did not show heterogeneity p-value = 0.80 (I2 = 0%). The pooled proportion of cPR (clinical Partial Response) calculated from trials based on per-protocol analysis was 0.47 (95% CI 0.39 to 0.56, P= 0.59). Tests for statistical heterogeneity did not show heterogeneity p-value = 0.93 (I2 = 0%). Conclusions: Carboplatin based chemotherapy has shown significant efficacy in terms of over-all response rate, pathologic complete response and clinical complete response.