bluuebunny/crossref_metadata_2025 huggingface dataset:
Utility of CT texture for identification of FGFR2 fusion in cholangiocarcinoma: A radiogenomic pilot study.
Authors: DeLeon Thomas , Borad Mitesh J. , Wu Teresa , Li Jing , Zwart Christine M. , Yang George , Holeman Scott , Silva Alvin C.
Published: September 2018

e15626

Background: FGFR2 fusions are found in 10-15% of intrahepatic cholangiocarcinomas. Individuals with FGFR2 fusions have a better prognosis and more indolent natural history. More recently FGFR2 fusions have been described as a predictive marker for tyrosine kinase inhibitors targeting the FGFR2 pathway. Texture analysis from CT imaging has been used in the past to estimate degree of fibrosis and angiogenesis in various tumors types; however, texture analysis has not been used in the past to detect FGFR2 rearrangements. Methods: This is a retrospective study of 33 patients with intrahepatic cholangiocarcinoma who were previously tested for FGFR2 fusions with either a FISH break apart assay or with clinically available next generation sequencing assays. All patients had a contrast enhanced CT performed. To address physiological and pathological variations, matched-size regions of interest (ROIs) over areas of non-necrotic tumor and unaffected liver during the portal venous phase were drawn. The paired ROIs for each patient were then processed via an imaging analytic pipeline for (1) ROI normalization, (2) texture panel creation, and (3) machine learning predictive model development. Results: Fifteen patients with FGFR2 fusions and 18 patients without FGFR2 fusions were included in the study. Using the developed predictive model, accurate FGFR2 fusion classification in 90% of cases was achieved (sensitivity = 87%, specificity = 94%). Conclusions: Utilizing advanced analytics with machine learning techniques, multi-textural data obtained from conventional CT images has the capability to detect genetic aberrations in intrahepatic cholangiocarcinoma, including FGFR2 gene fusions. Radiogenomic evaluation has several attractive benefits including the cost effective and expeditious detection of actionable mutations such as FGFR2 fusions as well as avoidance of invasive procedures such as percutaneous core biopsies. [Table: see text]
Phase I study of personalized peptide vaccination combined with radiotherapy for advanced hepatocellular carcinoma patients.
Authors: Shen Jie , Wang Lifeng , Zou Zhengyun , Wei Jia , Liu Baorui
Published: September 2018

e15628

Background: Advanced hepatocellular carcinoma is a challenging disease to treat because of its late stage, rapid progression. We conducted a new treatment modality, meaning a cellular immune therapy based on personalized peptide vaccination (PPV-DC-CTL) combined with radiotherapy, to treat advanced hepatocellular carcinoma. It integrates personalized peptide vaccination in tumor immunotherapy, takes full advantages of the immune modulation of radiotherapy, promotes tumor cells releasing antigens and results in more effective therapeutic strategy in local control and system treatment. Methods: A total of 9 patients with advanced hepatocellular carcinoma were admitted. Multidisciplinary consultation confirmed that all the patients were clearly no surgical opportunity. 4 patients with multiple liver metastases (liver lesions > 3 pieces), 1 patient with liver metastases and portal vein tumor thrombosis, 1 patient with lung and bone metastasis, 2 patients with liver and lung metastasis, and 1 patients with liver metastases and peritoneal metastasis. Patients with metastasis were treated with precise radiotherapy combined with PPV-DC-CTL. Results: After radiotherapy and 1-3 cycles of PPV-DC-CTL treatment, AFP levels were significantly decreased in 6 patients, of which, imaging assessment of lesions researched PR for 3 patients and SD for another 3 patients. Response rate (RR) was 33%, and disease control rate (DCR) was 66%. This scheme is safe and well tolerated. None of the patients had side effects on liver and kidney function. Only one patient had Grade2 of bone marrow suppression, and the rest had no significant side effects on hemogram. Conclusions: Radiotherapy combined with PPV-DC-CTL provides a new therapeutic strategy for patients with advanced hepatocellular carcinoma, which is well tolerated, safe, feasible, and effective. Clinical trial information: ChiCTR-OIC-16010025.
GALNT14 genotype-guided, sorafenib in combination with transarterial chemoembolization in hepatocellular carcinoma: An interim report of a prospective randomized controlled trial.
Authors: Yeh Chau-Ting , Lee Wei-Chen , Lin Shi-Ming , Lin Chih-Lang , Hsu Chao-Wei , Wu Ting-Jung , Yu Ming-Chin , Hung Chien-Fu , Tseng Jeng-Hwei , Lin Chen-Chun , Chen Wei-Ting , Teng Wei , Chen Yi-Cheng , Chang Ming-Ling
Published: September 2018

e15657

Background: Sorafenib is the only approved targeted agent for treatment of unresectable hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) is the mainstay of treatment for advanced HCC patients in Barcelona Clinical Liver Cancer (BCLC) stage B. Previous randomized controlled trials did not show definite beneficial effect for TACE + sorafenib combination therapy in Asian HCC patients. Recently, an SNP marker on GALNT14gene, rs9679162, was found associated with therapeutic outcomes in HCC patients receiving chemotherapy or chemoembolization, wherein rs9679162-TT genotype was associated with a favorable therapeutic response. In this study, we examined whether this marker could be used as a guide for TACE + sorafenib therapy. Methods: From 2015-Aug, HCC patients in BCLC stage B were genotyped for GALNT14-rs9679162. Patients with genotype TT were treated with TACE alone. Patients with non-TT (CT or CC) were randomized 1:1 to receive TACE + sorafenib treatment or TACE treatment alone (NCT02504983). Results: Interim analysis was performed on 2017-Jan. Totally 40 patients were enrolled. Of them, 16 and 24 patients had GALNT14-TT and non-TT genotypes, respectively. Of the non-TT patients, 11 and 13 patients were randomized into TACE alone (TACEA) and TACE + sorafenib (TACE+S) group. TACEA patients had significant shorter time-to-tumor progression compared with TACE+S (P = 0.019) and GALNT14-TT patients (P < 0.001). No significant difference was found for time-to-therapeutic response (CR + PR) between the three groups. However, when evaluating the time-to-therapeutic response occurring > 3 m of the first TACE (excluding early response), it was found that TACEA patients had significant longer time-to-therapeutic response compared with TACE+S (P = 0.046) and GALNT14-TT patients (P = 0.034). Conclusions: The interim analysis confirmed that patients with GALNT14-TT genotype had a favorable TACE response compared with the non-TT genotype. In addition, in patients with non-TT genotype, TACE + sorafenib combination therapy had a significantly better therapeutic response compared with TACE alone. Clinical trial information: NCT02504983.
Anti-mitochondrial therapy in bile duct cancer.
Authors: Alistar Angela Tatiana , Pasche Boris , Morris Bonny , Desnoyer Rodwige , D'Agostino Ralph
Published: September 2018

e15661

Background: Biliary duct carcinoma is a rare but highly fatal malignancy. The five-year survival rate for advanced bile duct cancer is 2%, per SEER data. As such, new treatment options are desperately needed. CPI-613, a novel anticancer agent that selectively inhibits mitochondrial metabolism in cancer cells, was employed in this study. Methods: This phase 1 study utilized a two-stage dose-escalation schema to determine the maximum-tolerated dose (MTD) and safety of single agent CPI-613 in patients with locally advanced or metastatic bile duct cancers. The 1st cohort enrolled 4 patients at 2300 mg/m2, with no dose-limiting toxicities (DLT) observed. The 2nd cohort enrolled patients at 1200 mg/m2/day for pre-cycle (days 1-5) and 3000 mg/m2 on days 1 and 4 weekly for 3 weeks (28 day cycle). The 5th and 6th patient experienced a DLT. The 3rd cohort was initiated at 600 mg/m2 pre-cycle and 3000 mg/m2 weekly with no other DLTs observed. Results: To-date, 14 patients have been enrolled in the study. The MTD was determined at 600 mg/m2/day pre-cycle and 3000 mg/m2 as per schedule. Once the MTD was determined, the cohort was expanded and, 8 patients have been treated at the MTD with no DLTs observed. Two additional patients are planned to be enrolled at this dose prior to trial completion. Of these 8 patients, 3 are still alive with 1 having prolonged survival (15 months) and the other 2 still on treatment. The most commonly observed toxicities were mild, such as anemia, anorexia, dehydration, fatigue, nausea and thrombocytopenia. Conclusions: Treatment with CPI-613 was well tolerated by patients with heavy tumor burden and refractory disease. CPI-613 has recently been shown to be well tolerated in combination with FOLFIRINOX in pancreatic cancer patients. Due to the low toxicity of CPI-613 in this study, even among highly symptomatic patients, it is anticipated that combination with other active agents is feasible in patients with advanced bile duct cancer. CPI-613 represents a novel treatment that could prove to be an exciting therapeutic alternative for patients with previously limited options and poor survival. Clinical trial information: NCT01766219.
A prospective biomarker study to assess IGF-1 score ability to sub-stratify Child-Turcotte-Pugh classes and predict response to systemic therapy in hepatocellular carcinoma.
Authors: Kaseb Ahmed Omar , Abdel-Wahab Reham , Hassan Manal , Xiao Lianchun , Raghav Kanwal Pratap Singh , Girard Lauren , Amin Hesham M. , Morris Jeffrey , Wolff Robert A. , Yao James C.
Published: September 2018

e15662

Background: Our recent studies showed that lower insulin like growth factors-I (IGF-I) associated with shorter overall survival (OS) in HCC. Furthermore, integrating IGF-I into Child Pugh Score (CTP) (IGF-CTP) led to better prognostic stratification (Kaseb et al., JNCI 2014). Since CTP class A is the standard criterion for active therapy and trials entry, we aimed at assessing the ability of IGF-CTP to predict systemic therapy outcome. Methods: 78 patients were prospectively enrolled and treated with sorafenib. Pre-treatment blood sample were tested for IGF-I and IGF-CTP was calculated after study completion. Survival analysis was done to measure the estimated median OS and progression free survival (PFS), and log rank test was used to compare PFS and OS between subgroups of IGF-CTP score of patients. Results: For CTP A patients, the estimated median OS in months (95% confidence interval, CI) was 9.1m (5.3 – 19.7) and PFS was 5.6m (3.8 – 7.9). Patients who were reclassified as IGF-CTP (B) (OldA/newB = AB) had significantly shorter OS 5.2m (2.8 - NA) and PFS of 4.3m (2.1 – NA), as compared to patients’ who classified as class A by both scoring systems (AA), who had OS of 11.1m (5.7 – 21.3) and PFS of 7.2 m (3.9 – 15.1), P < .001. Interestingly, patients who classified as CTP-B but IGF-CTP-A ( = BA) had significantly longer OS 10.2 (2.89 – NA) and PFS 8.1 (2.9 – NA), as compared to (BB) patients who had OS of 5.8 (3.2 –NA) and PFS of 5.1 (3.19 – NA), P < .001 Conclusions: Our study concluded that IGF-CTP score was more accurate than original CTP score in predicting survival outcomes of systemic therapy in HCC. If validated, this approach may change the standard stratification criteria for active therapy in routine clinical practice and patient selection for clinical trial entry in HCC.
Osteoponstin expression and presence of EGFR-positive liver macrophage to predict outcome after liver transplantation for hepatocellular carcinoma.
Authors: Tsuchiya Kaoru , Sieghart Wolfgang , Herac Merima , Hucke Florian , Oberhuber Georg , Sibilia Maria , Peck-Radosavljevic Markus
Published: September 2018

e15664

Background: Orthotopic liver transplantation (OLT) is the most effective therapy for patients with hepatocellular carcinoma (HCC) of limited extent. We focused on biomarkers, which could serve as tools for patient selection for OLT with good outcome even when transplanted beyond the standard size limits. Methods: Osteopontin(OPN) expression and presence of Epidermal Growth Factor Receptor (EGFR)-positive liver macrophage had been shown previously to be associated with the risk of tumor recurrence post OLT and were investigated immunohistochemically in 125 HCC-patients undergoing OLT between 1982 and 2002. Multivariate analyses of these and other well-described factors associated with median overall survival (OS) and time to recurrence (TTR) were performed. Results: The OS rates of the 125 patients at 1, 3, 5, 7 and 10 years were 77%, 52%, 43%, 37% and 32%. The 3-, 5-, and 7-year survival rates for patients without expression of both biomarkers (OPN and EGFR-positive liver macrophage) were 66.1%, 61.0% and 54.1%. These were significantly better than for the other groups (p < .0001), whereas the 3- and 7-year survival rates for patients with expression of both biomarkers were 25.0% and 5.0%. Fifty-eight patients (38.4%) developed tumor recurrence.There was no significant difference in OS and TTR between the patients beyond the Milan criteria (MC) without expression of both biomarkers (n = 26) and the patients within MC with expression of one or two biomarkers (n = 20).On multivariate analysis, vascular invasion and presence of EGFR-positive liver macrophage in HCC were independent factors associated with OS. Both biomarkers were independent factors associated with TTR.On multivariate analysis, morphologic criteria including MC and Up-to-7 criteria were not significantly associated with OS and TTR once OPN and EGRF+ macrophage presence was introduced into the analysis. Conclusions: Staining for OPN and EGFR-positive liver macrophage in HCC can give important prognostic information. The discussion about the selection for OLT in HCC patients should likely consider the expression of biomarkers in addition to relying on morphologic criteria.
Effect of adjuvant therapy on resected gallbladder adenocarcinoma: A propensity score matched analysis of national data.
Authors: Kasumova Gyulnara G. , Tabatabaie Omidreza , Miksad Rebecca A. , Ng Sing Chau , Hidalgo Manuel M. , Tseng Jennifer F.
Published: September 2018

e15669

Background: There is a paucity of data and no consensus regarding administration of adjuvant therapy after resection of gallbladder cancer. In the absence of a completed clinical trial, we retrospectively reviewed US cancer data. Methods: National Cancer Data Base was queried for patients diagnosed with gallbladder adenocarcinoma between 2004-2014 who underwent definitive resection for non-metastatic disease (pT1b, pT2, pT3, pN0, pN1, pNX) and had R0 and R1 resection margins. One-to-one propensity score matching was used to account for potential selection bias in patient and tumor characteristics. Kaplan-Meier method was used to compare overall survival. Results: Of 4830 patients identified, 1489 (30.8%) received adjuvant chemotherapy. Patients who received adjuvant chemotherapy were more likely to be younger, have private insurance or Medicare, have no comorbidities, higher T stage, and moderately to poorly differentiated tumors (all p-values < 0.0001). The majority of patients who received adjuvant chemotherapy also received adjuvant radiation (58.0%). On unadjusted analysis, patients who received adjuvant chemotherapy had no difference in median overall survival compared to those who did not (25.8 vs 29.0 mo; p = 0.3060). After matching for sex, age, race, insurance, comorbidity, facility type, pT stage, lymph node status, resection margins (R0 vs R1), adjuvant radiation, and tumor grade no difference in median overall survival remained between patients who did (21.8 mo) and did not (22.6 mo) receive adjuvant chemo (p = 0.6843). However, after matching on the propensity to receive adjuvant radiation in addition to the above covariates, receipt of adjuvant radiation resulted in a persistently significant increase in median overall survival (27.8 vs 22.2 mo; p = 0.0005). Conclusions: After matching for potential confounders, there is no difference in overall survival for patients who did and did not receive adjuvant chemotherapy after R0/R1 resection for pT1b, pT2, and pT3 gallbladder adenocarcinoma; however, adjuvant radiation does appear to confer a survival advantage. These results support the current treatment guidelines until evidence from RCTs becomes available.
Initial signals of efficacy in cholangiocarcinoma from a phase Ib trial of varlitinib in combination with doublet chemotherapy (cisplatin + 5-fluororacil or capecitabine).
Authors: Hsieh Chih-Yi , Wu Ming-Shiang , McHale Mark , Lindmark Bertil , Chow Lilian , Chao Yee
Published: September 2018

e15671

Background: Varlitinib (ASLAN001) is a potent, reversible, small molecule pan-HER inhibitor that selectively binds to HER1 (IC50 7nM), HER2 (IC50 2nM) and HER4 (IC504nM). Clinical data in cholangiocarcinoma, gastric cancer, colorectal cancer and breast cancer indicate that varlitinib is a safe and well tolerated inhibitor of tumor growth and survival. Here we conducted a phase Ib trial to determine the safety and early efficacy signals of varlitinib in combination with cisplatin (CIS) and 5-fluorouracil (5-FU) or CIS and capecitabine (CAP). Methods: Eligible patients had metastatic solid tumors. Doses of varlitinib were escalated in a standard 3+3 design with corresponding chemotherapy for 6 cycles after which patients remained on varlitinib montherapy. Responses were defined using RECIST 1.1 criteria. Results: To date, 27 patients have been enrolled. Most common treatment related adverse events ( > 10%) were nausea (56%; ≥G3 4%), vomiting (48%; ≥G3 4%), decreased appetite (44%; ≥G3 7%), diarrhea (37%; ≥G3 11%), anemia (26%; ≥G3 11%), fatigue (22%; ≥G3 0%), creatinine increase (19%; ≥G3 4%), stomatitis (15%; ≥G3 4%), acute kidney injury (11%; ≥G3 11%), bilirubin increase (11%; ≥G3 7%), leukopenia (11%; ≥G3 7%), abdominal pain (11%; ≥G3 0%), and neutropenia (11%; ≥G3 0%). All patients with diarrhea, including those with G3 diarrhea were well controlled with standard doses of loperamide. Of 15 patients evaluable for response, three had partial response (20%), ten had stable disease (67%), and two had progressive disease (13%). Of note were strong and durable responses in cholangiocarcinoma. One cholangiocarcinoma patient demonstrated an 87% reduction in liver tumor size by cycle 2 and a complete resolution in one liver lesion by cycle 4. Another cholangiocarcinoma patient without measurable lesions in the liver or biliary tract achieved long-term disease control for a total of 15.2 months with good tolerability on varlitinib as monotherapy. Conclusions: The combination of varlitinib and CIS + 5-FU or CAP doublet chemotherapy is safe, well tolerated and has demonstrated strong efficacy signals in cholangiocarcinoma. Clinical trial information: NCT02648425.
The impact of pathologic differentiation (well/ poorly) and the degree of Ki-67 index in patients with metastatic WHO grade 3 GEP-NECs.
Authors: Kim Seung Tae , Lee Su Jin , Lee Jeeyun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: September 2018

e15686

Background: Herein, we investigated the impact of pathologic differentiation (well or poorly differentiated) in metastatic grade 3 GEP-NEC patients receiving etoposide and platinum-based therapy. Simultaneously, we evaluated a more exact Ki67 index cut-off point to select patients with grade 3 GEP-NEC who might benefit from etoposide plus platinum (EP)-based therapy. Methods: Among patients pathologically diagnosed with metastatic grade 3 GEP-NECs at Samsung Medical Center between June 2013 and March 2016, 31 GEP-NEC patients receiving etoposide and platinum-based therapy were included in this study. Results: Primary sites included 13 foregut-derived GEP-NECs [stomach (n = 4), duodenum (n = 4), and pancreas (n = 5)] and 2 hindgut-derived GEP-NECs of the rectum. Sixteen unclassified GEP-NECs originated from 7 gall-bladder (GB), 6 liver and 3 unknown primary sites. According to pathologic differentiation, 14 patients had well differentiated and 17 had poorly differentiated grade 3 GEP-NECs. Between well differentiated and poorly differentiated grade 3 GEP-NECs, there was a significant difference in the distribution of Ki67 index. There was no significant difference of treatment efficacy between well and poorly differentiated grade 3 GEP-NECs (RR; 35.7% vs. 41.2%, p = 0.525). Tumor response to EP occurred in 5 of 7 patients with Ki67 > 60% and 7 of 24 with Ki67≤60%, which was significantly different (RR; 71.4% vs. 29.2%, P = 0.043). There was no significant difference in PFS according to pathologic differentiation (well differentiated vs. poorly differentiated) and Ki67 index ( > 60% vs ≤60%). Conclusions: Grade 3 GEP-NECs could be morphologically classified into well and poorly differentiated NETs. Additionally, among grade 3 GEP-NECs, there was a significant difference in ranges of Ki67 index between well and poorly differentiated NECs. Higher levels ( > 60%) of Ki67 index might be a predictive marker for efficacy of EP as a standard regimen in grade 3 GEP-NECs.
The role of modified FOLFIRINOX regimen in unresectable advanced pancreatic cancer: A retrospective clinical study.
Authors: Qian Yuan , Zheng Song , Jia Changku
Published: September 2018

e15709

Background:Pancreatic cancer was the fourth leading cause of death from cancer in the United States in 2015, with a 5-year survival rate only 6%.More than 85% of patients has an unresectable disease at diagnosis for most patients remain asymptomatic. This population including locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). Gemcitabine has been the standard treatment option for these patients for more than a decade, with a median overall survival nearly 6 months. In 2011, the phase 3 randomised controlled trial(PRODIGE 4/ACCORD 11) reported that FOLFIRINOX regimen had a significantly improved OS,PFS and a predominant ORR in patients with metastatic disease.FOLFIRINOX, as an encouraging regimen, its actual higher adverse events rate in clinical practice should not be underestimated, especially the grade 3/4 neutropenia and sensory neuropathy. The aim of our study is to explore whether a modified FOLFIRINOX regimen with the decrements of oxaliplatin and irinotecan had maintained efficacy and decreased grade 3/4 adverse events rate for the advanced pancreatic cancer. Methods:Retrospectively collected data of all patients carrying a diagnosis of advanced pancreatic cancer at the department of medical oncology, Hangzhou First People’s Hospital and Hangzhou cancer hospital between January 2014 and September 2016.The endpoint were overall survival, objective response rate and grade 3/ 4 adverse events. Results:Among 21 patients who received median 5(1-12) cycles modified FOLFIRINOX regimen,15 of total patients received this regimen for more than 4 cycles (71.4%). The median overall survival of MPC patients in this study is 12.6 months (95% CI, 6.2 months to 19 months). The objective response rate was 42.9%, with partial remission in 9 cases, stable disease in 8 cases and progression disease in 4 cases. Totally 8 patients had grade 3/4 adverse events, the most frequent were neutropenia (14.3%), neuropathy (14.3%) and diarrhea (9.5%). No chemotherapy-related death occurred. Conclusions:mFOLFIRINOX regimen in this study has maintained efficacy for its high objective response rate and an improved safety profile in patients with advanced pancreatic cancer.
Outcomes of resectable and borderline resectable pancreatic cancer patients in rural practice.
Authors: Rashad Sadaf , Bulbul Ajaz , Jean Brian , Gholam Sami , Araujo-Mino Emilio Paul , Braik Tareq , Khorsand-Sahbaie Masoud ,   Kymera Physicians
Published: September 2018

e15712

Background: Accurate selection of patients based on radiological and biological variables is crucial to avoid over treatment and unnecessary R1 resection in pancreatic cancer (PC). Methods: We retrospectively investigated 73 patients diagnosed with PC treated between January 1998 to October 2015. We applied NCCN definitions for Resectable (RD), borderline resectable (BRD) and unresectable disease(URD). Logistic regression was used to identify significant indicators of R0 resection. Odds ratios were used to compare differences of overall survivability by R0 and No surgery. Fisher’s Exact Test was used for significance on all tabulated data. Wilcoxon Rank-Sum was used for the comparison of two medians and Kruskal-Wallis to compare more than two medians, and log-rank test was used to compare Kaplan-Meyer Curves. Results: Radiologically RD comprised 21% (15/73) of total cases, 80% (12/15) of these underwent R0 resection. URD comprised 79% (58/73). Patients presenting with abdominal pain were 2.5 times (Odds Ratio; p = 0.0275) more likely to be URD. The mean tumor size for R0 resectability was 2.28 cm (n = 12). The median CA 19-9 for URD was 1473 vs 162 for RD (p = 0.0124). Stage at presentation and resectability were statistically associated. (p = 0.0002): 100% of Stage 1 (n = 4) and, 27% of Stage 2, (11/41) were resectable. Twenty-three cases were identified as BRD, 21/23 received neoadjuvant chemotherapy, 47.83% had radiological PR, 28.26% had SD and 23.91% PD. There was no association between type of Neoadjuvant treatment (Chemo XRT vs Chemotherapy) and radiological response (p = 0.8798). None of the 21 BRD patients underwent surgery. Median Overall Survival for R0 resection was 22.3 months (95% CI 15.23, 36.50) vs. 5.1 who did not have surgery (95% CI 3.55, 7.57) (p = 0.0010). Conclusions: Nearly 80% patients identified as resectable on imaging underwent R0 resection. Although there were partial responses seen in BRD patients that underwent neoadjuvant treatment eventually none underwent R0 resection. Patients presenting with abdominal pain and high CA19-9 ( > 1400 U/ml) are likely to URD. Early stage and R0 resection were associated with positive outcomes.
A phase II study of oral S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy for metastatic pancreatic cancer with helical tomotherapy.
Authors: Ren Gang , Zhu Feng , Wang Yingjie , Xia Tingyi
Published: September 2018

e15720

Background: This study was conducted to evaluate the efficacy as well as toxicity of oral S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy for metastatic pancreatic cancer using helical Tomotherapy. Methods: Patients with metastatic pancreatic cancer, adequate organ and marrow function and no prior anticancer therapy were enrolled in our study. S-1 was administered orally at a day of 40mg/m2 twice daily from day for 2 weeks, repeated every 3 weeks. Dose to the primary lesion was delivered as PTV for 50Gy, CTV for 60Gy and GTV for 70Gy in 15 to 20 fractions. Radiation induced toxicities were evaluated with the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.02. The overall survival (OS), progressive-free survival (PFS) and freedom from local progression (FFLP) were estimated using the Kaplan-Meier survival curve. Results: 45 patients were enrolled in this prospective clinical study. Pain relief rate was 91.7% (33/36). 1 year FFLP rate of the pancreatic lesion was 92.5%. 1 year OS rate was 17.6%. 1 year PFS was 4.2%. Median OS was 6 months. Grade 3 gastrointestinal reaction and blood reaction both appeared in 3 cases (13.3%). Conclusions: S-1 with concurrent hypofractionated simultaneous integrated boost radiotherapy using helical Tomotherapy resulted in high pain relief rate for patient with metastatic pancreatic cancer, with a tolerable side effect.
The prognostic significance of exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC).
Authors: Khushman Moh'd M. , Bhardwaj Arun , Patel Girijesh K. , Laurini Javier , Roveda Kelly , Donnell Robert , Sherling Kelley , Case Brittany , Tan Marcus Chuan Beng , Thompson Lee W. , Nelson Cindy , Wyatt Mary , Singh Seema , Taylor William R. , Singh Ajay
Published: September 2018

e15730

Background: Exosomes are important mediators of intercellular communication, and play pivotal roles in cancer progression, metastasis and chemoresistance. Exosomal membranes are enriched in endosomes-specific tetraspanins (CD63 and CD9). In patients with PDAC, positive correlation between CD9 expression and overall survival (OS) was reported. However, CD63 expression was conserved in all patients without reported prognostic significance. Here, we explored the prognostic significance of CD63 expression using IHC in patients with PDAC of mixed gender and racial background. Methods: Between 2012 and 2016, 49 patients with PDAC treated at Mitchell Cancer Institute had available tissue (pancreatic resected tissue/biopsy [N = 29] or metastatic site biopsy liver, omentum or bone (N = 20)) for CD63 staining using IHC. Two pathologists independently scored the expression of CD63. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Unpaired t test was used for statistical analysis. Results: Median age was 64 years (range 42-85). 53% are males. 67% white, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV disease while 49% had stage I, II and III. Tumor involved the head (51%), body (20%) and tail (29%). The mean CD63 Q score is slightly higher in AA compared to white (157 vs 149, P = 0.76). The mean CD63 Q score is higher in the pancreatic tissues compared to metastatic sites tissues (185 Vs 102, P = 0.0002). In our cohort, patients with mean CD63 Q score > = 140 had longer median OS compared to patients with mean Q score of < 140 (19 months Vs 3 months, P = 0.0003) and progression free survival (PFS) (12 months vs 1 month, P = 0.0043). Conclusions: In our cohort of patients with PDAC, there was no racial difference in CD63 expression between white and AA. The expression of CD63 is higher in the pancreas compared to metastatic sites (liver, omentum and bone). There is positive correlation between CD63 expression and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC.
The impact of second-line chemotherapy on advanced pancreatic cancer: A retrospective study in Reggio Emilia Clinical Cancer Centre.
Authors: Baldi Licia , Panebianco Michele , Giorgi Rossi Paolo , Mancuso Pamela , Cassetti Tiziana , Sassatelli Romano , Pinto Carmine
Published: September 2018

e15732

Background: There is currently no standard second-line treatment for metastatic pancreatic adenocarcinoma. The aim of this study is to evaluate the impact of a second-line therapy prior to the introduction of nab-paclitaxel. Methods: From 01/2009 to 12/2014, 204 patients were treated for pancreatic cancer. 166 (81.3%) received first(I)-line chemotherapy. Patients treated in second(II)-line were evaluated in two different periods, before and after FOLFIRINOX introduction. Results: 99 patients (59.6% treated in I line) received II line therapy. The main regimens used in I line were gemcitabine during the period 2009-2011 and FOLFIRINOX from 2012 to 2014 (some patients were treated with nab-paclitaxel/gemcitabine approved before AIFA registration). We observed that the increased use of gemcitabine in the second period was related to a reduction in I line use (52.1% patients after 2012 vs 21.4% before 2012). Considering the different therapeutic regimens employed in I and II line, no statistically significant differences in overall survival were observed over the two periods (Table). The probability of receiving II line chemotherapy did not change in the two groups (HR 0.6; p=0.2). Conclusions: Within the limits of a retrospective analysis, all II line regimens used showed the same effectiveness, regardless of I line treatment employed. It is likely that the large number of patients treated with effective therapies in II line have concealed the impact of front-line schemes. In an ongoing study we are evaluating the impact of introducing nab-paclitaxel in clinical practice. [Table: see text]
FOLFIRINOX versus gemcitabine nab-paclitaxel for advanced pancreatic cancer: KU Cancer Center experience.
Authors: Kasi Anup , Middinti Akshay , Cao An , Vekaria Pratikkumar , Patel Devangi , Subramaniam Dipti , Chen Guoqing J. , Saeed Anwaar Mohammed , Paluri Ravi Kumar
Published: September 2018

e15744

Background: FOLFIRINOX (FFN) and Gemcitabine plus nab-paclitaxel (GN) have been established as first line chemotherapy in advanced pancreatic cancer (PC). But there is no head-to-head randomized trial data available to support preferable first line choice between these two regimens. Methods: We retrospectively evaluated 154 chemotherapy-naïve locally advanced and metastatic PC patients treated with FFN or GN at KU Cancer Center between January 2011 and November 2016. FFN consisted of Oxaliplatin 85mg/m2, Irinotecan 180mg/m2, 5-FU 400mg/m2 as a bolus and 2,400 mg/m2over 46 hour on days 1 and 15 every 4 weeks. GN consisted of Gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day1,8,15 every 4 weeks. We compared characteristics, efficacy and adverse events between FFN and GN. Results: 107 patients were treated with FFN and 47 patients with GN as first line therapy. Demographic and baseline characteristics (FFN/GN) were as follows: Median age 61/63 years, ECOG performance status (0-1): 90% / 83%, Gender (male): 57% / 54%, distant metastases: 52%/70%, biliary stenting: 41%/20%, locally advanced tumor: 48%/30%, pancreatic head tumors: 63%/55%, median number of cycles: 4/4 respectively. Objective response rate (13% vs. 10%), Stable disease rate (76% vs 82%) and disease control rate (89% vs. 92%, p = 0.5) were similar in FFN and in GN. Median PFS was 11.7 months (95% CI: 7.2-16.1) in FFN and 5.7 months (95% CI: 2.7-8.8) in GN [p = 0.07]. Median OS was 15.9 months (95% CI: 13.7-18.1) in FFN and 10.8 months (95% CI: 7.1 – 14.5) in GN [p = 0.17]. Incidences of grade 3 or higher adverse effects were neutropenia (33% vs. 17%), anemia (14% vs 31%), thrombocytopenia (28% vs 6%), elevated creatinine (2.8% vs 4%), elevated transminases (3.7% vs 6%), diarrhea (5% vs. 0%), and peripheral neuropathy (6% vs. 6%) respectively. Conclusions: Patients treated with FFN showed statistically better PFS compared to GN. However this difference in PFS did not translate into statistically significant difference in OS. Response rates were similar. Incidences of adverse events were relatively more with FFN compared to GN as expected.
Predictive value of hENT1 immunohistochemistry for gemcitabine-treated pancreatic cancer is antibody dependent.
Authors: Yusuf Dimas , Lui Arthur , Abdelaziz Zainab , Spratlin Jennifer L. , Mackey John Robert
Published: September 2018

e15746

Background: Pancreatic cancer (PC) continues to have poor outcomes, and biomarkers to guide individualized therapy are needed. Gemcitabine (GEM), a pyrimidine nucleoside, requires plasma membrane transporter proteins to enter cells, and deficiency of the human equilibrative nucleoside transporter 1 (hENT1) protein confers high-level GEM resistance in pre-clinical models. Furthermore, abundance of hENT in PC cells, as determined by immunohistochemistry (IHC), has been variably reported to be associated with improved survival in people with PC treated with GEM. The antibodies (Abs) used for IHC differ in targeted epitope, method of generation, and species of origin. The purpose of this review is to evaluate the contribution of anti-hENT1 Ab choice in finding a link between hENT1 expression and outcomes. Methods: We reviewed the published literature investigating relationships between hENT1 IHC tumor expression and survival in people with PC treated with GEM. Results: Eighteen studies were identified, using five distinct Abs (Table 1). We identified apparent differences in predictive value among Abs (Chi square test p = 0.065). All seven studies using the 10D7G2 Ab reported that high hENT1 expression is associated with significantly better outcomes in GEM-treated patients. Studies that used other anti-hENT1 Abs, in particular SP120 and 11337-1-AP, had lower rates of success. Pooled HRs and additional metrics will be presented. Conclusions: There is significant heterogeneity among studies evaluating the link between hENT1 expression and outcomes. hENT1 IHC with the 10D7G2 Ab is a strong and reproducible predictive marker for improved survival in people with PC treated with GEM. [Table: see text]
Prognostic role of neutrophil-to-lymphocyte ratio (NLR) dynamics during first-line FOLFOXIRI in advanced pancreatic cancer (aPC).
Authors: Pecora Irene , Musettini Gianna , Catanese Silvia , Vivaldi Caterina , Pasquini Giulia , Caparello Chiara , Lencioni Monica , Falcone Alfredo , Fornaro Lorenzo , Vasile Enrico
Published: September 2018

e15754

Background: Elevated pre-treatment NLR is a well-known poor prognostic factor in several tumours, including aPC. However, the role of NLR changes during first-line chemotherapy is less investigated. Methods: We retrospectively evaluated aPC patients (pts) treated with FOLFOXIRI (infusional 5-fluorouracil, oxaliplatin, irinotecan). NLR was calculated before the first (NLR-0) and the fourth (NLR-3) cycle, high NLR being defined as > 4. We evaluated the correlation between NLR change and overall survival (OS), progression-free survival (PFS), response rate (RR) and disease-control-rate (DCR). Survival curves were estimated using the Kaplan-Meier method. Log-rank and chi-square tests were applied. Multivariate analysis was performed by Cox proportional hazards model. Results: Ninety-four pts were evaluable. Median age was 62 years; at diagnosis, 38 (40.4%) pts had unresectable stage III and 56 (59.6%) had stage IV disease. In the overall population, median PFS (mPFS) and OS (mOS) were 8.0 and 12.9 months, respectively. NLR-0 was significantly associated with poor prognosis: among the 12 pts with NLR-0 > 4 mOS was 5.1 months compared with 13.5 months for the 82 pts with NLR-0 ≤4 (p < 0.001). As regards NLR dynamics, NLR-3 remained high or was increased (H/I) in 5 pts (5.3%) while was stably low or decreased (L/D) in 89 pts (94.7%). mOS was 5.1 months (95%CI 0.4-9.8) in H/I and 13.5 months (95%CI 10.9-16.1) in L/D (p < 0.001) pts. The same association was found for PFS, with 4.7 (95%CI 2.1-7.3) vs 8.3 months (95%CI 6.2-10.4, p = 0.004), respectively, but not for RR and DCR. At multivariate analysis, NLR change was confirmed as independent predictor of OS (HR 6.854, 95%CI 2.109-22.269, p = 0.001) and, when added to performance status, liver metastases and NLR-0, allowed a better risk stratification in good (no negative factors), intermediate (1-2 factors) and poor (3-4 factors) risk groups, with mOS of 18.0, 10.0 and 5.1 months, respectively (p = 0.012). Conclusions: Not only NLR-0, but also changes after 3 cycles of first-line FOLFOXIRI could predict OS in aPC pts. Early variations in NLR might be a cheap, reproducible and useful factor to predict prognosis and to better refine treatment strategy.
Feasibility and clinical utility of EUS guided biopsy of pancreatic cancer for next-generation genomic sequencing.
Authors: Dreyer Stephan , Jamieson Nigel , Evers Lisa , Jones Marc , Martin Sancha , Duthie Fraser , Musgrove Liz , Cooke Susie , Bailey Peter , McKay Colin J , Chang David Kuang-Fu , Biankin Andrew
Published: September 2018

e15755

Background: Next-generation sequencing (NGS) has made genomic profiling to guide therapy a reality for many cancer types. The aim of this study is to investigate the feasibility of genomic profiling using standard clinical endoscopic ultrasound (EUS) core biopsy samples of Pancreatic Cancer (PC) to allow personalised cancer care. Methods:Patients undergoing EUS and biopsy for suspicion of PC underwent additional biopsies which was snap frozen. En-face frozen section enabled targeted macro-dissection prior to DNA extraction, quantification and targeted sequencing using a commercially available 151 gene ClearSeq Comprehensive Cancer Panel. Matching formalin-fixed (FFPE) diagnostic EUS biopsy and fresh frozen surgical resection specimens underwent genomic profiling for comparison. Whole genome sequencing (WGS) was performed in 2 patients. RNA sequencing was performed in samples with sufficient RNA yield. Results: Known PC genes ( KRAS, GNAS, TP53, CDKN2A, SMAD4) were identified in 27 out of 30 (90%) patients with histological diagnosis of PC. Potentially actionable somatic mutations (BRCA1, BRCA2, ATM, BRAF, JAK3) were found in 6 (20%) patients. In the 2 samples selected, WGS of the EUS samples confirmed point mutations identified on panel sequencing and revealed relevant mutational signatures and structural variation patterns. Targeted panel sequencing was successful in all FFPE samples. In 1 chemotherapy naïve patient, sequencing of a matching trio of fresh frozen and FFPE EUS biopsies, and resection sample revealed evidence of spatial intra-tumoral heterogeneity. In another patient, pre-treatment biopsy revealed a somatic BRCA1 mutation, and patient had a near complete pathological response to platinum containing neoadjuvant therapy in the resected specimen. RNA sequencing segregated patients into key clinically relevant molecular PC subtypes based on transcriptome as recently described. Conclusions: We demonstrate here novel multi-omic analysis of pancreatic cancer using standard clinical EUS guided fine needle biopsies. Multi-omic analysis of EUS biopsies offers potential clinical utility to guide personalized therapy of PC in the neoadjuvant and advanced settings.
Efficacy of alternating-week fixed dose rate gemcitabine (FDR gem) plus capecitabine (CAP) in advanced pancreatic cancer (APC).
Authors: Johns Claire , Diaz Celso L. , Kerridge William , Hwang Jimmy , Ko Andrew H. , Tempero Margaret A.
Published: September 2018

e15758

Background: Phase III trials support the use of FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel as first-line treatment options in patients with APC. However, these treatments have significant side effects including cumulative neuropathy and cytopenias that limit their use. Our group previously reported results from a phase II trial evaluating a regimen of alternating-week FDR GEM/CAP showing promising efficacy as well as good tolerability. In the current analysis, we examined a larger retrospective cohort of APC patients treated using this strategy. Methods: Eligible patients received FDR GEM (1000 mg/m2) infusion on days 1 and 15, along with CAP 1,000 mg/m2 on days 1 to 7 and 15-22, in 28-day cycles. We evaluated OS, PFS, and objective radiologic response (ORR) by RECIST 1.1; as well as tabulated adverse events that necessitated dose or schedule modification. Results: 62 patients were treated at UCSF from 2008-2016 (52% male; and 48% female with a median age of 64.3 years. 49 had metastatic disease and 13 were locally advanced. Median OS was 10.3 and 12.0 months in the metastatic and locally advanced cohorts, respectively; median PFS was 5.4 and 5.6 months. ORR in evaluable patients with metastatic disease was 19% (all partial responses), with a disease control rate of 64%. In total, 37% of patients required dose modification at some point during therapy; the most common reason was hand-foot syndrome. Conclusions: FDR GEM/CAP represents an active and safe regimen for patients with APC, with OS and PFS rates comparable to those achieved with other first-line treatments. This regimen, based on its ease of administration and tolerability, may represent a suitable alternative option in select patients.
Effect of Rho/ROCK pathway inhibition on metastasis-free and overall survival in biomarker selected, orthotopic, patient-derived models of pancreatic cancer.
Authors: Chin Venessa T. , Nagrial Adnan , Conway James , Vennin Claire , Chantrill Lorraine A. , Chou Angela , Steinmann Angela , Gill Anthony J. , Humprhis Jeremy , Drury Alison , Froio Danielle , Morgan Ashleigh , Biankin Andrew , Timpson Paul , Pajic Marina
Published: September 2018

e15759

Background: PC is a highly lethal disease which metastasises early. The sequencing efforts of the Australian Pancreatic Cancer Genome Initiative (APGI) identified ROCK-1 as a target of interest. The Rho/ROCK pathway is essential in cellular movement, metastasis, vasculogenesis and stromal signaling. Fasudil (F) is a ROCK inhibitor which has been shown to be safe for human use. Using unique, patient derived models, we have previously shown that F plus gemcitabine (G) does not reduce cellular proliferation in vitro but reduces tumour size and improves overall survival (OS) in subcutaneous patient-derived xenografts (PDX). However, PDXs are critisised for not fully recapitulating the human condition. Here we aimed to generate a patient-derived orthotopic xenograft (O-PDX) which could be used to assess the effects of F + G on metastasis formation and OS. Methods: One patient-derived cell line (PDCL) was labled with firefly luciferase. This was injected into the pancreas of NOD/Shi- scid/IL-2Rγnull (NSG) mice to generate the O-PDX model. The O-PDX was imaged weekly with the IVIS imaging system. The O-PDXs were treated with saline control (S) (n = 8), gemcitabine (G) (n = 10) fasudil (F) (n = 6) or gemcitabine + fasudil (GF) (n = 10). Mice were culled once radiographic or clinical evidence of ascites was detected. Metastasis free (MFS) and OS were recorded. Vessel quantification was performed via CD-31 staining. Results: Metastases seen (spleen, liver, lung, ovary) on imaging were confirmed using GFP stains on immunohistochemistry. F prolonged MFS but not OS when compared with S. GF significantly prolonged MFS (33.5 versus 43 days; p = 0.0339) and OS (51.5 versus 64 days; p = 0.0035). CD-31 staining showed that treatment with F resulted in increased vascularity in the liver metastases and normal liver tissue but not in the pancreas tumour. Conclusions: The addition of Fasudil to gemcitabine improves MFS and OS in an orthotopic model of PC and is a promising new therapeutic option. The increase in vascularity of the metastases and normal liver tissue suggest that changes in vascularity are important and may result in improved delivery of gemcitabine.
Clinical study of nab-paclitaxel in combination with S-1 as first-line therapy in patients with advanced pancreatic cancer.
Authors: Hu Yi , Sun Danyang
Published: September 2018

e15765

Background: Pancreatic cancer is one of the highest cancer-mortality diseases worldwide with limited treatment. Most patients had local advanced or metastatic disease at the time of diagnosis. Gemcitabine-based therapy has been standard regimen in the past few decades. It is necessary to find new strategies of treatment. Methods: The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel in combination with S-1 as first-line therapy in advanced pancreatic cancer. We retrospectively evaluated 79 patients with advanced pancreatic cancer from 2014 to 2016 treated in our medical center. All the patients received at least two cycles of combination therapy. Nab-paclitaxel was administered 260mg/ m2 as a total dose on day 1 and 5 or on day 1 and 8. S-1 was administered orally twice a day for 14 days according to body surface area. S-1 monotherapy was administered as maintenance treatment after 6 to 8 cycles of combination therapy until the progression of disease. Results: In all the 79 patients enrolled, the median age was 56, range from 36 to 77, 56 (70.9%) patients had KPS 90, 58 (73.4%) patients had multiple metastatic sites. The overall response rate was 51.9%; median progression-free survival was 5.7 months (95%CI 5.010-6.292); median overall survival was 11.9 months (95%CI 9.731-13.990). The efficacy of CA19-9 decrease > 50% was significant higher compared with those of CA19-9 decrease < 50%. Treatment was well tolerated. Grade 4 toxicity was only reported in neutropenia of 5 patients. Grade 3 adverse events include neutropenia in patients (13.9%), nausea and vomiting in one patient (1.3%), peripheral sensory in one patient (1.3%) and alopecia in 3 patients (3.8%). Conclusions: Nab-paclitaxel in combination with S-1 as first-line therapy demonstrated promising antitumor activity and well-tolerated toxicities and presents a new alternative for locally advanced and metastatic pancreatic cancer.