bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of immunotherapy use in patients with stage IV biliary carcinoma.
Authors: Rojas Mariajose , Komiya Takefumi , Sharma Neil R. , Powell Emily
Published: May 2020

e16597

Background: Most patients with cholangiocarcinoma have non resectable disease at the time of diagnosis and usually die within 6-12 months. The 5-year survival rate is very low (about 5%), and since most patients present with advanced disease at time of diagnosis, treatment includes chemoradiation and biliary stenting. Recently, trials with immunotherapy (IO) for treatment of advanced cancer have shown promising results as alternative therapeutic options. Despite indications in other solid tumors, the role of IO is unknown for biliary cancer. Methods: Using National Cancer Database (NCDB), cases of Stage IV biliary cancers (including gallbladder and cholangiocarcinoma) diagnosed in the period of 2014-2016 with at least 30-day follow up were analyzed. The following clinical demographics were included: age (younger than 70 vs. older than 70), sex (male vs. female), race (whites vs. others), insurance (uninsured vs. insured), liver metastasis (Yes vs. No). We also analyzed data regarding cancer treatment, including radiation (Yes vs. No), chemotherapy (Yes vs. No), and IO (Yes vs. No). Survival analysis was performed using Kaplan-Meier curves and Log-rank tests. A p-value < 0.05 was considered significant. Results: Among 6,344 eligible cases, 57 patients were treated with IO. No significant association between use of IO and clinical demographics was observed except for use of chemotherapy (p = 0.001) and primary location (gallbladder vs. others, p = 0.042). Chemotherapy was administered in 52 (91%) and 4112 (65%) of cases in IO and non-IO groups, respectively. Use of IO was associated with improved overall survival in both univariate and multivariate analyses (p = 0.0005and 0.0156, respectively). Median overall survival (in months) was 14.0 in the IO group vs 7.0 in the non-IO group. Landmark analysis in the IO group showed 12 and 24-month survival of 56.1% and 19.3% respectively, as compared with 27.8% and 7.6% in the non-IO group. Conclusions: This retrospective data analysis using a large cancer database suggests that use of IO could improve survival in patients with advanced biliary cancer. More studies will be needed in the future to validate these results.
Lenvatinib plus hepatic arterial infusion of modified FOLFOX regime in patients with advanced hepatocellular carcinoma.
Authors: Mai Qicong , Mo Zhiqiang , Shi Feng , Chen Xiaoming
Published: May 2020

e16603

Background: Recently, Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of modified FOLFOX regime has shown promising results for patients with advanced hepatocellular carcinoma. Lenvatinib is also the first-line treatment for advanced hepatocellular carcinoma, it has shown the better objective response rate (ORR) and longer progression free survival (PFS) than sorafenib. This retrospective study evaluated the combination of lenvatinib plus HAIC of modified FOLFOX regime in patients with advanced hepatocellular carcinoma. Methods: This study retrospectively enrolled and analyzed 24 patients from Nov 2018 to May 2019 from Guangdong provincial people’s hospital. Patients with advanced hepatocellular carcinoma were treated with 8 mg(≤60kg) or 12mg( > 60kg) lenvatinib once daily plus HAIC of modified FOLFOX regime (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). Best response according to the RECIST 1.1 and mRECIST criteria. PFS, overall survival (OS) and treatment-related adverse events(TRAE) were also evaluated. Results: 24 patients(median age: 49.2 years) underwent a total of 91 cycles of HAIC therapy (mean: 3.79; range: 2-8). 22 (91.7%) patients had cirrhosis caused by HBV infection.17(70.8%) patients were diagnosed with vascular invasion and 7 (29.2%) were both vascular invasion and extrahepatic spread. 20 (83.3%) patients were classified as Child-pugh A class and 4 (16.7%) patients were Child-pugh B class. The ORR were 58.3% (RECIST) and 66.7% (mRECIST), the disease control rate (DCR) was 79.2% (RECIST/mRECIST). With a median follow-up period of 11.3 months, the median PFS was 8.1 months. 6-, 9-, and 12-months OS rates were 91.7, 83.3%, and 75%, respectively. TRAE occurred in 20 of 24 patients (83.3%), most common TRAE were hypertension (41.7%) and hand-foot skin reaction(25%). No grade 3/4 TRAE was observed. Conclusions: Lenvatinib plus HAIC of modified FOLFOX regime was well tolerated and had shown promising ORR, PFS and 6-, 9-, and 12-months OS rates in advanced hepatocellular carcinoma. A prospective large-scale trial is needed to justify these results. [Table: see text]
To biopsy or to not biopsy, that is the question: A single-center retrospective analysis of outcomes of liver biopsy with hepatocellular carcinoma and other liver diseases.
Authors: Lee Sophia Seo-hyeon , Yang Wei , Rowe Julie Haewon
Published: May 2020

e16606

Background: Unlike other malignancies, hepatocellular carcinoma (HCC) is most often diagnosed radiologically, based on previous studies suggesting complication rates of 1.4%-3.4% (e.g., bleeding) and concerns regarding “tumor seeding.” Lack of tissue for analysis has led to a lag in understanding the molecular biology of HCC. Molecular characterization of biopsies may allow HCC subtyping in order to personalize medicine, thus the potential of liver biopsy’s safety and utility needs to be reassessed. Methods: We performed a retrospective review of patients who underwent biopsy for suspected HCC or other liver diseases between Jan 1, 2010 and Jan 1, 2020. Demographics and clinical data including comorbidities, renal function, ascites, hepatic encephalopathy, varices, and labs including hemoglobin, WBC, platelets, sodium, creatinine, liver function test and coagulation studies were collected. Child Pugh (CP) and MELD-Na scores were calculated. Adherent medications at the time of biopsy and type of biopsy with any complications were included. Results: A total of 427 patients underwent liver biopsy. Patient characteristics are given in the table. Most patients (97%) underwent core needle biopsy. Biopsy complication rate was 1.23% (n = 5); these included bleeding (80%, n = 4), hospitalization (60%, n = 3), infection (20%, n = 1), and death (20%, n = 1). In the 5 patients, increased creatinine was associated with bleeding complications; however, one patient was on dialysis (Cr = 11.20), and this should be interpreted with caution. Existing comorbidities, concurrent medication use (including anticoagulants), CP and MELD-NA score, and lab findings were not associated with biopsy complications. Conclusions: To our knowledge, this review is first to demonstrate a low complication rate of 1.23% in suspected HCC patients who underwent liver biopsy in the current era of improved radiological techniques. This is consistent with historical data in liver disease patients. Comorbidities, being on anticoagulants, CP and MELD scores do not predict for biopsy complications. Higher creatinine was associated with more complications, but this needs to be examined in a larger study. Biopsy should be considered a valuable tool in understanding the molecular profiles of HCC, which could lead to more novel treatment. [Table: see text]
Correlation of serum PIVKA-II and AFP level with portal vein tumor thrombus and BCLC stage in newly diagnosed hepatocellular carcinoma patients.
Authors: Gandham Goutham , Jayamohanan Hridya , Ponnada Bharadwaj , Kumar Anil , S Sudhindran , Keechilat Pavithran
Published: May 2020

e16608

Background: Protein Induced by Vitamin K Absence-II (PIVKA-II) is a tumor marker specific for hepatocellular carcinoma (HCC). PIVKA-II levels correspond with HCC oncogenesis and disease progression. Portal vein tumor thrombus (PVTT) in patients with HCC is a significant factor that affect treatment and prognosis. In this study we assessed the predictive value of PIVKA-II and AFP for vascular invasion and BCLC stage in newly diagnosed HCC patients. Methods: We retrospectively reviewed records of newly diagnosed HCC patients at a tertiary hospital in India between January 2019 to December 2019. Clinical details, BCLC stage, radiological imaging records, serum levels of PIVKA-II and AFP at the time of diagnosis were obtained from medical records. Diagnostic accuracy and cut-off value of PIVKA-II in patients with portal invasion were calculated using receiver operator curve (ROC) analysis. Multiple pairwise comparisions between BCLC stage with PIVKA-II and AFP levels were analysed using Kruskal-Wallis test. Results: Out of 162 newly diagnosed HCC patients 42(25.9%) were detected with PVTT on imaging such as contrast-enhanced computed tomography or magnetic resonance imaging at the time of diagnosis.120(74.1%) patients without PVTT were taken as controls for the analysis. Serum level of PIVKA-II in HCC patients with PVTT was significantly higher than in HCC patients without PVTT (1152.57 mAU/ml vs 146.39 mAU/ml; p = 0.001). AUROC of PIVKA-II was 0.796 (95%CI 0.70-0.892, p = 0.000).The optimal cut-off value of PIVKA-II was 271.81 mAU/ml with a sensitivity of 78.6% and specificity of 52.4%, and the diagnostic accuracy was 59.98%. AUROC of AFP was 0.619 (95%CI 0.59-0.72, p = 0.001). Median PIVKA-II value increased from BCLC stage A to D. Kruskal-Wallis test showed a significant difference of PIVKA-II levels between all stages except stage A and B (p values for stage A-B (0.297), A-C (0.000), A-D(0.000),whereas for AFP results were significant only between stages A and C (p values for stage A-B (0.348), A-C (0.003), A-D(0.206). Conclusions: Serum PIVKA-II level appears as a good predictive marker for PVTT and BCLC stage when compared to AFP which may guide therapeutic strategy and assessment of prognosis in newly diagnosed HCC patients.
Efficacy and safety of immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC): A systematic review and meta-analysis of randomized clinical trials (RCTs).
Authors: Jácome Alexandre A. , De Castro Ana Carolina Guimaraes , Solar Vasconcelos João Paulo , Silva Maria Helena Cruz Rangel , Lessa Marco Antonio Oliveira , Moraes Eduardo Dias de , Andrade Aline Chaves , Ferreira Barbara Sodre Figueiredo , Lima Frederico M. T. , Bulcao Marcela Lima , Ferreira Artur Rodrigues , Fogacci De Farias Joao Paulo , Prolla Gabriel , Garicochea Bernardo
Published: May 2020

e16631

Background: ICIs have ushered a new era in cancer therapy, but their efficacy in HCC is uncertain. Single-arm phase II studies with sorafenib-refractory patients have suggested clinical activity of nivolumab and pembrolizumab, which have become FDA-approved therapies. Nevertheless, the overall effect of ICIs compared with the standard of care (SOC) in unresectable HCC patients is still unknown. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, LILACS, and ASCO and ESMO Meeting Proceedings in the last 10 years for RCTs that have compared the efficacy of ICIs versus the SOC in the systemic therapy of unresectable HCC. Outcomes of interest included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3-4 treatment-related adverse events (TRAEs). A summary hazard ratio (HR) of OS and PFS was calculated using 95% confidence intervals (CI) by fixed-effects model. The likelihood of ICIs being associated with ORR and TRAEs was expressed by odds ratio (OR) and 95% CI using a random-effects model (PROSPERO ID 162599). Results: Of the 2,334 studies yielded by the search, 3 studies were retained (KEYNOTE-240, CheckMate-459, and IMbrave150), totaling 1,657 patients (985 ICIs versus 672 SOC). Two studies compared ICIs versus sorafenib in 1st line setting, and one study compared with placebo in 2nd line. The ICIs studied were pembrolizumab, nivolumab, and atezolizumab. RCTs with anti-CTLA4 have not been reported. Two studies evaluated ICIs as monotherapy, and one study investigated the association with bevacizumab. Compared with the SOC (sorafenib in 1st line or placebo in 2nd line), ICIs significantly improved OS (HR: 0.78, 95% CI 0.68 – 0.89, p = 0.0002), PFS (HR: 0.79, 95% CI 0.71 – 0.89, p < 0.0001), and ORR (OR: 2.82, 95% CI 2.02 – 3.93, p < 0.0001). ICIs were associated with a lower probability of grade 3-4 TRAEs when compared to sorafenib (OR: 0.44, 95% CI 0.20 – 0.96, p = 0.04). No significant heterogeneity was found among studies when OS and ORR were analyzed, but it was found in the analysis of PFS and TRAEs. Conclusions: ICIs demonstrated superior efficacy and safety compared to the standard therapy of patients with unresectable HCC. The analysis of ICIs as monotherapy and combination therapy increased the heterogeneity among studies. The association of anti-angiogenic therapy with ICIs improved the survival benefit of immunotherapy and should become the new SOC in the 1st line systemic therapy of unresectable HCC.
Novel systemic therapies in hard to treat fibrolamellar hepatocellular carcinoma.
Authors: Gliksberg Ariel , O'Grady Claire , Kent Paul
Published: May 2020

e16653

Background: Fibrolamellar Carcinoma (FLC) is a very rare liver malignancy of young adults without underlying liver disease (0.02 per 100,000 in the US).. Complete resection is the primary therapy, but recurrence rates are still > 50%. Currently there are no established systemic treatments, especially for high-risk disease (unresectable, relapse, progression, or metastatic disease). At our institution triple therapy “TT” with Nivolumab/5FU/Interferon α-2b is our first line, followed by other novel combination therapies such as Gemcitabine/Oxaliplatin/Lenvantinib (GOL) or Nivolumb/Lenvantinib/Quecertin (NLQ). Objective: To evaluate the tolerability and early response of multi-agent systemic therapies in patients with high-risk FLC. Methods: Data from all patients with FLC who received systemic therapies from 5/2018 to 2/2020 was reviewed to assess tolerability, survival and toxicity. Results: Nineteen patients were treated with systemic therapies of which 16 (10F, 6M median age of 19) were evaluable based on follow up scans. Between our 16 patients they had relapsed 28 times, 12 had metastatic disease and 7 had tried 2+ systemic therapies. RECIST 1.1 objective response (CR+PR) and tumor control (CR+PR+SD) are 44% and 69%. Since starting multi-agent therapy, all 6 patients who had previously been treated with monotherapy, have already exceeded their previous longest time to progression. Thirteen patients were treated with “TT” [12.5 median cycles (6-38)]. Three patients were treated with NLQ including 2 who failed TT. Of these, the 1 evaluable patient achieved CR. Two patients were treated with GOL, 1 who failed TT and one who was post liver transplant, both had sustained PR of 6 and 9 months. Subsequently one died and one achieved CR. For the 6 patients who achieved remission before or during therapy, only 1 has relapsed. To date the period of response is already 68% longer than the previous best length of response. There was 1 withdrawal due to grade 3 colitis and 2 dose adjustments. All experienced mild adverse effects, most commonly fever, headache, and hypertension, with 3 patients with grade 3 toxicities. Conclusions: FLC is a devastating disease with patients often relapsing even after successful surgical remission. Currently there is a need for tolerable systemic therapies. Although at our institution, TT is our frontline therapy, there are other combinations of immunochemotherapies that we have used to treat FLC with preliminary success and minimal toxicities. Our early results show that multi-agent systemic therapy in hard-to-treat FLC is worthy of further study.
Controversial risk factors for cholangiocarcinoma.
Authors: Sarmini Muhammad Talal , Baidoun Firas , Saad Anas M , Gad Mohamed , Alhaj Moustafa Muhamad
Published: May 2020

e16662

Background: Cholangiocarcinoma (CCA) is a relatively rare malignancy accounting for 3% of gastrointestinal cancers in the US. While multiple risk factors for CCA are established and well-studied, other potential risk factors are still controversial and not well established. Herein, we used a large national database to investigate possible risk factors and associations. Methods: We used the National Inpatient Sample (NIS) database to review all admissions between 2011 and 2015. We grouped patients based on the presence and absence of CCA using the appropriate ICD-9 codes. We used multivariate logistic regression to assess the association between obesity, alcohol abuse, smoking, diabetes mellitus (DM), and non-alcoholic fatty liver disease (NAFLD). Results: We reviewed 30,955,295 admissions of which 20,030 had CCA. CCA Patients were older compared to the rest of the patients (mean age 67 years ±12.8 vs. 57±20.6, P < .001) and had less female patients (48% vs 59%, P < .001). Patients’ characteristics are shown in the table. After adjusting for viral hepatitis B (HBV), viral hepatitis C (HCV), liver cirrhosis, inflammatory bowel disease (IBD), primary sclerosing cholangitis (PSC), and bile duct stones, logistic regression showed DM to be proportionately associated with CCA (OR = 1.04, 95%CI[1.01-1.08], P < .001), whereas alcohol, smoking and obesity were all inversely associated with CCA; OR = 0.75, 95%CI [0.69-0.81], P < .001, OR = 0.75, 95%CI [0.71-0.79], P < .001 and OR = 0.71, 95%CI [0.67-0.75], P < .001, respectively. In addition, compared to whites, Hispanic and Asian/Pacific Islander races were proportionally associated with CCA; OR = 1.27, 95%CI [1.21-1.34], P < .001, and OR = 1.79, 95%CI, [1.67-1.92], P < .001, respectively, while black race was inversely associated with CCA (OR = 0.85, 95%CI [0.81-0.89], P < .001). Conclusions: In our large database study, we found that patients with diagnosis of DM or being from certain minority ethnic groups are associated with increased incidence of CCA. Other factors like alcohol and smoking were associated with decreased incidence of CCA, but those factors may be under reported. This raises the need for further evaluation for these factors and their effect on CCA incidence and outcomes in those specific groups. [Table: see text]
Treatment outcomes of well-differentiated high-grade (G3) neuroendocrine tumors.
Authors: Liu Alex John , Ueberroth Benjamin Edward , Buckner Petty Skye , McGarrah Patrick Walsh , Kendi Ayse T. , Hobday Timothy J. , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad Bassam
Published: May 2020

e16691

Background: Recent WHO classification of NET has defined high-grade well-differentiated NET (NET G3) as a distinct entity that is clinically different from neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aims to evaluate NET G3 response to different treatment regimens. Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics along with treatment responses and survival were assessed. Primary end points were progression-free survival (PFS) and objective response rate (ORR) by RECIST 1.1 criteria. Results: 71 patients with NET G3 were identified. Systemic treatment data was available in 30 patients who had a median age of 59.5 years at time of diagnosis. The primary tumor was most commonly pancreatic (73.3%). Ki 67 index was ≥55% in 26.7% of cases. 56.7% of cases had > 1 metastatic site. Treatment regimens included: capecitabine+temozolomide (CAPTEM) (n = 20), somatostatin analog (SSA) (n = 14), carboplatin/cisplatin+etoposide (EP) (n = 7), everolimus (n = 2), FOLFOX (n = 7), and lutetium Lu 177 DOTATATE (PRRT) (n = 10). CAPTEM was the most commonly used regimen (10 first-line, and 10 second-line) with ORR of 35%, disease control rate (DCR) of 65%, and median PFS of 9.4 months. The table summarizes the treatment data and responses rates for the various therapies used. Conclusions: Among NET G3 patients treated at Mayo Clinic, CAPTEM was found to be the most commonly used treatment with reasonable efficacy and disease control. Other treatment options include SSA, PRRT, FOLFOX, and EP. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. [Table: see text]
Retrospective analysis of Peptide Receptor Radionuclide Therapy (PRRT) in Japanese patients with unresectable neuroendocrine tumor.
Authors: Kobayashi Noritoshi , Wild Damian , Kaul Felix , Ichikawa Yasushi
Published: May 2020

e16700

Background: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is an innovative treatment for inoperable or metastasized, well/moderately differentiated, neuroendocrine tumors (NETs). Currently PRRT cannot be performed in Japan, because there is no approval and insurance cover until now. Methods: We rely on University Hospital Basel to perform PRRT for Japanese patients with NET since 2011. In this retrospective analysis we evaluated the efficacy and safety of PRRT for Japanese patients with NET (IRB B180100019). Inclusion criteria were pathologically confirmed NET, inoperable or metastasized disease, and visible tumor uptake in the pre-therapeutic somatostatin receptor scintigraphy. We excluded patients with concurrent antitumor treatment, concomitant severe illness, and pre-existing severe hematologic, renal, and liver damage. 5.55GBq(150mCi) of 177Lu-DOTATOC was used as standard treatment and patients received three infusions every 8 weeks. Until end of 2017, combination treatment with 90Y-DOTATOC and 177Lu-DOTATOC was performed using the same protocol. We checked blood count and renal function parameter every two weeks after PRRT. CT or MRI examination were performed 10-12 weeks after the last PRRT cycle. We evaluated the morphological changes according to RECIST 1.1 criteria. With the execption of Somatostatin analogues further treatments were refrained until tumor progression. Results: Thirty-three patients (male: 16, female: 17) were recruited with a median age of 56 years. (range: 26-71). Primary lesions were pancreas (n = 18), rectum (n = 6), small intestine (n = 3), stomach (n = 1), and other locations (n = 5). The period between diagnosis and PRRT was about 3years. Median Ki67 index was 6.3% (range: 0.7%-30%). Partial response rate was 39.3% and disease control rate is 63.6%. Progression free survival (PFS) was 421 days (95%CI:269-572 days) and overall survival was 580 days (95%CI:259-900days). We compared PFS with the treatment line (front line: first or second-line vs late line: third or fourth-line), there was no significant difference between the two groups (front line: 329.0 days vs late line: 497.0 days Log Rank test P = 0.189). Conclusions: PRRT in Japanese patients with NET was effective and a reliable treatment option.
Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients.
Authors: Villa Erica , Piscaglia Fabio , Geva Rabit , Dalecos George , Papatheodoridis George , Ciomei Marina , Davite Christina , Crivori Patrizia , Palejwala Vaseem , Jacob Jules , Hamzeh Fayez , Shailubhai Kunwar , Santoro Armando , Sangiovanni Angelo
Published: May 2020

e16711

Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients. Methods: Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CBR). Results: A total of 31 patients were enrolled and 28 were evaluable for efficacy, of which 14 (50%) completed 6-months of treatment. Milciclib was well-tolerated with manageable toxicities. Eighteen of 31 treated patients had drug-related adverse events (AEs) with most frequent (≥5%) occurrence of drug-related diarrhea, nausea, asthenia, fatigue, retinal hemorrhage, rash and myalgia. No drug-related deaths were recorded. Nine of 14 patients (64%) continued treatment under Compassionate Use after study completion. Seven patients received milciclib until 9, 9, 10, 11, 13, 13 and 16 months. The remaining 2 patients are in the 16th month of treatment. Clinical response to treatment, assessed by mRECIST (independent radiological review), is shown in the Table. Both median TTP and PFS were 5.9 months. Conclusions: Milciclib, acting via a new mechanism, was safe, well-tolerated and met primary and secondary endpoints with 61% CBR. These promising clinical data warrant further evaluation of milciclib. Clinical trial information: NCT03109886 . [Table: see text]
The oncogenic role of ARG2 in hepatocellular carcinoma.
Authors: Lin Pin-Jen , Chiu Fang-Yen , Wang Shu-Chi , Li Chia-Yang
Published: May 2020

e16713

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in adult and is a leading cause of cancer-related death worldwide. In most mammals, two isoforms of arginase have been identified (ARG1 and ARG2). Clinical Data revealed that ARG2 is highly expressed in various types of cancers including HCC. However, the role of ARG2 in regulating the progression of HCC has not yet been examined. The present study aimed to examine the role of ARG2 on the progression of HCC. Methods: Cell growth and proliferation were examined by MTT assay and colony formation assay, respectively. Cell migration was determined using wound-healing assay. The expression of ARG2 and its correlated survival rate in HCC was analyzed by DriverDBv3 database. Results: Our experimental results showed that knockdown of ARG2 suppresses cell growth, colony formation and migration ability in HepG2 cells. In HCC patients, ARG2 is highly expressed in primary solid tumor and recurrence solid tumor samples comparing to solid tissue normal samples. In addition, high level of ARG2 is associated with poor overall survival in HCC patients. Conclusions: These results suggest that ARG2 plays an oncogenic role in modulating HCC progression.
HIFU for the treatment of difficult colorectal liver metastases with unsuitable indications for resection and radiofrequency ablation: A phase I clinical trial.
Authors: Yang Tong
Published: May 2020

e16715

Background: Previous studies showed that high intensity focused ultrasound (HIFU) treatment could treat liver tumor and pancreatic cancer, with fewer serious adverse reactions.To evaluate the safety and efficacy of HIFU for patients with colorectal liver metastases(CRLM) that were contraindicated for resection and radiofrequency ablation. Methods: Patients between 20 to 80 years of age with 1-3 liver metastases from colorectal cancer were included. The primary colorectal lesions were thoroughly resected and any case with extra-hepatic metastasis was excluded. Ultrasound guided HIFU system was employed and target region ablation was achieved with repeated sonications from the deep to shallow regions of the tumor section by section. Results: Thirteen patients were enrolled. Pain was the most common adverse events(AEs) (n = 8), followed by fatigue (n = 7), increased aspartate aminotransferase (AST) (n = 7), increased alanine aminotransferase(ALT) (n = 5), and skin edema (n = 4). No grade≥3 AEs occurred.The majority of patients (76.9%) had a complete response and the remaining three patients achieved partial response. The objective response rate was 100% after the first HIFU treatment. Nine patients relapsed but most were isolated only in the liver (8/9). The median follow-up was 25 months. The 2-year progression-free survival (PFS) was 16.7%, and median PFS was 9 months. Notably, the 2-year overall survival (OS) was 77.8%, and median OS was 25 months. Conclusions: This study indicates that HIFU treatment is safe, has an excellent tumor response and long-termprognosis even when the foci in risky locations, and is probably a considerable option for patients who were unsuitable for other local treatments.
A new prognostic model for high-grade appendiceal mucinous neoplasms with peritoneal carcinomatosis.
Authors: Mouabbi Jason A , Malapati Sindhu Janarthanam , Abdalla Ahmed , Biedny Adam , Hayward David , Szpunar Susan , Hadid Tarik H. , Berri Richard N , Kafri Zyad
Published: May 2020

e16718

Background: Peritoneal carcinomatosis of appendiceal origin (PCAO) is a rare malignancy accounting for less than 1% of all cancers. High-grade appendiceal mucinous neoplasms (HAMN) have a poor prognosis and are often treated with cytoreductive surgery (CRS), with hyperthermic intraperitoneal chemotherapy (HIPEC) followed by adjuvant systemic chemotherapy (ASC). Peritoneal cancer index (PCI) and completeness of cytoreduction score (CCR) are useful prognostic tools in patients with PCAO undergoing CRS/HIPEC. However, neither PCI nor CCR take response to ASC into account. Therefore, we propose an enhanced prognostic scoring system (tumor response index, TRI) that incorporates response to ASC as assessed at the completion of treatment. Methods: We retrospectively reviewed the charts of patients with PCAO who received care at the Van Elslander Cancer Center between January 2011 until December 2018. All patients with HAMN who underwent CRS/HIPEC followed by ASC were included. TRI was assessed by comparing the patients' performance status, tumor markers and imaging at the completion of ASC to those prior to the initiation of ASC. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used to estimate correlations between TRI and clinical outcomes (PFS and OS). TRI was also compared to PCI and CCR using the Akaike’s Information Criteria (AIC). Results: A total of 84 charts were reviewed. Patients were divided into groups based on their TRI score. The median age was 57 years with 55% females and 85% Caucasians. Approximately 20% of patients had signet-ring features. The most common ASC regimen used was a combination of 5-fluorouracil, oxaliplatin (FOLFOX) and bevacizumab (65%). The table depicts the median PFS and OS of each TRI group. Lower TRI was associated with significantly better PFS and OS. For all outcomes, AIC was substantially reduced by adding TRI to PCI and CCR, suggesting that TRI is a better predictor of PFS and OS. Conclusions: This study proposes TRI as an effective prognostic tool in patients with PCAO and HAMN after CRS/HIPEC/ASC. [Table: see text]
Real-world hypothesis-generating cohort of pancreatic cancer patients with brain metastases.
Authors: Cridebring Derek , Hadley David , Scott Timothy S , Vilner Alex B , Heckman Tammy M , Gosselin Kevin , Jameson Gayle S. , Haag Susan , Borazanci Erkut Hasan
Published: May 2020

e16720

Background: Pancreatic cancer (PC) is the third most lethal form of cancer in the United States, and is most often diagnosed having already metastasized, making its 5-year survival rate one of the lowest. Metastatic PC (mPC) is most common at sites such as liver, lymph nodes, and lung while, in contrast, brain metastases from PC are rare. Brain metastases present a major challenge for future oncological research, as they are difficult to treat. If PC patients most likely to develop brain metastases can be identified earlier, there is an opportunity for rapid therapeutic intervention. There is limited research and understanding of the relationship between pancreatic cancer and brain metastases. Methods: We performed a retrospective, non-interventional study using deidentified data. Inteliquet’s data was aggregated from its consortium of 175 US healthcare locations, which includes a variety of source systems at each site. These sources include electronic medical record systems, laboratory information management systems, and other sources. A subset of the adult mPC data originally treated at HonorHealth was identified as an exploratory cohort. Results: 833 patient records were identified with drug treated mPC, 33 (4%) of which had metastasized to the brain. The PC dataset had a median diagnosis age of 65 and was 46% female. The site of the primary tumor within the pancreas was acquired from ICD10 code: 35% were in the head, 14% in the tail, 15% in the body, 5% in overlapping sites, 6% in other parts and 26% where location was unspecified. Metastatic locations came from secondary malignancy ICD10 codes: 63% had liver and 25% had lung metastases, which aligns with prior studies. For patients with brain metastases, the gender distribution was 42% female, while the distribution of primary PC site was: 33% head, 9% tail, 6% body, 6% in overlapping locations, 12% in other parts and 33% with unspecified location. The median age of diagnosis in the brain metastasis group was 67 years. Conclusions: This is the largest study of PC patients with brain metastases that we could find. 33 patients out of 833 had brain metastases compared to a recent review which had 25 cases. Our data suggests that specification of the primary pancreatic site is more difficult, aside from the head of the pancreas. Analyses are underway to explore correlations between other clinical factors and brain metastases, and to calculate the time in between the initial pancreatic cancer diagnosis and detection of the brain metastasis. This hypothesis-generating cohort will be tested in patient data from the rest of the consortium.
A multicenter chart review study of patients with metastatic pancreatic ductal adenocarcinoma receiving liposomal irinotecan after gemcitabine-based therapy.
Authors: Yu Kenneth H. , Hendifar Andrew Eugene , Alese Olatunji B. , Draper Amber , Abdelrahim Maen , Burns Ethan , Khan Gazala Naaz , Cockrum Paul , Bhak Rachel , DerSarkissian Maral , Nguyen Catherine , Duh Mei Sheng , Bahary Nathan
Published: May 2020

e16733

Background: Real-world data allows healthcare decision-makers to assess and manage therapeutic and economic options for patients, including those who would and would not have met eligibility criteria for randomized control trials (RCT) and are instead managed under usual care. This retrospective multi-academic center chart review study describes real-world characteristics and outcomes of US patients receiving liposomal irinotecan for the management of metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: Patients with mPDAC treated with liposomal irinotecan were eligible. Initiation of liposomal irinotecan defined index date; covariates assessed included clinical characteristics and treatment patterns; real-world overall survival (rwOS) was assessed via Kaplan-Meier methodology. The target enrollment is 300 patients. The study centers included were Memorial Sloan Kettering Cancer Center, Cedars-Sinai Medical Center, Emory Winship Cancer Institute, Houston Methodist Cancer Center, Henry Ford Cancer Institute, and University of Pittsburgh Medical Center. Results: Data on 26 patients were available for initial analyses. Mean age was 68 years; 58% were female and 65% Caucasian. 54% of patients had stage IV disease at first diagnosis, and 17%, 65%, and 17% had index ECOG score of 0, 1, and 2, respectively. Common genetic mutations include KRAS (40%) and TP53 (40%). Prior to liposomal irinotecan, treatments received for metastatic disease include gemcitabine+nab-paclitaxel (77%) and fluorouracil (5-FU)/leucovorin (LV)+irinotecan+oxaliplatin (19%). Patients had received 0 (12%), 1 (23%), and ≥2 (65%) lines of therapy in the metastatic setting prior to liposomal irinotecan. Mean duration of liposomal irinotecan use was 3.0 months; liposomal irinotecan was mostly received with 5-FU (23%) or 5-FU/LV (69%). Median rwOS was 4.9 months (95% CI: 3.0, 6.3). Conclusions: Real-world data of the first 26 patients in this study show patients treated with liposomal irinotecan are older, sicker, and have had more lines of therapy than previously reported in RCT data.
Error-free, automated data integration of exosome cargo protein data with extensive clinical data in an ongoing, multi-omic translational research study.
Authors: Oromendia Ana , Ismailgeci Dorina , Ciofii Michele , Donnelly Taylor , Bojmar Linda , Jyazbek John , Chatterjee Arnaub , Lyden David , Yu Kenneth H. , Kelsen David Paul
Published: May 2020

e16743

Background: Major advances in understanding the biology of cancer have come from genomic analysis of tumor and normal tissue. Integrating extensive patient-related data with deep analysis of omic data is crucial to informing omic data interpretation. Currently, such integrations are a highly manual, asynchronous, and costly process as well as error-prone and time-consuming. To develop new blood assays that may detect very early stage PDAC, a multi-omic investigation with deep clinical annotation is needed. Using pilot data from an on-going study, we test a new platform allowing automated error-free integration of an extensive clinical database with extensive omic data. Methods: Demographic, clinical, family pedigree and pathology data were collected on the Rave EDC platform. Exosomes were purified from 46 plasma samples from 14 controls and 24 PDAC patients and cargo proteins were quantified via SILAC. The Rave Omics platform was used to ingest and integrate clinical and omic data, run quality checks and generate integrated clinical-omic datasets. Data fidelity was validated by systematically computing differences between corresponding values in the source flies with those present in the extracted data object (integrated data). The root mean squared error (RMSE) was calculated for numeric values in each sample. Additional validation was conducted by manual inspection to ascertain data integrity. Results: We demonstrated automatic integration, without human intervention, of a subset of the clinical data and all available SILAC data into an analysis-ready data object. Data transfer was completely faithful, with 100% concordance between the source and the integrated data without loss of features. All proteins (n = 1515) and clinical variables (n = 64) were imported. Their nomenclature and corresponding sample values (n = 69690) and clinical values (n = 2432) matched exactly between datasets. In all samples, the RMSE was exactly zero, indicating no deviation between data sources. Conclusions: We demonstrated that automatic, efficient, and reliable integration of clinical-omic data is achievable during an in-flight PDAC trial. Automatic exploratory analytics supporting biomarker discovery are currently being used to uncover associations between omic and clinical features. The Rave Omics platform is disease-agnostic and we plan to expand to trials of varying size, indication, and completion status where systematic, automated integration of clinical and (multi)omic data is needed.
Nanomaterials augmented LDI-TOF-MS for pancreatic ductal adenocarcinoma diagnosis and classification.
Authors: Xu Yaolin , WANG Dansong , Kuang Tiantao , Wu Wenchuan , Xu Xuefeng , Jin Dayong , Zhang Hua , Zhong Sheng , Wang Yunbing , Lou Wenhui
Published: May 2020

e16761

Background: Pancreatic ductal adenocarcinoma (PAAD) is one type of cancer with poor prognosis. Although CA 19-9 was the most common serological marker for cancer screening and surveillance after treatment, there are still unignorable limitations, including low sensitivity, possible false-negatives/positives owing to confounding conditions. Reliable non-invasive diagnostics is in urgent need. As PAAD is increasingly considered as a metabolic disorder, serum metabolite profiling is becoming critical to reveal important cancer-related bioinformation. This work proposes a novel LDI-TOF-MS technique for PAAD screening and diagnosis. Methods: An LDI-TOF-MS platform was established for cancer screening. All mass spectrum was collected within a mass range of 100 to 1,100 Da, while the spectra were manually examined using the FlexAnalysis 3.4 software (Bruker Daltonics, Bremen, Germany). In a typical process, 0.5 uL of serum samples were spotted on a polished steel target plate MTP 384 and air-dried followed by another 1 uL of GNS or SiNW nanomaterials. The spectra were then acquired in the reflection positive mode with smartbeam-II laser at 355 nm with laser frequency of 1,000 Hz. A random walk of 25 shots at raster spot and 20 different spots were measured for each individual sample, therefore, 500 satisfactory shots were obtained. Results: By taking advantage of 3D nanostructures and machine learning, we applied proposed approach to 94 patients with PAAD, as well as 203 healthy controls (Table). The results demonstrated an average sensitivity of 99% and a specificity over 98% in detecting cancers. 11 of 94 PAAD patients (11.70%) were CA 19-9 negative (CA19-9 < 37U/ml, stage I n = 2, stage II n = 7, stage III n = 1 and stage IV n = 1). LDI-TOF-MS recognized almost all CA 19-9-negative PAAD. The sensitivity and specificity were obviously superior to CA 19-9 in PAAD: only 1 of 94 PAAD (1.06%) were misclassified as healthy controls. In contrast, CA19-9 positive and CA 19-9 negative PAADs were not readily distinguished by this method. Therefore, this method was independent of tumor markers. Conclusions: Result suggested strong potential of proposed technique as a low-cost, superior precision, and high-throughput procedure for PAAD diagnosis and beyond. [Table: see text]
Survival and prognostic tests in a real-world phase II experience with a safe, moderate-dose, sequential chemotherapy (CT) algorithm (ALGO) for metastatic pancreatic adenocarcinoma (PANC).
Authors: De Jager Robert L. , Bruckner Howard , Bassali Fred , Hirschfeld Azriel , Gurell Daniel , Nghiem Van , Distenfeld Shoshana , Weinberger Noah , Book AJ
Published: May 2020

e16763

Background: Gemcitabine (G), 5-fluorouracil (F), leucovorin (L), irinotecan (I), and oxaliplatin (O), (GFLIO) is safe, employs moderate 1/2-1/3 dosages, offers expanded eligibility (0-2 ECOG PS; no age limit)). Each step reverse resistance (RR) to CT; drug synergism 4-6 simultaneous pairs) improve responses (Rs) and survival (S) (Bruckner ASCO 05, 08, 11, AntiCancer Res 2016; 36 (1), 2018; 38 (1) (ACR), and the immune system (Correale P: J. Immunother 2014; 37). M Caraglia: Front Oncol. 2019). Methods: Eligibility: intent to treat active metastatic PANC, no prior CT: any age: PS 0-2 and expected > 6 weeks S. IRB required safety < 1/10 severe events. ALGO in mg/m2: G 500, F 12-1500 over 24 hrs, L 180, I 80, day2 O (GFLIO) q2 wks, and on progression added in sequence, day 2, docetaxel 20-25 and good counts only mitomycin C 3-6 then bevacizumab 10mg/kg with prior monitoring and modifications (ACR). Median 12, 18, 24 mos Overall Survival (OS), Kaplan Meier estimates with 95% CI were evaluated with age, sex and normal nl and abnl baseline bloods: neutrophils N ANC; Lymphs Ly ALC; platelets; albumin (ALB); Alkaline phosphatase (Alk Ph) abn N alb 3.5 N/L; 2.1 L/monocyte ratios and the A.L.A.N (AS) composite prognostic score (M. Salati E.J.Ca. 2019; 117: 84-90). Results: OS @ 6, 12, 18 & 24 mos, for 53 pts, was 75; 57; 36; 26 % (+/- 8-10%). Median M S was 14.5 mo (CI 9-17mos); S @ all ages ≥ 60, 65 or 70, was not inferior. Women's M S 17 mo. was > men's 10.5: 95/65; 75/46; 48/29; 42/29%. AS for abnl tests was: 0 (18pts): 93: 81: 48; 34% & MS 17 mo vs 1-2 (23)90: 58;42;32% & MS 15.5mo vs 3-4 (12)MS 3 mo. Pts with best 17-14.5 mo MS had nl AS 0 > Alb > AS 1-2 > APh > ANC. Pts with worst 3-6 mo MS had abnl: AS 3-4 < Alb < ANC. No pt had severe infection, neuropathy or gastroenteritis. Pts -/+ 75-100gm ascorbic acid, 25, did not have inferior S in ALAN subsets (H.Bruckner AACR 17). Conclusions: The sequential moderate dose CT ALGO improves eligbility and provides pts with metastatic PANC of any age a well tolerated CT regimen with a high therapeutic index and strong, 12, 18, 24 mo, survival. Prognostic tests can identify subgroups ≥ 75% with favorable vs. unfavorable criteria and improve personalized choices and measures to remedy individual risk factors. Clinical trial information: NCT01905150 .
GRP78 expression and clinical outcomes in pancreatic cancer: A single institution review.
Authors: Johnson Brian Ernest , Hemrajani Anshu , Ding Xianzhong , Wesolowski Michael , Hill Reginald , Zhang Echo , Dhanarajan Asha R.
Published: May 2020

e16767

Background: Pancreatic Ductal Adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers. Poor prognosis can be attributed in part to late detection and chemoresistance. Perioperative chemotherapy with or without radiation is the standard treatment for resectable PDAC, however recurrence rates remain high. GRP78 (HSPA5/BiP) is an endoplasmic reticulum (ER) chaperone protein involved in regulation of the ER stress response that leads to pro-survival pathway activation and chemoresistance in tumor cells. Prior studies of suppression of GRP78 expression in PDAC cell lines led to increased pancreatic cell apoptosis in response to gemcitabine. In vivo studies of human PDAC xenografts showed that tumors with higher GRP78 expression were associated with increased chemoresistance. Methods: We conducted a single institution retrospective review of 53 patients who underwent resection of PDAC from 1/1/2009-7/1/2016. Archived tumor tissue expression of GRP78 was assessed by immunohistochemistry (IHC) and scored as 0-3+. GRP78 IHC scores of 0-1+ were categorized as low and scores of 2-3+ as high. Corresponding clinical data were collected. Adjusted effects of GRP78 expression on the hazard of treatment failure or death were estimated using Cox proportional hazards models. Type III Wald Chi-square p-values are reported for the overall effect in each model. Results: GRP78 expression level demonstrated a significant effect on disease free survival (DFS) in unadjusted analyses (HR 2.00, p = 0.05), as well as after adjusting for performance status (p = 0.03), initial overall stage (p = 0.05), pathological tumor stage (p = 0.02), pathological node stage (p < 0.01), resection margins (p = 0.05), and neoadjuvant therapy (p = 0.05) in separate models. In unadjusted analysis, high GRP78 expression showed a trend towards worsened overall survival (OS), but did not reach statistical significance (HR 1.8, p = 0.11). The effect on OS was significant when adjusting for pathological tumor stage (p = 0.04) and pathological node stage (p = 0.01). (575). Conclusions: Consistent with prior animal studies, our retrospective review revealed that high GRP78 expression was associated with worsened DFS in patients with resectable PDAC. When adjusting for pathological staging, high GRP78 expression had a similar impact on OS. These findings warrant further evaluation of the role of GRP78 in prognosis, response to therapy and as a potential treatment target.