bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of enhanced antitumor effects via co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR signaling pathways in human gastric cancer.
Authors: Choi Moon Young , Cho Min-Hee , Chang Hye Jung , Lee Soon-Nam , Lee Kyoung Eun
Published: May 2019

e15553

Background: Gastric cancer, a highly aggressive malignancy, frequently recurs despite curative surgery and metastasizes to lymph node and distant sites. Epithelial-mesenchymal transition (EMT) is the main phenomenon of cancer progression, including invasion and metastasis. It is regulated by crosstalks between diverse intracellular signaling pathways such as Wnt/β-catenin and phosphatidylinositol-3-kinase(PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways. Here, this study elucidated the effects of co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways on gastric cancer. Methods: It is known that Wnt/β-catenin signaling pathways are constitutively activated in two of gastric cancer cell lines, AGS and MKN-28. ICG-001 (β-catenin transcription inhibitor) and rapamycin (mTOR inhibitor) were used for dual blockade, and then the combinatory effects were examined. Results: As a result, both cell lines were significantly affected by the β-catenin transcription inhibitor, ICG-001, and addition of the mTOR inhibitor, rapamycin induced marginal inhibitory effects on cancer cell proliferation and target gene expression. In addition, invasive activity was 62.3 ± 15.7% and 53 ± 14.4% inhibited by single treatment, but it was 79 ± 13.3% inhibited by co-treatment. Moreover, migratory activity was 33 ± 13%, 42 ± 9% inhibited by single treatment, but it was 82 ± 4% by co-treatment. Interestingly, Snail, one of the important regulatory protein during EMT process, was significantly decreased by co-treatment. Conclusions: Taken together, these results suggest that co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways could effectively enhance antitumor effects on gastric cancer via the inhibition of invasion and migration as well as decrease of Snail expression.
Patient-reported distress and symptoms predict post-esophagectomy outcomes.
Authors: Salo Jonathan C. , Meadors Patrick Leland , Trufan Sally J , Gower Nicole Lee , Watson Michael David , Jeck Lauren A , Hill Joshua S. , Walsh Declan
Published: May 2019

e15567

Background: Esophagectomy is accompanied by significant morbidity, mortality and altered quality of life. Understanding the factors responsible for adverse post-operative outcomes is essential for risk stratification in the selection of patients for surgery. Patient-reported measures are important not only as treatment outcome metrics, but also in predicting tolerance to therapy. Postoperative length of stay is a convenient measurement of patient tolerance of surgery. Our study aim was to determine whether preoperative patient-reported measures could add additional predictive power to clinical variables in predicting postoperative length of stay. Methods: A tablet-based symptom screening tool measured Distress, Anxiety (GAD-2), and cancer-related symptoms preoperatively. A generalized linear model predicting postoperative length of stay was constructed using age, gender, insurance status, income, T stage, and sarcopenia (hand-grip strength < 25kg). Patient-reported variables were then evaluated for their ability to predict length of stay in addition to these clinical factors. Factors found not significant (p > 0.05) are indicated N.S. Results: Esophagectomy (n = 58): Median age 62 (IQR 54-70) and 46 men (79%). Adenocarcinoma in 52 (90%). Neoadjuvant chemoradiation administered in 37 (64%). Major complications occurred in 13 (22%). Median postoperative length of stay was 8 days (IQR 6-10). Distress, Pain, Nausea/Vomiting, Trouble Swallowing, and Insurance or Financial Concerns independently predicted postoperative longer length of stay on multivariable analysis, while accounting for preoperative clinical factors. Conclusions: Preoperative cancer patient symptom reporting adds additional information to traditional clinical factors in predicting length of stay post-esophagectomy. Patient-reported measures may identify patients who benefit from interventions for preoperative optimization.[Table: see text]
Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).
Authors: Mukherjee Sarbajit , Fountzilas Christos , Boland Patrick McKay , Attwood Kristopher , Tan Wei , Khushalani Nikhil I. , Iyer Renuka V.
Published: May 2019

e15569

Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]
Is it possible to effectively treat second-line gastric cancer, given the prognosis factors?
Authors: Manikhas Georgy M. , Orlova Rashida , Beliak Natalia P. , Kutukova Svetlana I. , Erdniev Sanal , Zhukova Natalia V. , Popova Natalia V. , Ivanova Anastasia , Antimonik Nina , Avramenko Inna , Zorina Ekaterina
Published: May 2019

e15570

Background: Ramucirumab is the first anti-angiogenic targeted agent to demonstrate improved survival as monotherapy or in combination with CT among patients with disseminated stomach cancer. Methods: Under our supervision there were 24 patients: 12 men (50%) and 12 women (50%), from 29 to 72 years old, the median age was 52 years (95% CI 43.56-60.32). The median time to diagnosis of the 4th stage of the disease was 2 months (95% CI 0-11.44). All patients received 1 line of treatment; the median duration of 1-line therapy was 5 months (95% CI 4.00-6.83). Results: The duration of therapy with ramucirumab ranged from 2 to 16 months; median duration was 5.0 months (95% CI 3.00-7.44). The therapy with ramucirumab in 11 patients (45.83%) was followed by SD, in 3 patients (12.50%) - PR, in 4 patients (16.67%) - PD, and in 6 patients (25 , 00%) assessment of the effectiveness of therapy was not conducted due to the deterioration of the general condition during treatment. Thus, the ORR was 58.33%. The median overall survival was 18 months (95% CI 14–23). In order to identify adverse factors affecting overall survival, we constructed a Cox's regression model showing the dependence of overall survival on unfavourable prognosis factors. In general, the constructed model was reliable - p = 0.0013. The gender of the patients (p = 0.0642), the time before staging the 4th stage of the disease (p = 0.4312) and the duration of the 1st line therapy (p = 0.8675) did not have a significant effect on the survival of patients. Such factors as the patients' age (p = 0.0121), the localisation of the primary tumor (p = 0.0441), the differentiation of the tumor (p = 0.0095), the fact of removal of the primary tumor (p = 0.0133) had a significant impact, general status on the ECOG scale (p = 0.0250), the presence of anemia (p = 0.0192), damage to the peritoneum (p = 0.0022) and damage to metastases of more than 3 organs (p = 0.0062). Conclusions: An increase in OS in patients who received a combination of ramucirumab and paclitaxel can be considered clinically significant for this patient population and will allow considering this therapeutic regimen as a new standard of second line treatment of patients with poor prognosis of gastric cancer.
Preoperative CA 19-9 and CEA as predictors of operative outcomes in resectable gastric cancer (GC).
Authors: Gangi Alexandra , David John , Guan Michelle , Placencio-Hickok Veronica , Hendifar Andrew Eugene , Klempner Samuel Jacob , Burch Miguel , Chao Joseph , Kamrava Mitchell , Tuli Richard , Gong Jun
Published: May 2019

e15581

Background: We sought to investigate whether preoperative serum CA 19-9 and CEA levels are predictive of resectability, postoperative outcomes, and survival in resectable GC. Methods: The National Cancer Database (NCDB) was interrogated to identify resectable GC patients between 2004-2015. Gastric adenocarcinoma cases without M1 disease and who did or did not undergo definitive surgery were included. Pretreatment CA 19-9 and CEA levels were classified as high (≥98 U/mL) or low ( < 98 U/mL). Proportions of categorical variables were compared using the Chi-squared test (two-tailed). Hazard ratios (HRs) for overall survival (OS) were compared using multivariate Cox regression, adjusting for baseline demographic and clinical variables. Results: From 183,204 GC cases screened, a final 5,447 patients were available. Resection rates for patients with low (n = 1920) and high (n = 294) CA 19-9 were 69.2% and 40.8% (χ² 90.6, p < 0.00001). 69.6% were resectable with low CEA (n = 5044) and 35.1% were resectable with high CEA (n = 97, χ² 53.0, p < 0.00001). Mortality within 30 days of definitive surgery was 7.5% and 0% in those with high (n = 120) and low CA 19-9 (n = 1286, χ² 85.6, p < 0.00001). There was no significant difference between 30-day mortality across high and low CEA and between 30-day readmission rates across high and low CA 19-9 and CEA levels. Age, median income, high school graduation rate, Charlson comorbidity index, and AJCC clinical N stage all significantly correlated with OS in this cohort. Compared to low preoperative CA 19-9, high CA 19-9 was significantly associated with worse OS (HR 1.24, 95% confidence interval (CI) 1.13-1.37, p < 0.0001). Similarly, a high CEA correlated with worse OS compared to low CEA (HR 1.44, 95% CI 1.32-1.57, p < 0.0001). Conclusions: High preoperative CA 19-9 and CEA are associated wither lower resection rates and worse OS in resectable GC. CA 19-9 but not CEA level predicts for 30-day mortality. Prospective validation is warranted.
Novel genomic prognostic factors for nonsurgical esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.
Authors: Dai Honghai , Shao Yang , Tong Xiaoling , Wu Xue , Pang Jiaohui , Feng Alei , Yang Zhe
Published: May 2019

e15589

Background: Definitive concurrent chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients demonstrated great variations in responses and post-treatment progression inevitably. Methods: To identify prognostic factors that could assist in clinical judgment and make predictions ahead of disease relapse, we performed a targeted next generation sequencing of 416 cancer-related genes on primary tumor biopsies from 47 ESCC patients with locally advanced or metastatic nonsurgical diseases. Patients were subjected to dCRT treatment and local recurrence free survival (LRFS), progression free survival (PFS) and overall survival (OS) times were analyzed. Results: TP53 (78%), NOTCH1 (32%), ARID1A (13%), FAT1 (13%) and CDKN2A (13%) are the most commonly mutated genes in ESCC, while copy number gains are frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%) and YAP1 (11%). Multivariate analysis including clinical variables (age, gender and disease stage) and individual genetic alterations suggested that gender is an independent prognostic factor and male tend to have longer LRFS, PFS and OS after dCRT treatment. In addition, YAP1 amplification likely increased the risk of disease progression and death. To remove the impact of gender on prognosis, gender stratified survival analysis was performed and found that male patients with YAP1 amplification had significantly shorter LRFS (p = 0.002) and OS (p = 0.03), and also demonstrated a certain trend toward a shorter PFS (p = 0.06) than male patients without YAP1 amplification. Conclusions: YAP1 amplification might be a potentially useful biomarker in predicting treatment outcomes and selecting patients with high relapse risk for closely monitoring.
Improved survival following transarterial radioembolization of infiltrative-appearance hepatocellular carcinoma.
Authors: Nisiewicz Michael J , Patel Reema Anil , Dugan Adam J , Owen Joseph W
Published: May 2019

e15591

Background: Infiltrative-appearance hepatocellular carcinoma (IHCC), also known as diffuse HCC, presents a distinct challenge to clinicians as evidence-based treatment guidelines have yet to be established. While transarterial radioembolization (TARE) has shown efficacy in HCC, many studies exclude IHCC in their analysis. The purpose of this study was to evaluate whether TARE of IHCC improves survival. Methods: With IRB approval, patients with IHCC were identified. Patient were divided into two groups: TARE versus systemic therapy/palliative care. Demographics, date of diagnosis, date of expiry, albumin, international normalized ratio (INR), sodium, alpha-fetoprotein (AFP), creatinine, Child-Pugh class, model for end-stage liver disease (MELD) score, and bilirubin were collected. Patients with bilirubin >3 were excluded. Mann-Whitney U test and Fisher’s exact test assessed for differences between groups. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. Results: Forty-one patients were identified, 10 underwent TARE while the remaining 31 served as a control. Mean age was 62, 30 patients were male. The mean overall survival of the TARE treatment group was 16.6 months (506 days) and the mean overall survival of the control group was 5.6 months (170 days) (Log-rank p < 0.004), with a combined overall survival of 8.5 months (259 days). Cox proportional regression analysis revealed statistically significant associations between survival and albumin (hazard ratio 0.12, 0.032-0.41, p < 0.001), Child-Pugh class B (hazard ratio 0.25, 0.064-0.941, p < 0.041), and sorafenib therapy (hazard ratio 0.246, 0.071 – 0.847, p < 0.026). Conclusions: Transarterial radioembolization for patients with IHCC improves life expectancy compared to treatment with comfort measures or systemic therapy.[Table: see text]
Use of DNA methylation to distinguish gallbladder carcinoma.
Authors: Jiang Xiaoqing , Li Bin , Qiu Zhiquan , Yu Yong , Li Zhishuai , Zheng Jingjing , Wang Chenyang , Qiu Fujun , Fang Shuai , Li Bingsi , Zhang Zhihong
Published: May 2019

e15605

Background: Gallbladder cancer (GBC), an uncommon malignancy with a high mortality rate, is often diagnosed late due to lack of early symptoms and the relative hidden nature of the gallbladder. Despite the advancements in imaging technologies, there is no reliable screening test for GBC. The role of aberrant DNA methylation in the process of tumorigenesis both at individual genes and a genome-wide scale has been well elucidated. It occurs very early in cancer development, thus capable of serving as a screening marker. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were derived using a Bayesian hierarchical model-DSS with an adjusted p-value < 0.05. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. This panel contains 12,196 GBC relevant CpG sites. We performed targeted bisulfite sequencing on 23 GBC patients (6 stage II-III, 17 stage IV) and 13 patients with non-malignant gallbladder diseases (cholecystitis and gallstones). Of the 23 GBC patients, we obtained adjacent normal tissue from 7 of them. Basic clinical features such as age, gender, of patients with GBC and patients with non-malignant gallbladder diseases were comparable. Results: Among the 12,196 GBC relevant CpG sites, 10,216 sites were statistically significantly hypermethylated and 275 sites were statistically significantly hypomethylated comparing to patients with non-malignant gallbladder disease as well as adjacent normal gallbladder tissues. Subsequently, we used the derived differentially methylated CpG sites to construct a linear regression model, achieving an area under curve of 99%. Collectively, the methylation levels were comparable between tissues with non-malignant disease and adjacent normal. Interestingly, when considering the 275 hypomethylated markers alone, we observed that the methylation level of adjacent normal tissues is significantly higher than tissues with non-malignant disease. Conclusions: Collectively, our panel can effectively distinguish GBC samples from non-cancerous samples, demonstrating the potential of DNA methylation in GBC screening. Furthermore, hypomethylation markers can be used to distinguish non-malignant disease from the healthy.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced hepatocellular carcinoma.
Authors: Li Mao , Wei Ailin , Xie Wenzhuan , Zhao Jing , Zhao Zhengyi , Zhang Yuzi , Wang Guoqiang , Cai Shangli , Li Ang , Cao Dan
Published: May 2019

e15606

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a particularly high prevalence in China. The genomic profiling in HCC had been widely explored with tissue biopsy, however, given the intrinsic risks of invasive approach, blood-based circulating tumor DNA (ctDNA) has been proposed as a promising alternative. In this study, we aim to investigate whether the ctDNA may serve as a reliable tool to provide a more accurate molecular snapshot of HCC in Chinese patients. Methods: Plasma samples from 385 Chinese patients with advanced HCC were assayed for somatic genomic alternations by hybrid capture-based next-generation sequencing (NGS) with 150 genes and a mean sequencing depth of more than 3000×. The results were compared with our internal tissue genomic database of Chinese HCC patients (N = 873) tested by NGS and TCGA database (N = 373) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Among 385 patients with ctDNA testing, somatic genomic alternations were detected in 97% of the patients (median = 5 alterations/patient). The most prevalent SNV mutations from ctDNA sequencing were TP53 (45.7%), TERT (19.5%), CTNNB1 (12.5%), and LRP1B (8.3%) compared to our tissue database (TP53 (61.2%), CTNNB1 (15.6%), TERT (13.3%), and LRP1B (11.0%)). While in TCGA database, the most common SNV mutations were found in TP53 (30.1%), CTNNB1 (26.0%), LRP1B (8.8%), ARID1A (8.6%), and SPTA1 (7.5%). Moreover, the level of MSAF was associated with detectable variant types, evidenced by a significant higher MSAF level observed when amplifications (P < 0.0001) or fusions (P = 0.008) were detected in the samples. Conclusions: Molecular analysis of patients with advanced HCC through ctDNA can serve as a reliable alternative to tissue biopsy. Chinese HCC patients may have different mutational landscapes to Western population. The utility of ctDNA analysis can provide therapeutically exploitable genomic profiles to identify potentially actionable gene alterations for targeted therapies.
Outcomes and patterns of failures after hypofractionated radiation therapy for intrahepatic cholangiocarcinoma.
Authors: Abu-Gheida Ibrahim , Patel Aashini , Zaid Mohamed , Elganainy Dalia , Javle Milind M. , Raghav Kanwal Pratap Singh , Vauthey Jean-Nicolas , Aloia Thomas A. , Tzeng Ching-Wei David , Minsky Bruce D. , Smith Grace L. , Holliday Emma B , Taniguchi Cullen M. , Koong Albert , Krishnan Sunil , Herman Joseph M. , Das Prajnan , Crane Christopher H. , Koay Eugene Jon
Published: May 2019

e15609

Background: Locally advanced unresectable intrahepatic cholangiocarcinoma (IHCC) remains incurable. Prior data has shown the effectiveness of hypofractionated radiation therapy (HRT) with biological equivalent doses (BED) greater than 80.5 Gy in improving local control and survival for this patient population. This is an updated report of our IHCC experience with HRT in 15 or 25 fractions using a simultaneous integrated boost technique. Methods: A retrospective analysis of 63 patients (median age 64, range 29-87) diagnosed between 2007-2016 who received HRT was performed. RT dose ranged from 58-90 Gy in 15 fractions and 62.5-100 Gy in 25 fractions, translating to a median BED of 97.5 (range 78.1-144 Gy). Median primary tumor size at diagnosis was 7.8 cm (2.4-17cm). Forty-eight (76%) patients received gemcitabine-based therapy prior to HRT. Results: Median follow up was 31 months (4-110). The 2 year overall-survival (OS), local-progression-free-survival (LPFS), intrahepatic-distant-metastasis-free-survival (IH-DMFS) and extraheptic-distant-metastasis-free-survival (EH-DMFS) were 71% (95% CI 58-82), 67% (95% CI 50-80), 40% (95% CI 28-54) and 40% (95% CI 27-54) respectively. Pattern of failure analysis revealed 16 patients with local failure after HRT, of which only 5 (8% of total) progressed within the high iso-dose field line (BED > 80.5). After HRT, 41 (65%) patients had intrahepatic metastasis that occurred outside the radiation field, and 34 (54%) patients developed extrahepatic metastasis. On multi-variate analysis, T-stage was an independent predictor of OS, LPFS, IH-DMFS, and EH-DMFS. Larger normal liver volume and 15 fraction treatments were independently associated with better LPFS and IH-MFS respectively. There were no significant HRT-related toxicities. Conclusions: HRT demonstrates safety and efficacy for durable local control and prolonged overall survival in patients with unresectable IHCC. Dominant modes of failure are outside the HRT field. Improvements in systemic therapies could further improve outcomes for this patient population.
Lenvatinib for the treatment of HCC: A single institute experience.
Authors: Chen San-Chi , Chao Yee , Chen Ming Huang
Published: May 2019

e15611

Background: Lenvatinib, a multiple kinase inhibitor, is an emerging for the treatment of advanced HCC. In REFLECT study, lenvatinib demonstrated higher ORR and longer PFS than sorafenib as the first line treatment for patients with Child-Pugh score A and tumor less than 50% of liver occupation. However, the efficacy for patients failed with sorafenib, with Child-Pugh score B and C, tumor more than 50% of liver occupation is not clear. Methods: A retrospective clinicopathological analysis was performed on 70 patients with HCC who received lenvatinib in our institute between 2017 and 2018. Lenvatinib was given orally 10 mg once daily. Treatment response, progression-free survival, overall survival and prognostic factors were explored. Results: Among 70 patients in this cohort, the mean age was 59.7 year-old and 78.6% were male, 58.6% were HBV(+) and 18.6% HCV(+). Among these patients, 65.7% had experienced sorafenib and 57.1% anti-PD-1. Patients who were not eligible for REFLECT study including having tumor more that 50% of liver occupation (40%), main portal vein invasion (34.3%) and Child-Pugh Score B and C (30.0% and 21.4%) were also enrolled. Treatment response was evaluable in 51 patients. Best responses were CR in 1 patients (2%), PR in 21 (41%), SD in 23 (45%) and PD in 6 (12%) by mRECIST criteria. Tumor with > 50% of liver occupation has higher ORR. However, no significant difference of response was observed regarding etiologies, AFP levels, tumor types, Child-Pugh Score, main portal vein thrombosis, sorafenib and anti-PD-1 experienced. The median PFS was 5.3 months and OS 8.5 months. Regression analysis showed AFP > 20 and Child-Pugh score B and C were poor prognostic factors for survival. Conclusions: Lenvatinib is potent drug for both treatment naïve and sorafenib-resistance HCC. Lenvatinib is also effective for patients with Child-Pugh Score B and C, tumor > 50% of liver occupation who were ineligible to REFLECT study.
Retrospective analysis of outcomes in patients with non metastatic cholangiocarcinoma: A single network experience.
Authors: Mamadgi Jyothika , Lundeen Kristina , Hasan Shaakir , Patruni Sunita , Khattab Ahmed , Yellala Amulya , Kirichenko Alexander V. , Raj Moses S.
Published: May 2019

e15643

Background: Biliary tract cancers are rare cancers with an annual incidence of about 8,000. In resected non-metastatic BTCs (NM-BTCs), cure rates decrease significantly due to local and distant recurrence. However, guidelines to use adjuvant therapies are not well established due to the lack of well-structured phase three randomized trials, given the rarity of the disease. We present a retrospective study analyzing outcomes of NM-BTCs managed within Allegheny Health Network (AHN) with specific focus on patients who underwent resection and received different adjuvant treatment modalities. Methods: Data of all patients with NM-BTCs treated at AHN from January 2012 to December 2017 was collected and outcomes analyzed for patients treated with surgery vs no surgery We then sub-stratified the patients who received surgery into three groups based on the modality of adjuvant therapy. Group 1 included patients with no additional therapy , Group 2 with adjuvant chemotherapy and Group 3 with adjuvant chemotherapy+radiation. We compared Mean Progression-Free Survival (PFS) and Overall Survival (OS) in these three groups. Results: Of the 59 NM-BTCs treated at AHN, 32(52.4%) underwent surgery. The OS for surgical vs non-surgically treated patients was 23 vs 17 months (p = 0.008) and PFS 26 vs 19 months (P = 0.06) respectively. Of the resected –patients, PFS for patients in Group1 vs Group2 vs Group3 was 16 vs 21 vs 34 months (pooled P = 0.05) and OS was 19 vs 22 vs 19 months respectively (pooled P = 0.5). PFS for patients in Group1 vs Group (2+3),i.e, patients treated surgery only vs surgery+ any adjuvant treatment was 16 vs 28 months (P = 0.1), OS was 19 vs 22 months (P = 0.7)respectively. PFS in patients in Group 3 vs Group (1+2),i.e, patients treated with adjuvant chemotherapy+radiation vs others was 34 vs 19 months. (p = 0.0183) respectively. Conclusions: This analysis revealed a statistically significant improvement in OS in patients with NM-BTCs who received surgery. There was a trend towards improvement in PFS/OS in patients who received adjuvant therapy, though not statistically-significant. Use of adjuvant chemotherapy+radiation resulted in statistically significant improvements in PFS as compared to other treatment modalities.
Prediction of hepatocellular carcinoma patient survival using machine learning classification rules.
Authors: Zhou Wei , Chen Huan , Han Wenbo , He Ji , Zhang Henghui
Published: May 2019

e15649

Background: The outcome prediction of hepatocellular carcinoma (HCC) is conventionally determined by evaluating tissue samples obtained during surgical removal of the primary tumor focusing on their clinical and pathologic features. Recently, accumulating evidence suggests that cancer development is comprehensively modulated by the host’s immune system underlying the importance of immunological biomarkers for the prediction of HCC prognosis. However, an integrated predictive algorism incorporating clinical characteristic and immune features still remain to be established. Methods: We obtained respectable stage II HCC specimens, along with adjacent para-tumor tissues from 221 patients who underwent surgical resection at Eastern Hepatobiliary Surgery Hospital, (Shanghai, China) from 2015 through April 2018. Characteristics such as CD8+, CD163+, tumor-infiltrating lymphocytes (TILs) were obtained for further model construction used to predict the status of 3 survival indexes: Overall Survival (OS ,≤ 24 or > 24 month), Progression Free Survival (PFS, ≤ 6 or > 6 month), and Recurrence/Death (RD). Mutual information and coefficient between each feature and the survival indexes were tested to remove low scoring features after data cleaning and standardization. Furthermore, recursive features selection was preformed to obtain the optimal features combination. Finally, supervised learning techniques include either boosting or bagging strategy were used to fit and predict model with a grid-search method optimizing the parameters. Meanwhile, a cross validation procedure with 0.2 proportion of test cohort was randomly carried out for 10 times to evaluate the model. Results: We finally confirmed 15 biomarkers from the 46 candidates as features for the survival status prediction by using a 221 patients cohort. Among them, the top 10 most important biomarkers, included both clinical and immune attributes. The AUC of our model for survival indexes (OS, PFS, RD) was ranged from 0.76 (RD) to 0.8 (PFS), and the accuracy was above 0.85. Conclusions: We describe the integrative analysis of the clinical and immune features which collectively contribute to the survival index of HCC. Machine learning techniques, such as Gradient Boosting and random forest classifier , have a great promise for using in HCC cancer survival prediction.
Tumor size and location affecting the treatment selection for solitary small recurrent hepatocellular carcinoma (≤3.0 cm) after initial hepatectomy.
Authors: Chen Shu-Ling , Peng Zhenwei , Xiao Han , Wei Mengchao , Kuang Ming
Published: May 2019

e15660

Background: We aimed to investigate the optimal treatment modality between radiofrequency ablation (RFA) and repeated hepatectomy in the treatment of solitary recurrent HCC (rHCC) after hepatectomy, considering the influence of tumor size and location. Methods: From Jan 2009 to Dec 2016, 630 consecutive patients with solitary small rHCC (≤3.0cm) after initial hepatectomy who underwent RFA or repeated hepatectomy were enrolled in three tertiary referral centers. Patients were divided into four groups according to tumor size (≤ 2.0cm or > 2.0cm) and location (central or peripheral) respectively. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between RFA and repeated hepatectomy in these four groups. Results: For central rHCC ≤ 2.0cm, the OS and RFS rates at 5 years after RFA were significantly higher than those after repeated hepatectomy (69.9% vs 53.1%, P= 0.001; 56.2% vs 42.6%, P= 0.038). For central rHCC > 2.0cm, the 5-year OS and RFS rates were not significantly different between repeated hepatectomy and RFA (55.9% vs 48.2%, P= 0.080; 27.0% vs 19.2%, P= 0.103). For peripheral tumors ≤ 2.0cm (58.8% vs. 47.7%, P= 0.001; 45.2% vs. 25.6%, P= 0.001) or > 2.0cm (62.6% vs. 45.4%, P= 0.001; 44.7% vs. 21.1%, P= 0.010), the OS and RFS rates at 5 years after repeated hepatectomy were both significantly higher than those after RFA. Complications were more common in patients after repeated hepatectomy than RFA, especially for central tumors. Conclusions: RFA might be the optimal treatment for patients with central rHCC ≤ 2.0 cm whereas repeated hepatectomy should be recommended for patients with peripheral tumors.
The heterogeneity of genomic biomarkers for immune checkpoint inhibitor in therapy-naïve primary hepatocellular carcinoma and their metachronous metastases.
Authors: Sun Yun-Fan , Zhou Jian , Jia Fan
Published: May 2019

e15665

Background: Immune checkpoint blockade (ICB) has delivered unprecedented success in treating patients with metastatic cancers to extend overall survival, yet only a small percentage of patients respond. Immune-relevant genomic biomarkers, such as tumor mutation burden (TMB), neoantigen, and human leukocyte antigen class I (HLA-I) are emerging as potential predictors for immunotherapy response. However, little is known about their heterogeneity in metastatic cancer patients. In this study, we aim to characterize these immune-relevant genomic biomarkers in primary and matched metastatic hepatocellular carcinoma (HCC). Methods: Two cohorts of samples were included in this study. Cohort 1: a total of 24 pairs of surgical resected primary and matched metastatic HCC tissue. Cohort 2: 29 surgical resected primary HCC tissue from patients with long-term relapse-free survival. All samples were characterized using whole exome sequencing and RNA sequencing. We compared TMB, neoantigen and HLA-I genotype between primary and matched metastatic tumors, as well as between primary tumors with or without postoperative metastatic relapse. Results: The TMB of primary HCC with metastatic relapse was significantly higher than that with long-term relapse-free survival (Mean, 32 vs 17 mutations/Mb, P< 0.05), while neoantigen and HLA-I genotype failed to show statistical difference. Paired comparison between primary and matched metastatic tumors indicated that both TMB and neoantigen were significantly decreased in metastases ( P< 0.05). We further categorized metastases into two subgroups based on their HLA-I genotype. HLA-I homozygosity in at least one locus (homozygous) occurred in 9 metastases, while the rest metastases showed maximal heterozygosity at HLA-loci (heterozygous). HLA-I heterozygous metastases were associated with significantly higher neoantigen load compared with HLA-I homozygous metastases ( P< 0.05). Conclusions: High TMB might be a poor prognostic factor in patients with resected HCC and a potential predictor for postoperative adjuvant therapy with ICB. Metastatic HCC showed lower antigenicity than the corresponding primary tumors. Therefore, they might not show the same responsiveness to immunotherapy as primary tumor did. However, our HLA-I genotype analysis provides evidence that HLA-I heterozygosity has potential implication for predicting response of metastatic HCC to ICB.
Genomic landscape of HBV-related hepatocellular carcinoma in south China patients with high mutational frequency of TP53 and TERT promoter.
Authors: Ye Jiazhou , Wang Yinguang , Liang Rong , Wu Xue , Shao Yang , Wu Feixiang
Published: May 2019

e15670

Background: Development of hepatocellular carcinoma (HCC) is a complex process with accumulations of polygene abnormalities and multi-pathway misregulation. Hepatitis B virus (HBV) exposure can cause liver damage and promote hepatocarcinogenesis via various biological effects. We aimed to investigate the molecular mechanisms underlying the etiology of HBV-related HCC development, and provide new insights into novel molecular targets. Methods: 84 HBV-positive HCC patients from Guangxi Province, South China, who underwent hepatic resection, were enrolled in this study. Genomic alterations were analyzed in pair-matched tumor and adjacent normal tissue using a hybridization capture-based next-generation sequencing (NGS) assay targeting 422 cancer-relevant genes. Results: In total, 691 somatic mutations, 166 copy number variations and 10 gene fusions were detected in 81 (96.4%) of 84 tumor samples. The most commonly mutated gene is TP53 in this cohort (84% of the patients), which is much higher than its frequency in the reported overall HCC patients. TERT promoter has somatic mutations in 32% of the patients, reactivation of which has been implicated in multiple cancer types. Dysfunction in the cell cycle control pathway (TP53, RB1, CCND1, CDKN2A and CCNE1) was dominant, followed by PI3K/AKT cascade (PIK3CA, AKT3, MTOR, TSC1 and TSC2), while genes of WNT signaling pathway (CTNNB1, APC and AXIN2) were mutated at a lower frequency. In addition, 69 variants in 25 DNA damage repair (DDR) genes were identified in 37 (45.7%) patients. Patients with DDR mutations had a higher tumor mutation burden (TMB) than those without DDR mutations. Conclusions: This study revealed a unique genomic landscape of HBV-related HCC. Besides TP53 being the highest mutated gene, a significant fraction of patients was identified with TERT promoter mutations, suggesting that TERT may play a role in HBV-related hepatocarcinogenesis as a novel molecular marker. Furthermore, the most common biological processes affected by HBV status in HCC were cell cycle control, PI3K/AKT and WNT signaling pathways. The possible synergistic effects of HBV in hepatocarcinogenesis warrant further investigations.
Molecular profiling by circulating tumor DNA (ctDNA) and benefit from anti-PD-1 in HCC.
Authors: Carmagnani Pestana Roberto , Abugabal Yehia I. , Xiao Lianchun , Hassan Manal , Hassan Reham Abdel wahab , Girard Lauren , Raghav Kanwal Pratap Singh , Morris Jeffrey , Rashid Asif , Qayyum Aliya , Meric-Bernstam Funda , Wolff Robert A. , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar
Published: May 2019

e15679

Background: Molecular profiling has defined actionable mutations in HCC, and has the potential to be used for selection of targeted therapies, as well as for the characterization of predictive biomarkers from approved treatments. Noninvasive strategies are critical to HCC given the challenge of obtaining liver biopsies. We investigated whether profiling by ctDNA could provide predictive and/or prognostic information for HCC patients (pt) treated with immune checkpoint inhibitors. Methods: We analyzed blood samples from 22 HCC pt who underwent treatment with anti-PD-1 using comprehensive genomic testing of ctDNA with a commercially-available platform (Guardant Health, CA). Demographic and treatment data were retrospectively collected with the goal of correlating treatment outcomes and drug response (by imaging and/or AFP) with molecular abnormalities. Results: 17/22 (77.3%) were men; median age was 66 years. 21 patients received nivolumab and 1 received pembrolizumab. 9 were HCV positive and 5 were HBV positive. 15/22 patients had > 1 alteration identified. The median number of alterations/pt was 3 (range, 1-8). TP53 was the common altered gene (n = 11) followed by CTNBB1 (n = 8) , TERT (n = 5) KRAS (n = 3) , GNAS (n = 2). Mutations were also seen (n = 1) in KIT, PIK3CA, PTEN, EGFR, NTRK, FGFR2 among others. 6 pt (27.3%) had AFP response and 8 (36.4%) achieved disease control > 12 weeks. Mutations involving KIT, PIK3CA and PTEN were associated with shorter progression-free (PFS) (p < .001 for all) and overall survival (OS) (p = .028 for all), whereas GNAS mutation was associated with shorter PFS (p = 0.019) but not OS. No differences in OS or PFS was observed for other alterations, including the presence of CTNNB1 mutation. There were no correlations between specific alterations and objective tumor response (either by imaging or AFP). 32% of pt were progression-free at 6 months. Median OS was not reached, and 62% were alive after 1 year. Conclusions: Identifying non-invasive predictive biomarkers of benefit to immunotherapy is a priority in HCC. Our data suggest that specific ctDNA alterations can provide predictive information for survival (OS and PFS) on immune checkpoint inhibitors. Further larger studies are warranted for confirmation.
Meta-analysis of prognostic biomarkers for pancreatic neuroendocrine tumors (PNETs).
Authors: Zhu Mojun , Halfdanarson Thorvardur Ragnar , Gould Rothberg Bonnie Elyssa
Published: May 2019

e15688

Background: PNETs are marked by histological heterogeneity and variable clinical outcomes. Other than Ki67 index, reliable circulating or tissue biomarkers for prognosis do not exist. Methods: PubMed was searched through 01/31/2017. Inclusion criteria were: 1) prospective/retrospective cohort with defined source population, boundary dates, and justifications for exclusions; 2) assay of primary tumors; 3) clear descriptions of methods including techniques and controls; 4) use of multivariate proportional hazards modeling adjusted for prognostic factors including but not limited to stage or grade; and 5) reporting adjusted hazard ratios (HR) with 95 % confidence intervals and P values. Studies with < 50 % PNETs were excluded. PNET-specific data was summarized in the table. Results: A total of 2958 manuscripts were identified and 462 manuscripts were reviewed. Only 23 multivariate studies met all inclusion criteria. These altogether analyzed 24 unique targets and 14 were associated with survival. Conclusions: This meta-analysis identified 14 markers associated with survival of PNET patients. Future studies should adhere to the REMARK criteria and incorporate the 2017 WHO grading system for multivariate analysis. 1. I-immunohistochemistry, F-fluorescence in situ hybridization, E-enzyme linked immunosorbent assay, M- methylation specific PCR, P-polymerase chain reaction; 2. O-overall survival, F-disease free survival, S-disease specific survival, P- progression free survival.[Table: see text]
Methylation and mRNA analysis of differential genes between primary tumor and liver metastasis in pancreatic neuroendocrine neoplasm.
Authors: Feng Mengyu , Qiu Jiangdong , Cao Zhe , Yang Gang , Liu Yueze , Zhang Taiping
Published: May 2019

e15689

Background: The liver metastasis of pNEN is rare, and the underlying mechanisms remain unclear. The objective of this study is to compare the DNA methylation status and mRNA expression between primary tumor and liver metastasis in pNEN, aiming to find the potential gene responsible for liver metastasis in pNEN. Methods: The liver metastasis of pNEN is rare, and the underlying mechanisms remain unclear. The objective of this study is to compare the DNA methylation status and mRNA expression between primary tumor and liver metastasis in pNEN, aiming to find the potential genes responsible for liver metastasis in pNEN. Results: The differential methylation counts in the two patients were 17756 and 214321 respectively, indicating 1975 and 26176 differential genes (|diff.Beta| > 0.14, at least one sample FPKM > 0). mRAN analysis revealed 1302 and 3729 differential mRNAs (|log2fold change| > 1, Q value < 0.05). When combining these results together, 106 and 1513 genes were discovered, and the two patients had 39 differential genes in common. 13 genes with high mutation frequency in pNEN and 52 relevant pathways were selected in literatures. Among the 39 genes, only four genes were involved in these pathways: GREM1, PAX5, CLDN11 and FGFR2. However, only FGFR2 had both decreased methylation and increased mRNA expression in the two patients, and pyrosequencing confirmed that methylation position in FGFR2 was in accordance with results from methylation microarrays. Conclusions: The present study reveals that the gene expression varies greatly between primary tumor and liver metastasis in pNEN. The decreased methylation and increased mRNA expression of FGFR2 may play an important role in liver metastasis and further mechanisms are worthy of exploring.
First real-world experience of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) since US FDA approval.
Authors: Konda Bhavana , Rogers Sherise C. , Grenade Cassandra Natalie , Verschraegen Claire F. , Zhou Ye , Goyal Ashima , Natwa Mona , Wright Chadwick , Hussein Akram , Barr Hallie , Konate Dramane , Brown Andrew , Batdorf Rochelle , Williams Bonnie , Zhao Songzhu , Wei Lai , Shah Manisha H.
Published: May 2019

e15691

Background: PRRT using 177Lu-DOTATATE was US FDA approved in Jan 2018, and real world data in the US is lacking. Methods: We retrospectively reviewed medical records of patients who began PRRT 03/14/18 - 10/01/18 at our institution. 177Lu-DOTATATE was administered at a dose of 200mCi over 20-30 min every 8 weeks for 4 doses. Infusion of arginine-lysine 25gm/25gm in 1-liter normal saline was given over 4 hours starting 30 min prior to treatment, in addition to intravenous palonosetron 0.25mg. Results: 51 patients received at least 1 of 4 doses and 40/51 were no longer on active therapy. 28/40 received all 4 doses and 12/40 discontinued treatment after < 4 doses. 25/40 were evaluable for response per RECIST v1.1. 16/25 (64%) had GI NET, 3/25 (12%) pancreatic NET, 4/25 (16%) atypical lung carcinoid, 1/25 (4%) multifocal NET, and 1/25 (4%) had paraganglioma. 28% had grade 1, 56% grade 2, and 8% (2/25) had grade 3 (Ki 67: 25% and 40%) NET. 12/25 (48%) had received ≥2 prior systemic therapies not including somatostatin analogs, and 10/25 (40%) had ≥1 prior liver-directed therapy. Median follow-up from date of last PRRT was 61.5 days. Objective response (partial response) rate was 16% (4/25; table). 18/25 (72%) had stable disease and 3/25 (12%) had progressive disease. Most adverse events (AEs) were grade 1-2 and included fatigue, nausea, abdominal pain, and cytopenias. ≥Grade 3 AEs requiring treatment discontinuation included symptomatic gastric outlet obstruction (2/51), small bowel obstruction (1/51), ischemic enteritis (1/51), confusion/bone pains (1/51), liver failure (1/51), and severe neutropenia (1/51). All patients with ≥grade 3 AEs had a high tumor burden at baseline. Conclusions: 177Lu-DOTATATE is an effective and safe treatment in advanced NET, and our results are consistent with NETTER 1 data.[Table: see text]
Video-based patient education on carcinoid syndrome: Positive knowledge and behavior shift for patients.
Authors: Roc Anne , Turell Wendy , Goldstein Grace , Wolin Edward M.
Published: May 2019

e15697

Background: Carcinoid syndrome (CS) negatively affects quality of life (QOL), compromising physical, daily, and emotional functioning. Reticence to discuss symptoms, particularly debilitating diarrhea, perpetuates negative QOL, as does confusion of CS symptoms with other conditions and dietary challenges. To address these needs, we created video-based patient education activities with the Carcinoid Cancer Foundation (CCF) to empower patients with information and resources on CS facts, diagnosis, medical management, eating well and self-care. Methods: Two 1-hour patient education activities were broadcast live online and on-demand in 2017 and 2018 at CancerCoachLive.com , carcinoid.org, and Facebook Live for 6+ months. Features included panel discussions, slides, live polling and Q&A, and video vignettes of real patient experiences. Knowledge-focused test questions were administered at 3 time points (pre-activity, immediate post-activity, and 8-week [follow-up] post). Behavioral and communication-focused questions were also asked at follow up. Data from these questions, live poll responses, and learner-submitted questions pre-event and during live Q&A were analyzed to determine engagement, lessons learned and continuing patient needs. Results: In total, 1,893 patients took part in the activities, and attracted 39,821 Facebook engagements (“views”). Respondents (n = 116-119) reported: 57%, improved communication with their healthcare providers (HCPs) regarding CS; 44%, improved feeling of being “in-control” of health care decision; 31%, improved care behaviors for their health. Improved communication with their HCPs were specific to: their disease and symptoms, treatments, and diet. Changes in behaviors included: dietary changes, more “involved” in care decisions, asking questions of HCPs, and proactively learning about CS. Knowledge improvements were observed on 7 of 8 questions on CS facts, diet, and treatment (5 of 7 statistically significant; average effect size = 1.16; n averaged 382 pre and 96 post). Conclusions: Patient education on CS can yield immediate and sustained gains in knowledge and behavior, which may improve diagnosis, treatment, and improve patient QOL.