bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic similarities between gastric adenosquamous carcinoma and typical gastric adenocarcinoma: A large population-based and propensity score-matched study.
Authors: Zhao Feng , Wang Jili , Cheng Xiaofei , Li Xinke , Lu Zhongjie , Chen Xin , Yan Senxiang
Published: May 2020

e16559

Background: Gastric adenosquamous carcinoma (ASC) is an extremely rare form of stomach malignancy. To date, the limited knowledge of its biology and outcomes stems from mostly small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016 to explore the treatment of ASC together with its prognostic factors to gain relatively large and consolidated insights. Methods: Propensity score matching (PSM) and Kaplan–Meier analyses were used to compare the prognosis between gastric ASC and typical gastric adenocarcinoma (AC). We assessed overall survival (OS) after patient stratification according to summary stage and treatment choice. Cox hazards regression analysis was performed to determine independent predictors of overall survival (OS). Results: A total of 171 gastric ASC were included (mean 65.20 ± 11.71 years-of-age). Patients with gastric ASC had similar OS to matched individuals with typical gastric AC (p = 0.915). In terms of treatment, 45.6% of gastric ASC patients underwent surgery, and 37.4% received radiotherapy (RT), and 64.3% received chemotherapy. Patients who underwent surgery had longer OS than those who did not receive surgery (p < 0.001), patients who received radiation therapy had longer OS than those who did not receive RT (p < 0.001), and patients who received chemotherapy had longer OS than those who did not receive chemotherapy (p < 0.001). A multivariate Cox analysis for OS showed that distant stage (HR, 3.334, 95% CI 1.544-7.199; p < 0.01) was independent prognostic factors for gastric ASC. Conclusions: Analysis of its outcomes indicates that gastric ASC is not a more malignant tumor as previously suspected. Gastric ASC shows a similar prognosis to typical gastric AC. Surgery, RT, and chemotherapy was associated with prolonged OS. Distant stage was associated with poor OS.
Clinical impact of oral intake on second-line treatment of advanced gastric cancer.
Authors: Ogata Takatsugu , Narita Yukiya , Kumanishi Ryosuke , Nakazawa Taiko , Matsubara Yuki , Nozawa Kazuki , Kato Kyoko , Honda Kazunori , Masuishi Toshiki , Bando Hideaki , Kadowaki Shigenori , Ando Masashi , Tajika Masahiro , Muro Kei
Published: May 2020

e16560

Background: Trifluridine/tipiracil, an oral drug, was approved in Japan for patients (pts) with advanced gastric cancer (AGC). Insufficient oral intake (INSUF) is one of the most common complications. We evaluated the clinical characteristics and impact of oral intake during 2nd line chemotherapy (CT). Methods: We retrospectively evaluated AGC pts receiving 2nd line CT from January 2012 to December 2018 at a single institution. We defined “INSUF” as a requirement for daily intravenous fluids or hyperalimentation and “improvement of oral intake (IMP)” as no such requirement for > 1 week. Exacerbation (EXA) was defined as a change from “sufficient oral intake (SUF)” to INSUF. Results: We enrolled 495 pts, of which 67 (13%) and 428 (87%) pts had INSUF and SUF at the start of 2nd line CT, respectively. Patient characteristics are summarized in the Table. There was no difference in the cytotoxic drugs of 2nd line CT. The causes of INSUF were peritoneal metastases (79%), cachexia (15%), and primary complications (3%). The objective response rates of INSUF and SUF pts were 9% and 26%, respectively. INSUF pts had poorer progression-free survival (PFS) (1.7 vs. 3.7 months [M]; adjusted HR [aHR], 1.51; p < 0.001) and overall survival (3.2 vs. 10.1 M; aHR, 2.01; p < 0.001) than SUF pts. At the end of 2nd line CT, 147 (32%) and 314 (68%) pts had INSUF and SUF, respectively. In SUF pts, the factors correlated with EXA were poor ECOG PS (odds ratio [OR], 5.26; p < 0.001), massive or moderate ascites (OR, 2.04; p = 0.031), palliative operation history (OR, 2.90; p = 0.007), and ramucirumab use (OR, 0.50; p = 0.034). Median PFS was shorter after CT in pts with EXA than in those without (1.7 vs. 4.2 M; aHR, 2.05; p < 0.001). Among INSUF pts, 11 pts (16%) achieved IMP; the rate of IMP did not differ according to regimen. Median PFS was shorter in pts without IMP than in pts with IMP (1.1 vs. 3.3 M; aHR, 4.97; p = 0.001). Subsequent CT was administered to 29% and 71% of INSUF and SUF pts, respectively. Conclusions: INSUF at the start of 2nd line CT was a poor prognostic factor. For appropriate use of oral drugs, CT should be changed in SUF pts with factors associated with EXA. [Table: see text]
Factors related to the incidence of esophageal stenosis after treatment of advanced esophagus cancer.
Authors: Freitas Carla Simone Moreira de , Bastos Tiago Magalhães , Alberti Luiz Ronaldo , Bastos Lívia Maria Nicoletti Ariano , Soares Aleida Nazareth
Published: May 2020

e16561

Background: Esophageal stenosis after curative treatment of esophageal cancer (CE) by radiochemotherapy has a high incidence, causing great impact to the patient’s health. Identifying risk factors for this type of pathology may provide earlier diagnosis and more effective follow-up for patients with CE undergoing curative radiotherapy. The objective of this study was to determine the risk factors for esophageal stenosis in patients with complete regression of the tumor lesion after advanced CE treatment with radiotherapy associated or not with chemotherapy. The choice of the theme is justified because there are no studies on esophageal stenosis after radiotherapy associated or not with chemotherapy in esophageal cancer in the west. Methods: Retrospective observational study with 103 patients of both sexes who presented total regression of esophageal squamous cancer, confirmed by endoscopy and biopsies, after treatment with or without chemotherapy. The relationship between the sexes, age, tumor staging, involvement of the esophageal circumference, tumor location, isolated use of radiotherapy or associated chemotherapy, and tumor extension with or without stenosis and its degree after treatment with total regression of the tumor. Results: Most patients are male (58.3%). There was a direct relationship between the degree of circumference involvement and the degree of stenosis and a significant association between tumor location and degrees of stenosis (p < 0.001). The higher the degree of posttreatment stenosis, the higher the percentage of more advanced tumors (p < 0.001). Regarding tumor extension, the greater the degree of stenosis after treatment, the greater the proportion of tumors larger than 60 mm (p < 0.001). T3 tumors increase in 23.77 chance of post-treatment stenosis compared to T2 tumors. T4 tumors, increase the chance of presenting post-treatment stenosis 23.94 times compared to T2 tumors. Conclusions: Our data show that impaired esophageal circunference, tumor extension, advanced stages, and pretreatment tumor stenosis are factors related to esophageal stenosis following treatment with advanced radiochemotherapy for esophageal cancer.
Weight loss after minimally-invasive esophagectomy for esophageal cancer.
Authors: Squires Malcolm Hart , Benbow Jennifer H , Trufan Sally Jeanne , Mann Della , Burchins Emily M , Byrne Meredith M , Hill Joshua , Gower Nicole Lee , Salo Jonathan C.
Published: May 2020

e16565

Background: Nutritional deficiencies are common in esophageal cancer patients after esophagectomy. Patients frequently present with weight loss due to obstruction. Cancer therapies (chemoradiation and esophagectomy) further compromise nutrient intake through alterations in appetite, gastrointestinal function, and the catabolic effects of therapy. We aimed to understand and identify risk factors associated with post-esophagectomy weight loss. Methods: Patients undergoing minimally-invasive esophagectomy via laparoscopic and thoracoscopic techniques with intra-thoracic anastomosis between January 2015 and July 2019 were identified. Post-operative weight loss at 3- and 6-months post-surgery was calculated as percent change from preoperative weight. Univariate and multivariable generalized linear method (GLM) analysis was performed. Results: 176 patients (145 male, 31 female) underwent esophagectomy, with a median age of 64 [IQR 57-71] and median 3-month postoperative weight loss of 7.9% [IQR 1.5-12.3%]. The majority of patients were Caucasian (89%), histologically diagnosed adenocarcinoma (90%), and received neoadjuvant chemoradiation (71%). Median preoperative BMI was 28.3 [IQR 25.5-32.5]. Preoperative enteral feeding tubes were placed in 86 patients (49%). Five patients (2.8%) were converted to open surgery (laparotomy) and anastomotic leaks occurred in 12 (6.8%) patients. The median length of stay was 9 days [IQR 8-13]. Among a subset of 147 patients with data available, the median 6-month postoperative weight loss was 10% [IQR 5.3-15.0%]. On multivariable analysis, greater preoperative BMI and anastomotic leak were associated with increased weight loss at 3 and 6 months post-esophagectomy. Conclusions: Significant postoperative weight loss is common among minimally-invasive esophagectomy patients. Higher preoperative BMI and postoperative anastomotic complications are significantly associated with increased postoperative weight loss at 3 and 6 months. Need for preoperative feeding tube and conversion to open surgery were further associated with postoperative weight loss. [Table: see text]
Clinical characteristics and outcomes of signet ring cell carcinoma of the stomach: A retrospective analysis of SEER database.
Authors: Ellithi Moataz , Elnair Radowan , Abdullah Hafez Mohammad
Published: May 2020

e16572

Background: Signet ring cell carcinoma (SRCC) of the stomach accounts for 8 to 30% of all gastric cancers, however the incidence has been rising. We performed a Surveillance, Epidemiology and End Results (SEER) database analysis to further characterize the biology and clinical aspects of this entity, in comparison to gastric adenocarcinoma (AC). Methods: Surveillance, Epidemiology and End Results (SEER) 18 database was used to obtain data on age, gender, ethnicity, survival, and tumor characteristics of 5,424 US patients diagnosed with gastric SRCC between 2012-2016 and these were compared to 40,657 patients with other gastric adenocarcinoma (AC) subtypes diagnosed during the same period. Results: The gender distribution of both types of cancer was similar with males making up 51.8% of gastric SRCC and 48.3% of gastric AC patients. Median age of diagnosis was 63 years for gastric SRCC as compared to 65 years for gastric AC patients. The age of diagnosis distribution for both types was similar with patient <40 years (7.2% versus 6.2% respectively), 40-60 years (34% versus 32% respectively), 60-80 years (44.6% versus 45.15% respectively) and at > 80 years (14.4% versus 16.6% respectively). Among the SRCC patients, 70.9 % were Caucasians, 15.5% were Asians/Pacific Islanders, and 11.6% were African-Americans. Amongst gastric AC patients, Caucasians made up 76% of the patients, while African-Americans made up 12.9% and Asian/Pacific Islanders made up 9.2 % of the patients. Median OS was 10 months for gastric SRCC compared to 24 months (p < 0.001) for gastric AC. Racial differences in overall survival (OS) was noted. The median OS in Caucasians, African-American, Asian/Pacific Islander, and Native American populations was 11,11,15,7 months respectively (p < 0.001). Conclusions: Gastric SRCC has significantly worse survival as compared to AC with median OS of 10 months vs 24 months. It is more common in patients with Asian/Pacific Islander ancestry as compared to gastric AC. There is a significant racial disparity in survival outcomes with significantly shorter survival in patients with Native american ancestry.
The impact of surgery induced immune-nutritional change on the outgrowth of micrometastasis after potentially curative resection for gastric cancer.
Authors: Aizawa Masaki , Yabusaki Hiroshi , Matsuki Atsushi , Bamba Takeo , Nakagawa Satoru
Published: May 2020

e16581

Background: Whereas radical resection for gastric cancer is only life-saving option, resulting host response have been suggested to trigger the outgrowth of previously disseminated foci at distant anatomical sites via alteration of anti-tumor immunity. The prognostic nutrition index (PNI) which was calculated as 10 × serum Alb concentration (g/dL) + 0.005 × peripheral total lymphocyte count (/µL) is a surrogate marker of inflammation related nutritional decline and the imbalance of T lymphocyte differentiation. The aim of study was to evaluate the impact of perioperative change of PNI. Methods: The medical record of 567 gastric cancer patients who matched with the following inclusion criteria, R0 resection between 2006 and 2018, no preoperative anticancer treatment, pStage IB-IIIC according to UICC TNM classification and no other organ cancer at surgery, was identified from the prospectively maintained database. The postoperative laboratory data was routinely evaluated at POD 1, 3, 7 and first visit after discharge (AD). The PNI was compared through the perioperative course. Then the predictive value of low PNI-AD which defined as PNI < 40 on the relapse free survival (RFS) after surgery was estimated by COX proportional hazards analysis. Results: The median value of PNI at base line, 1, 3, 7 POD and AD was 51.0, 35.9, 34.0, 38.3 and 48.2, respectively. The PNI as significantly decreased at 1, 3 and 7 POD. Though the PNI at AD had a proclivity to recover, which was still significantly lower than that at base line. During observation period after surgery, the recurrence was encountered in 80 patients. The 5-year RFS rate in patients of pStage IB (n = 164), II (n = 228) and III (n = 175) was 97.4%, 88.9% and 64.7%, respectively. The multivariate analysis identified female gender (HR: 1.715, 95%CI; 1.018-2.890, p = 0.04), pT3-4 (HR:3.620, 95%CI; 2.011-6.518, p < 0.01), pN1-3 (HR:2.741, 95%CI; 1.428-5.263, p = 0.02), vessel invasion (+) (HR:2.666, 95%CI; 1.681-4.229, p < 0.01), PNI-AD < 40 (HR:1.833, 95%CI; 1.002-3.352, p = 0.04) were independent predictors of recurrence. The low PNI-AD was significantly related to the recurrence in the population of pStage III, but not in pStage IB and II. Conclusions: The retardation of postoperative recovery of PNI might evoke the distant metastasis.
Efficacy of immune check point inhibitors (ICIs) in metastatic gastric or gastroesophageal junction (GEJ) cancer by patient subgroups: A systemic review and meta-analysis.
Authors: Goldvaser Hadar , Sternschuss Michal , Moore Assaf , Perl Gali , Brenner Baruch , Kundel Yulia
Published: May 2020

e16587

Background: Patients with metastatic gastric or GEJ cancer have short duration of response to chemotherapy and poor outcome. Treatment with ICIs has been investigated for this population with inconsistent results. It is uncertain whether the effect of ICIs is comparable in different subgroups. Methods: Randomized controlled trials (RCTs) that compared standard treatment to treatment with ICIs, either as a monotherapy or in combination with chemotherapy, for metastatic gastric or GEJ cancer were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival (OS) were extracted and pooled in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included: patients’ age at time of randomization (age < /≤ 65 years versus ≥/ > 65 years), gender (female versus male), ethnicity (Asians versus the rest of the world), Eastern Cooperative Oncology Group performance status (0 versus 1), primary tumor location (gastric versus GEJ) and histological subtype (diffuse versus other subtypes). Data on progression free survival (PFS) and on OS in patients with programmed death ligand (PDL1) positive were also collected. Results: Four RCTs comprising 1,765 patients were analyzed. Treatment with ICIs compared to standard therapy did not significantly improve OS (HR = 0.84, 95% CI 0.66-1.07, p = 0.17), PFS (HR = 1.22, 95% CI 0.75-1.96, p = 0.52), or OS in patients with PDL1 positive disease (HR = 0.86, 95% CI 0.73-1.02, p = 0.08). The effect of ICIs on OS was similar in all subgroups. Non-significantly greater effect sizes were seen in younger patients (HR = 0.82 versus 0.86, p for subgroup difference 0.80), male (HR = 0.81 versus 0.97, p = 0.32), performance status 0 (HR = 0.84 versus 0.88, p = 0.81), GEJ tumors (HR = 0.76 versus 0.89, p = 0.44) and non-diffuse subtype (HR = 0.71 versus 0.79, p = 0.62). Conclusions: Compared to standard treatment, ICIs in metastatic gastric or GEJ cancer did not improve OS significantly. As none of the evaluated subgroups has shown increased magnitude of effect to ICIs, other biomarkers for ICIs response are desired in order to optimize the risk versus benefit balance of these patients.
Safety and efficacy of lenvatinib in HCC beyond second-line treatment.
Authors: Jefremow André , Wiesmüller Marco , Rouse Rachel Amande , Dietrich Peter , Kremer Andreas Emanuel , Waldner Maximilian Josef , Neurath Markus Friedrich , Siebler Jurgen
Published: May 2020

e16592

Background: Until 2018 sorafenib was the only first-line systemic treatment option for advanced hepatocellular carcinoma (HCC). Ten years later a new agent, called lenvatinib, showed equal efficiency in comparison to sorafenib. Currently sorafenib and lenvatinib are options for first line treatment with regorafenib, cabozantinib and ramucirumab (if alpha fetoprotein > 400 ng / ml) as second-line treatment choices. The first published results from Imbrave150-trial shows promising effects regarding the combination of atezolizumab and bevacizumab for first line treatment in advanced HCC. This highlights the question for reasonable sequence therapies. Yet, it has so not been demonstrated, if lenvatinib is an option for a treatment line beyond the second. Methods: We identified 5 patients with advanced HCC from our hospital, who had been treated with local ablative procedures as well as at least three different systemic therapies with still excellent clinical performance status before receiving lenvatinib. Retrospective analysis was performed to examine clinical and radiologicresponse rates as well as side effects. Results: 3/5 patients achieved regression in at least third treatment lines. One patient showed stable disease, and only one of these five patients showed a mixed response. The toxicity profile was heterogeneous. One patient developed a mild hand-foot syndrome. Another one evolved hypertension. Developing of proteinuria led to stop treatment in one patient. One patient showed psychiatric disorder, which was possibly associated with lenvatinib. Response was independent of the underlying cause of HCC. Conclusions: Lenvatinib is a promising agent for treating advanced HCC in a later treatment line and revealed a tolerable toxicity profile.
Combination therapy with lenvatinib and anti-PD-1 antibodies for unresectable or advanced hepatocellular carcinoma: A real-world study.
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Huang Cheng , Shen Ying-Hao , Ge Ning-Ling , Chen Yi , Tan Chang-Jun , Zhou Jian , Fan Jia
Published: May 2020

e16610

Background: Combination therapy of anti-angiogenic therapy and anti-PD-1 antibody had shown promising anti-tumor effects for advanced hepatocellular carcinoma (HCC) in clinical trials. Here we report the effectiveness and safety of the combination therapy of lenvatinib and anti-PD-1 antibodies in a cohort of unresectable or advanced HCC pts. Methods: From Sep 2018 to Jan 2020, 77 consecutive pts received a combination treatment of lenvatinib and an anti-PD-1 antibody. Lenvatinib was given 8 mg/d regardless of patient body weight and anti-PD-1 antibody was used either q2wk (nivolumab or camrelizumab) or q3wk (pembrolizumab, sintilimab or toripalimab). pts who completed at least one efficacy and safety assessment were eligible for this study. Tumor response were evaluated with abdominal contrast-enhanced MRI/CT and/or chest CT every 2 mo (± 1 wk). Laboratory tests were monitored every 2-3 wk. Results: 59 pts were eligible for this study. Of them, 1 (1.7%) were BCLC stage A, 10 (16.9%) were BCLC stage B, 48 (81.4%) were BCLC stage C (including 20 pts in China Liver Cancer [CNLC] stage IIIa and 28 in CNLC stage IIIb). 43 (72.9%) pts were treated as first-line therapy. The table below shows efficacy results. R0 resection was performed in 6 (10.2%) pts due to tumor regression. By the data cut-off date, 13 pts died, and mOS was not mature. Overall, the combination treatment was well tolerated. 28 (47.5%) pts had at least one ≥ grade 3 treatment-emergent adverse event. 3 (5.1%) pts died from immune-related adverse events, 2 of them died from immune-related adverse events after hepatectomy. Conclusions: The combination of lenvatinib + anti-PD-1 antibody is effective and well-tolerated in pts with HCC as first-line or second-line treatment. It is also noted that initially unresectable HCC may be converted to resectable HCC following this combination treatment. [Table: see text]
Distinct clinical and genetic characteristics of AFP-negative hepatocellular carcinoma patients infected by HBV or HCV.
Authors: Zhang Bixiang , Duan Jingxian , Li Yingmei , Ding Zeyang , Zhang Zhanguo , Chen Shifu
Published: May 2020

e16620

Background: The serum level of alpha-fetoprotein (AFP) is a key biomarker in hepatocellular carcinoma (HCC) screening regardless of the high false-negative rates. Studies have characterized AFP negative HCC patients, however, the differences between HBV and HCV infected AFP negative HCC patients have not been discussed. Methods: The clinical profiles and whole-exome sequencing data of 243 patients were downloaded from the TCGA database. Patients were divided into 4 groups based on their virus infection status and serum AFP measurements as indicated in the table. The mutation profiles and clinical features of the patients were analyzed. Results: In the HBV infected groups, the AFP+ patients carried significantly larger tumors (n = 17, 85.88±11.87 mm) compared to the AFP- patients (n = 13, 49.08±8.933 mm, p = 0.026). The HBV+ AFP+ group exhibited the prevalence of vascular invasion (VI, 76%, 13/17) while less than half of the patients in the HBV+ AFP- group developed VI (46%, 6/13). The WES results identified shared mutations in more than 10% of patients in each group. It appeared that 126 shared mutations were restricted to the HBV+ AFP+ group, they are involved in the regulation of ion transmembrane transport (p < 0.001) and interaction between L1 and Ankyrins (p < 0.0001). Only 51 shared mutations were exclusive to the HBV+ AFP- group, they majorly affect developmental growth (p < 0.001) and skeletal system development (p < 0.01). In contrast, the tumor sizes of HCV+ AFP+ and HCV+ AFP- patients are similar (55.18±7.781 vs 48.19±5.564, p = 0.47), while the VI rate is higher in the HCV+ AFP- group (63%, 17/29, Table). In total, 11 shared mutations were restricted to the HCV+ AFP+ group, several of the genes were involved in the generation of precursor metabolites and energy (p < 0.01) and activation of immune response (p < 0.01). 27 shared mutations were exclusive to the HCV+ AFP- group, the enrichment analysis showed that they are related to the regulation of synapse organization (p < 0.0001) and the regulation of chromosome organization (p < 0.01). Conclusions: HBV and HCV infection were associated with distinct clinical features among the AFP positive and AFP negative patients. The differences were underpinned by the mutations exclusive to each group, and they were involved in distinct molecular and cellular functions. [Table: see text]
The role of targeted therapy (TKI) in the treatment of advanced hepatocellular carcinoma (aHCC) in the era of immunotherapy: Real-world data using AI analytics from an academic medical center.
Authors: Wong Rachel Su Jen , Wu Jiaxuan , Leen Alisha Joan , Tey Glenn Jin Chong , Asokumaran Yugarajah , Chan Gloria , Siddappan Chidambaram , Jeyasekharan Anand Devaprasath , Chee Cheng Ean , Yong Wei-Peng , Ngiam Kee Yuan , Sundar Raghav
Published: May 2020

e16623

Background: The management of aHCC has evolved dramatically in recent years, with new agents like immunotherapy receiving regulatory approval. As we begin incorporating these drugs into routine clinical practice, data on real-world sequencing of therapies and clinical outcomes are needed. Methods: We utilised the DISCOVERYAI platform, a virtual machine containing de-identified patient electronic health records to review HCC patients treated at the National University Health System, Singapore from January 2015 to December 2019. We then identified those who received systemic therapy and correlated their clinical outcomes. Results: In total, 395 HCC patients were identified; 75 received surgery, 174 received loco-regional therapy and 102 referred for consideration of systemic therapy. Of those considered for systemic therapy, median age was 65 years (range 23-87); 88% male (n = 90); hepatitis B/hepatitis C/non-hepatitis, 41(40.2%)/ 10(9.8%)/ 51(50.0%). 75.5% (n = 77) of them received systemic therapy with a TKI and/or immunotherapy. 39% (n = 30) of these received second-line treatment. Child-Pugh score at start of treatment was A5/A6/B7/B8, 38(49.3%)/ 32(41.6%)/ 5(6.5%)/ 2(2.6%) respectively. In the first-line, 66% (n = 51) received TKI and 34% (n = 26) received immunotherapy. Amongst those treated with first-line TKI, 45% (n = 23) received second-line therapy; 65% (n = 15) immunotherapy, 35% (n = 8) another TKI. Of those treated with first-line immunotherapy, 27% (n = 7) received second-line TKI. At a median follow-up of 35 months, first-line median progression-free survival (mPFS) for TKI vs immunotherapy was 3.7 vs 3.1 months (HR 0.73; 95% CI, 0.40-1.33; p = 0.31). mPFS for second-line immunotherapy vs TKI was 4.0 vs 2.9 months (HR 0.43; 95% CI, 0.19-0.96; p = 0.04). When comparing sequencing of therapies, the combined first and second mPFS for TKI-immunotherapy/TKI-TKI/immunotherapy-TKI is 9.5/7.6/7.6 months respectively (log-rank test, p = 0.71). Those patients that received both immunotherapy and TKI had significantly higher overall survival (OS) compared to those receiving only immunotherapy or only TKI or none (mOS NR vs 10.1 vs 13.2 vs 4.7 months; p < 0.001). Conclusions: TKI remains an important pillar of treatment in aHCC in the era of immunotherapy. While immunotherapy provides long durable responses and benefit in a minority of patients, the majority appear to benefit from TKI. Biomarker studies are needed to discern treatment algorithms for aHCC.
Genomic architecture of gallbladder cancer: Results of a first prospective study.
Authors: Patel Amol , Singh H P , Pandalanghat Suresh , Kumar Manish , Guleria Bhupesh , Mathighatta Shivarudraiah Shivashankara Swamy
Published: May 2020

e16628

Background: Rarity in western countries precluded Gallbladder cancer (GBC) from prospective research. Comprehensive Genomic profiling carries potential to determine oncogenic pathways, driver mutations and possible resistance mechanisms. This study is evaluating the role of comprehensive genomic profiling and role of targeted therapies therein. Methods: This is a single center, prospective, study conducted from Aug2018-Dec2019. All consecutive patients of unresectable and/or metastatic GBC of age ≥18 years were enrolled. Hybrid capture based comprehensive genomic profiling was performed by Foundation Medicine CDx. Microsatellite instability and PDL1 expression were studied. Results: Median age was 56 years (range:26-83) with male to female ratio of 1:1.6. NGS information was available for 50 patients. ERBB pathway was aberrated in 44% of patients. ERBB2 & ERBB3 amplification was seen in 9(18%) and 2(4%) patients respectively. ERBB2 mutations were present concurrently with amplification in 3 patients. MET amplification was present in 3 (6%) PIK3CA mutations were seen in 14% of cases. PIK3CA mutations were independent of ERBB aberrations. FGFR2 mutation, FGFR2 and FGFR3 amplification was present in one patient each. NF1 and NF2 mutations were seen in three and two patients respectively. Median TMB (n = 39) was 5 mut/Mb with range of 1-14 mut/Mb. PDL1 (n = 31) of ≥ 1% was present in 32% of cases and it ranged from 1-100%. MSI (n = 39) was stable in all cases. Other somatic mutations and/or amplifications are shown in Table. Conclusions: GBC is enriched in 28% of patients with ERBB2 & ERBB3 amplifications and/or mutations. FGFR2 mutation is rare in GBC. PIK3CA aberrations are common. Phase 2 trial of frontline Trastuzumab combined with chemotherapy is ongoing. [Table: see text]
Association of immune related adverse events with superior outcomes in patients with hepatocellular carcinoma (HCC) treated with nivolumab.
Authors: Ostios-Garcia Lorena , Ramiro-Cortijo David , Peters Mary Linton Bounetheau , Bullock Andrea J.
Published: May 2020

e16630

Background: Nivolumab, an anti-PD1 antibody, is FDA approved in patients (pts) with HCC. Anti-PD-1 promotes hyperstimulation of host immunity and is associated with a spectrum of toxicities known as immune-related adverse events (irAEs). In other malignancies, higher rates of irAEs are associated with improved cancer outcomes. This study shows correlation between irAEs and efficacy in pts with HCC treated with nivolumab. Methods: Demographic and toxicity data were collected retrospectively on all pts with HCC treated with nivolumab at a single institution from Jan 2012 – Sept 2019. Response was evaluated using RECISTv1.1. Adverse events were assessed according to CTCAEv5.0. Categorical variables were assessed by Fisher's exact test. Survival was estimated with the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed by the Cox-regression model. Results: 30 pts were treated; irAEs were detected in 16 (53%). There was no difference in baseline characteristics among those who did and did not experience irAEs (Table). The most frequent irAEs were elevated AST/ALT (n = 7; 44%), rash (n = 4; 25%), and hypothyroid (n = 4; 25%). 3 G3 (rash and transaminitis) and 1 G4 AE (pured red cell apalasia) were observed. Among all pts, overall response rate (RR) and disease control rate (DCR) were 13 and 50%, respectively. Median progression free survival (PFS) and overall survival (OS) were 27 and 56 weeks (w), respectively. The RR and DCR were higher among irAEs vs non-irAEs, although this did not reach statistical significance (RR 25 vs 0%; p = 0.05; DCR 62 vs 35%; p = 0.19). Median PFS and OS were longer in those with irAEs vs non-irAE; PFS 33 vs 16 w (HR: 0.26; CI 95%: 0.076-0.89; p = 0.028); (OS 69 vs 21 w HR: 0.18; CI 95%: 0.05-0.58; p = 0.002). On multivariate analysis, viral etiology was associated with prolonged PFS (p = 0.002) and MELD was associated with reduced OS (p = 0.004). Conclusions: Development of irAEs was associated with prolonged PFS and OS in pts with HCC treated with nivolumab. Further study is needed to determine whether type of irAE, onset time, or duration affect cancer outcomes. [Table: see text]
AST-to-APOA ratio to predict overall survival in hepatocellular carcinoma receiving TACE.
Authors: Chen Yongjian , Li Xing , Chen Jie , Qin Gang , Qiao Yidan , Huang Shaozhuo
Published: May 2020

e16637

Background: Current guidelines lack definitive evidences about the predictive capability of clinical parameters for transcatheter arterial chemoembolization (TACE). The aim of this study was to comprehensively investigate the predictive factor among stage I-IV liver hepatocellular carcinoma (LIHC) patients after TACE. Methods: We investigated the clinical features of 211 stage I-IV patients with LIHC in discover group and 341 patients in validation group. Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test. Results: Univariate Cox regression revealed that Monocyte count, TNM stage and AST-to-APOA ratio (AAR) were associated with unfavorable OS. AAR was identified as an independent predictor of OS using multivariate analysis. Kaplan-Meier curve demonstrated that patients with AAR < 50 displayed better prognosis. The median follow-up time was 17.1 (95%CI, 14.4 to 19.3) months, 3-year overall survival was 55.9% in the low AAR group versus 28.6% in the high AAR group, and there was significant difference in OS (Hazard ratio [HR] 0.47, 95%CI 0.33 to 0.67, P < 0.001). The AAR showed predictive ability for OS (12-month, AUC = 0.707). These findings were successfully validated in validation group (HR 0.62, 95%CI 0.46 to 0.84, P = 0.002; 12-month AUC = 0.636). Conclusions: AAR was an independent predictor among LIHC patients after TACE. Patients with lower AAR were optimal candidates for TACE.
A novel pretreatment model identifying high-risk of refractoriness after transcatheter arterial chemoembolization in unresectable hepatocellular carcinoma.
Authors: Yin Xin , Hu Ke Shu , Lu Shen Xin , Tang Bei , Ren Zhenggang
Published: May 2020

e16641

Background: Refractoriness to transcatheter arterial chemoembolization is common during the therapeutic process of hepatocellular carcinoma, which is an intractable issue and may compromise the prognosis. We aim to establish a pre-treatment model to identify patients with high risks of refractoriness. Methods: From 2010 to 2016, 824 patients who had initially underwent at least two sessions of transcatheter arterial chemoembolization in Zhongshan Hospital, Fudan University were retrospectively enrolled. These patients were randomly allocated into a training cohort and a validation cohort. The pre-treatment scoring model was established based on the clinical and radiological variables using logistic regression and nomogram. The discrimination and calibration of the model were also evaluated. Results: Logistic regression identified vascularization pattern, ALBI grade, serum alpha-fetoprotein level, serum γ- glutamyl transpeptidase level and major tumor size as the key parameters related to refractoriness. The p-TACE model was established using these variables (risk score range: 0-19.5). Patients were divided into six risk subgroups based on their scores ( < 4, ≥4, ≥7, ≥10, ≥13, ≥16). The discriminative ability, as determined by the area under receiver operating characteristic curve was 0.784 (95% confidence interval: 0.741-0.827) in the training cohort and 0.743 (95% confidence interval: 0.696-0.789) in the validation cohort. Moreover, satisfactory calibration was confirmed by Hosmer-Lemeshow test with P values of 0.767 and 0.913 in the training cohort and validation cohort. Conclusions: This study presents a pre-treatment model to identify patients with high risks of refractoriness after transcatheter arterial chemoembolization and shed light on clinical decision making.
PD-1 targeted immunotherapy for advanced hepatocellular cancer: Current utilization and outcomes in the United States.
Authors: Uhlig Johannes , Stein Stacey , Kim Kevin
Published: May 2020

e16647

Background: Novel oncological treatment strategies for hepatocellular carcinoma (HCC) include immunotherapies targeting programmed death protein 1 (PD-1). To date there is scarce data on the current real-world clinical utilization of immunotherapy for HCC in the US. Methods: The Flatiron Health EHR-derived de-identified database was queried in October 2019 for adult patients with advanced HCC. PD-1 targeted immunotherapy (PD-1 IMT) included Nivolumab and Pembrolizumab. Overall survival (OS) was evaluated using Cox proportional hazards models. Multivariable analyses adjusted for patient demographics (age, gender, race), documented liver disease risk factors (obesity, diabetes, alcohol abuse, hepatitis), documented liver disease complication (ascites, encephalopathy), local HCC treatment (resection, radiofrequency ablation, transarterial chemoembolization [TACE], transarterial radioembolization [TARE]) and systemic Sorafenib. Subgroup analyses were performed in patients with documented clinical performance status (Eastern Cooperative Oncology Group; ECOG) and albumin/bilirubin results (all measured nearest to HCC diagnosis). Results: A total of 2,912 patients with advanced HCC were included, of which n = 345 (11.8%) received PD-1 IMT. Utilization of PD-1 IMT continuously increased from 2004, accounting for 20.9% of all cases in 2018/19. Patients treated with and without PD-1 IMT were comparable regarding demographics, comorbidities and liver disease. PD-1 IMT was more commonly administered at academic centers (20.3% vs. 13% in non-academic centers, p < 0.001), and in patients receiving Sorafenib, TACE, TARE or HCC resection (vs. none of these treatments, each p < 0.05). Median follow-up time was 36.1 months. In univariate analyses, administration of PD-1 IMT was associated with longer OS (vs. no PD-1 IMT; HR = 0.67, 95% CI: 0.58-0.78, p < 0.001; OS rates in the table). In multivariable analyses, PD-1 IMT receipt was an independent prognosticator (vs. no PD-1 IMT; HR = 0.54, 95% CI: 0.46-0.63, p < 0.001). In a subset of n = 1560 patients, this effect persisted after adjustment for ECOG, albumin and bilirubin results (HR = 0.58; 95% CI: 0.48-0.69, p < 0.001). Conclusions: PD-1 targeted immunotherapy is increasingly used for advanced HCC, accounting for up to 20.9% of cases in 2018/19. After adjustment for potential confounders, immunotherapy was associated with an overall survival benefit. [Table: see text]
Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.
Authors: Guo Lingling , Kou Xiaoxia , Song Panpan , Zhang Xiaoyu , Zhang Hongjuan , Qiu Jinrong
Published: May 2020

e16650

Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( > 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.
Risk score and prognostication modeling based on mRNA expressivity in the tumor microenvironment of hepatocellular carcinoma.
Authors: Lee Sunyoung S. , Mohamed Yehia I. , Lee Sung Hwan , Baird Andrew , Dolan Jillian , furqan fateeha , Kaseb Ahmed Omar
Published: May 2020

e16658

Background: Stromal elements in the tumor microenvironment (TME) impact prognosis and response to therapy. Advances in mRNA-sequencing improved understanding of gene expressivity, but few models exist to model prognosis in association with mRNA expression. Methods: Clinical data and mRNA-seq of 256 patients (pts) with hepatocellular carcinoma (HCC) were obtained from TCGA. The expressivity of 191 genes enriched in cellular and structural components of the TME and clinical data were analyzed using machine learning, multivariable COX model, and Kaplan-Meier (KM) analysis to model risk score (RS) for prediction of prognosis. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis. Gene expression associated with poor (P) and good (G) in stage 1 and 2 HCC was identified (refer to presentation). RS (stage 1) = 5.997 - 0.589 × (Age at diagnosis−7.979E-06) - 4.818 × (P/G−0.009); RS (stage 2) = -5.704 - 0.780 × (Age at diagnosis−9.383E-06) + 7.228 × (P/G−0.004). Based on RS, pts were clustered into 2 groups in each stage - high and low RS groups, showing two KM curves with P < 0.05, HR = 3.213 (95% CI 2.212 – 4.347) in stage 1; HR = 2.733 (95% CI 2.131 – 3.426) in stage 2, confirming the validity of RS modeling. Analysis of immune profiles in high and low RS groups shows that expression of genes associated with immunosuppressive factors, desmoplastic reaction, neutrophils, and co-inhibitory factors of T-cells are higher in high RS group in both stages (p < 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis identified TME-related genes and gene groups that are strongly associated with worse prognosis in stage 1 and 2 of HCC. RS could potentially prognosticate pts in the clinic with available genomic profiles.
NTRK gene fusions in bilio-pancreatic cancers.
Authors: Demols Anne , Perez-Casanova Luis , Rocq Laureen , Charry Manon , De Nève Nancy , Verrellen Audrey , Ramadhan Ali , Van Campenhout Claude , De Clercq Sarah , Maris Calliope , Closset Jean , Lucidi Valerio , Salmon Isabelle , D'Haene Nicky
Published: May 2020

e16664

Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic tumors. It is of interest therefore to determine incidence and molecular characteristics of NTRK gene fusions in these patients. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors (BTC) including intra-hepatic (IH), extra-hepatic (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G), and pancreatic adenocarcinoma (PA) were retrieved from the tumor bank of CUB Hôpital Erasme between JAN 2010 and OCT 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) pattern (diffuse, focal or rare positive cells), and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay ThermoFisher Scientific). Results: For BTC, 162 archival tumors samples have been selected. 149 samples were suitable to perform IHC.17 samples were IHC positive including 9 IH, 3 PH, 2 EH and 3 G tumor samples. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). Pattern of staining was rare positive cells (2/17), focal (4/17) and diffuse (11/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this PH tumor, IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, percentage of NTRK fusions was 0.67 %. For PA, 319 archival tumor samples have been selected and 297 were suitable for IHC. 19 samples were IHC positive. Intensity of staining was weak in 18 samples and moderate in one. Staining location was cytoplasmic (18/19) and nuclear (1/19). Pattern of staining was focal in 2 cases and diffuse in 17 cases. No fusion was detected by NGS. Conclusions: NTRK gene fusions are rare in bilio-pancreatic cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors. These results support the use of NGS to confirm positive IHC results during diagnostic screening.
BRAF mutation in Chinese biliary tract cancer patients.
Authors: Li Wendong , Cui Yanzhi , Yin Fei , Peng Li , Liu Xiaogang , Shen Yunzhi , Guo Yuntong , Wen Shiwang , Shi Junping , Lei Mengping , Javle Milind M. , Wang Kai , Jiang Da
Published: May 2020

e16678

Background: Biliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA), and extrahepatic (ECC) cholangiocarcinoma. In the ROAR basket trial, dabrafenib, a BRAF inhibitor, combined with trametinib, a MEK inhibitor, demonstrated promising efficacy in patients with BTCs with an overall response rate (ORR) of 41% and a favorable safety profile. The frequency of BRAF mutations reported in BTC varies widely, and BRAF V600E mutations have been reported in 0% to 20% of BTCs. However, the frequencies of BRAF mutations in Chinese BTCs are not clear. Methods: A total of 926 BTC patients (203 ECC, 195 GBC, 59 HCCA, and 469 ICC) were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from these patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions and deletions, copy number variations, and fusions were assessed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: BRAF activating mutations were detected in 5.5% of Chinese BTC patients. There were 5.1% in ICC cases, 8.9% in ECC cases, 5.1% in HCCA cases, and 3.1% in GBC cases. BRAF V600E, the most common hotspot mutation, was detected in ICC and GBC with frequencies of 1.5% and 0.5%, respectively. No BRAF V600E was detected in ECC or HCCA. The top-ranked co-mutation genes with BRAF were TP53 (54%), ARID1A (40%), and SMAD4 (32%). Compared with BRAF wild-type cohort, the frequencies of ARID1A and SMAD4 mutations were significantly higher in patients with BRAF mutations cohort (40% vs 17%, P< 0.001; 32% vs 14%, P< 0.001), while KRAS mutations were mutually exclusive with BRAF mutations. Conclusions: To our knowledge, this is the largest BTCs cohort used to study the characterization of BRAF mutations in the Chinese patients. BRAF mutations occurred in 5.5% of patients, and BRAF V600E in 0.9%. These patients could benefit from treatment with a BRAF inhibitor combined with a MEK inhibitor. Analysis of BRAF V600E should be considered in patients with BTCs, especially in ICC and GBC. Clinical trial information: NCT03892577 .