bluuebunny/crossref_metadata_2025 huggingface dataset:
Extramural venous invasion on pretreatment MRI and surgical pathology: Is there a role in predicting prognosis in rectal cancer?
Authors: Kamran Sophia C. , Kordbacheh Hamed , Baliyan Vinit , Hong Theodore S. , Kambadakone Avinash
Published: September 2018

e15165

Background: Extramural venous invasion (EMVI) describes tumor cells invading the veins beyond the muscularis propria and has been previously recognized as a predictor for survival and disease recurrence in rectal cancer. EMVI is generally diagnosed on pathology after surgical resection. Pretreatment MRI has been proposed as a surrogate imaging biomarker for recognition of EMVI. Our objective is to study the prognostic significance of EMVI in rectal cancers based on pretreatment MRI imaging to determine its correlation with overall survival (OS), local recurrence (LR), and distant metastases (DM). We also compare MRI-detected EMVI to EMVI detected on pathology to evaluate correlation. Methods: In this ongoing study, records of rectal cancer patients with a pretreatment staging MRI diagnosed between 2004-2015 were retrospectively reviewed (n = 180). Pretreatment rectal MRIs were evaluated for different imaging characteristics, including EMVI. The endpoint of OS was calculated using the Kaplan-Meier method and compared with a log-rank test. A p< 0.05 was considered significant. Cox proportional hazard ratios for LR and DM were generated using clinical, imaging, and pathologic characteristics. Results: Most patients were male (63%) with a median age at diagnosis of 63 years (28.5-95.2). Eighty percent of patients received neoadjuvant chemoradiation (nCRT) followed by surgery and adjuvant chemotherapy (AC); 20% received nCRT followed by surgery. A pathologic complete response was achieved in 17% of patients. Median survival was 48.5 months (2.6-145.2); five-year OS was 85%. The receipt of AC improved OS (HR 0.40, CI 0.2-0.9). Of 70 patients with EMVI noted on the pretreatment MRI, 22 (31%) had EMVI on pathology (p = 0.05). EMVI on MR was not found to be prognostically significant for OS, LR, or DM. EMVI on pathology was found to be significant for DM (HR 3.74, CI 1.8-8.0). Conclusions: Preliminary results show that pretreatment MR-detected EMVI was not found to be predictive for OS, LR, or DM, but pathologically-detected EMVI was found to be a predictor for DM. Further analysis of the relationship between this surrogate imaging biomarker on post-CRT MRI and outcomes is ongoing.
Next-generation sequencing of esophageal carcinosarcoma to reveal high frequency of actionable PIK3CA gene mutations.
Authors: Lu Hongyang , Yang Shifeng , Jiang Zhiming , Xie Fajun , Qin Jing , Gong Lei , Han Na , Fan Yun , Mao Weimin
Published: September 2018

e15503

Background: Esophageal carcinosarcoma (ESC) is a rare malignant esophageal neoplasm consisting of both carcinomatous and sarcomatous components. Drive genes mutations may potentially serve as novel biomarkers to targeted therapy in ESC, and they also may explain the mechanisms of the unique dual-differentiation pattern. Actionable gene alterations with any significant frequency in ESC were unknown due to specimen numbers and limited studies. A comprehensive study of clinical characteristic and molecular alterations in ESC is needed to better understand biology and guide therapy. Methods: Fifteen cases of ESCs which received surgical resection were retrospectively collected from the Zhejiang Cancer Hospital in China between 2009 and 2016, next generation sequencing was performed to identify genotypic changes, and clinical characteristic of these patients was also collected and analyzed. Results: ESC patients are easily occurred in male, heavy smokers, and old patients. The mainly gross types were medullary and fungating type. Mutation of phosphatase and tensin homologue ( PTEN), MAP2K1(MEK1), anaplastic lymphoma kinase ( ALK), RET, and NF1 were detected in one patient respectively. Mutation of ERBB2(HER2), MET and single copy loss of Rb1 were detected in two patients respectively. Mutation of ROS1 and phosphoinositide-3-kinase catalytic alpha ( PIK3CA) were detected in three patients respectively. Conclusions:PIK/AKT pathway may be important in pathogenesis of ESCs, and it may be an ideal therapeutic target.
Bolus infusion of cisplatin, 5-fluorouracil, and leucovorin as alternative first-line therapy for advanced gastric cancer.
Authors: Coelho Rafael Correa , Abreu Pedro Duarte , Monteiro Mariana Ribeiro , Stramosk Ana Paula , Gil Roberto Almeida , Siqueira Mariana , Pereira Bruno dos Santos Vilhena , Guedes Duque Cristiano , Palladino Alexandre de Mendonca , Graudenz Marcia Silveira , Andrade Carlos J C
Published: September 2018

e15511

Background: Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide.Classic regimens in first line setting for advanced GC combine platinum compounds and fluoropirimidines ± antracyclines or docetaxel. At Brazilian National cancer Institute (INCA), there are limitations in hospital beds and infusion pumps, so the combination between cisplatin (CDDP) + 5-Fluorouracil (5-FU) in an infusion protocol has been out of possibility. An institutional project with an adapted protocol involving CDDP + 5-FU + Leucovorin (CFL) in bolus demonstrated good results and CFL became routine at INCA for more than 10 years. Methods: Retrospective cohort study evaluating 109 patients with advanced GC treated in first line setting with CDDP 80mg/m2(D1) + 5- FU 400mg/m2 (D1,D8,D15,D22)+ Leucovorin (LV) 20mg/m2 (D1,D8,D15,D22) in 28-day cycles from January 2008 to December 2014. Results: The median age was 54 years (24y-80y), 53.6% were male, 70% white and 20% mulatto, 49.1% formal smokers and 15.5% formal drinkers. Tumor staging at initial diagnosis was: E IIA 2.7%, E IIB 2.7%, E IIIA 1.8%, E IIIB 5.5%, E IIIC 5.5% and E IV 81.8%. Performance status ≤ 2 was present in 97.3% and G3 disease in 63.6%. The most common metastatic sites were: lymph nodes 31.8%, peritoneum 24.5%, liver 21.8% and lung 2.7%. The median of cycles received per patient was 4. Complete responses were achieved in 6.4%, partial responses in 14.5% and stable disease in 14.5%. Median PFS was 6.3 months (5.08 – 7.58) and median OS was 8.3 months (6.79 – 9.87). Seventy five (68.8%) patients were alive in 1-year and 26 (23.9%) in 2-years. Dose reduction was necessary in 9.1% and the most common toxicities were: nausea 27.3%, vomiting 19.3% fatigue 13.6%, diarrhea 10.6%, mucositis 4.2% and neutropenia 4.2%. Of all adverse events, grade 3 and 4 corresponded to 11.36% and 1.51%, respectively. Three patients had neutropenia G4. Only 26 patients (23.8%) received second line treatment. Conclusions: Chemotherapy protocol in bolus combining CDDP, 5-FU and LV could be an alternative for CDDP and 5-FU infusion protocol.
bghcng.
Authors: Castaneda Altamirano Carlos , Belmar Lopez Carolina , Castillo Garcia Miluska , Nieves Jais , Polo Julio , Chumpitaz Rodrigo , Gonzales Zoila , Bernabe Luis A. , Galvez Renato , Sanchez Joselyn , Payet Eduardo , Barreda Fernando , Chávez Iván
Published: September 2018

e15521

Background: Helicobacter pylori (HP) infection is one of the most common infections worldwide and is a risk factor for gastric cancer (GC) development. This study was conducted to determinate the prevalence rate of HP as well as presence of vacA and cagA in gastric cancer samples from Peruvian patients. Methods: GC samples were prospectively collected from patients who went to surgery between April 2015 and November 2016. Three types of gastric samples were obtained from each patient: tumoral area (T), proximal healthy (P) and distal healthy tissue (D) samples. HP status through H&E was analyzed by a pathologist. DNA was extracted from tissue, and detection of colonization (ureA and hspA) and virulence genes (vacA and cagA) of HP was performed through quantitative PCR (qPCR). Results: A total of 183 patients were studied with a mean age of 64 years and 51.9% were men. 52.2% had a primary from antrum, 47.8% was HG 3 and 60% were diffuse. Presence of HP through H&E was found in 58.4% (n=107/183). Positive HP cases through qPCR were determinate with positivity of at least one ureA/hspA gene and was found in 89.6% (n=164/183). HP detection rate and its concentration were higher in D (ureA: 62.8%, n=115, [703.58±245.47pg]; hspA: 73.8%, n=135, [42.77±10.17pg]) than P (ureA: 59.0%, n=108, [539.69±121.32pg]; hspA: 71.0%, n=130, [31.90±8.64pg]) and T (ureA: 49.7%, n=91, [296.32±164.98pg]; hspA: 70.5%, n=129, [4.6±1.33pg]) (p<.001). Antrum location was associated to higher level of hspA expression (p=0.047). Neither histology (p=0.45) nor HG (p=0.2) was associated to level of hspA expression. qPCR detected HP in 75% (n=57/76) of cases without evidence of HP by pathology evaluation (H&E) (ICC: 0.77 vs 0.58). cagA virulence gene was detected in 95.8% (n=159/166) while vacAm allele in 85.5% (n=142/166) and vacAs allele in 96.8% (n=160/166). vacA+cagA- combination was found in 0.6% (n=1/166), vacA+cagA+ cases in 95.8% (n=159/166) and vacA-cagA- cases in 3.6% (n=3/166). Conclusions: Our results show a significant presence of HP in Peruvian gastric cancer patients and combination of vacA+/-cagA+/- virulence genes had particular patterns.
Whole-exome sequencing to identify HOMEZ mutation as a prognostic marker in esophageal squamous cell carcinoma treated with concurrent chemoradiotherapy.
Authors: Luo Hong Lei , Jing Zhao , Xie Rui Fei , Wu Hong Jin , Zhang Xiao Yan , Zhang Hong Fang , Li Wen Xin , Hua Yu Hui , Wu Shi Xiu
Published: September 2018

e15523

Background: The outcomes of inoperable esophageal squamous carcinoma (ESCC) patients treated with concurrent chemoradiotherapy remain poor. The discovery of novel biomarkers for predicting prognosis could allow for more accurate risk stratification and identification of high-risk patients. Although previous studies have elucidated some genomic alterations could be predictors of survival in these patients, none has focused on comprehensive genetic analysis using high-throughput platforms. Methods: Whole-exome sequencing was done in 96 inoperable ESCC patients treated with concurrent chemoradiotherapy from our phase Ⅲ clinical trial (NCT00686114). The prognostic marker was developed using a Random Survival Forest supervised classification methods based on log-rank splitting rules. The independence of the marker in survival prediction was evaluated by multivariable Cox regression analysis. The marker was further validated for the prognostic utility in an independent cohort (n = 150). The biological function of the genomic alteration was predicted by GO annotations. Results: A HOMEZ mutation (chr14:23744800_ACATCAT/ACAT) was detected in 54.1% of patients with ESCC received concurrent chemoradiotherapy. We identified the mutation was significantly associated with overall survival (hazard ratio [HR] 1.842; 95% confidence interval [CI] 1.080-3.142; P = 0.025) and loco-regional free survival (HR 3.008; 95% CI 1.302-6.947; P = 0.010). Multivariable Cox regression analysis showed that the mutation was also an independent prognostic factors for patients with ESCC (mutation type vs. wild type, overall survival: HR 2.161; 95% CI 1.241-3.764; p = 0·007; loco-regional free survival: HR 3.576; 95% CI 1.509-8.473; p = 0.004). GO annotations showed that HOMEZ tended to be frequently related to transcription factor activity, sequence-specific DNA binding and transcription corepressor activity. Conclusions: HOMEZ mutation is a novel independent prognostic factor for inoperable ESCC patients treated with concurrent chemoradiotherapy, and may be a potential therapeutic target.
Serum tumor markers to predict cancer-related venous thromboembolism in gastric cancer.
Authors: Yang Yan , Yang Yang , Shen Jie , Jie Xia , Yu Lixia , Qian Hanqing , Wei Jia , Du Juan , Liu Baorui
Published: September 2018

e15526

Background: To investigate the relationship between the preoperative level of serum tumor markers and cancer-related venous thromboembolism in patients with gastric cancer. Methods: 1005 patients with gastric cancer who underwent curative resection were finally enrolled in this study. Serum tumor markers including CEA, CA19-9, CA242, CA72-4, CA125 were tested within one week before curative surgery. Measurement data between groups were compared with t test. The sensitivity, specificity, positive predictive values, and negative predictive values of five biomarkers and the combination group were calculated, respectively. The odds ratios were calculated via both univariate and multivariate logistic regression models. Results: Cancer-related venous thromboembolism was found in 540 (53.73%) patients. The increase of each cancer marker is remarkably related with cancer-related venous thromboembolism. The more abnormal serum tumor markers come out, the high the risk of positive cancer-related venous thromboembolism can be. The possibility of positive cancer-related venous thromboembolism would be 2.9 times as much as a normal patient as any of the tumor markers increases. With the increase of any 4 of the tumor markers can make the risk 16.4 times Conclusions: The status of postoperative cancer-related venous thromboembolism can be predicted from preoperative serum tumor markers. For those patients with a high risk of positive cancer-related venous thromboembolism, more aggressive treatment should be arranged.
RACK1 to modulate expression of MMP10 via Src/NF-κB pathway in gastric cancer.
Authors: Chen Ling , Chen Hao , Liu Fenglin
Published: September 2018

e15529

Background: Receptor of activated C kinase 1 (RACK1) is regarded as a scaffolding protein in multiple intracellular signal transduction pathways. Our previous works had demonstrated that RACK1 might involve in progression of gastric cancer, and could be a criterion to predict the good prognosis for the patients after surgical resection. The aim of this study is to explore the regulatory role of RACK1 in matrix metalloproteinase 10 (MMP10) autocrine, and which may be involved in invasion of gastric cancer. Methods: RACK1 knockdown gastric cell lines were established by shRNA. Secretion of cytokines secretion, as well as MMP10 was measured by antibody arrays and enzyme-linked immunosorbent assay. Cell migration and invasion was compared between normal and RACK1 knockdown cells. Pharmacological inhibitors were employed in searching specific signaling pathway. The correlation of RACK1 and MMP10 expression in gastric cancer samples was analyzed by Spearman’s ρ test. Results: Expression of MMP10 was substantially enhanced after knockdown of RACK1 in vitro, which contributed to enhanced migration and invasiveness of gastric cancer cells in autocrine manner. Specific inhibitors of NF-κB and c-Src, as well as overexpression of dominant-negative c-Src mutant, could suppress the expression of MMP10. Finally, an inverse correlation of RACK1 and IL-8 expression was confirmed in gastric cancer samples. Conclusions: Down-regulation of RACK1 resulted in the up-regulation of MMP10 in gastric cancer, which might enhance invasiveness via Src/NF-κB pathway partially.
Risk factors associated with early postoperative complications following laparoscopic total gastrectomy: Experience from the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) group.
Authors: Liu Jingdong , Li Haojie , Zhao Gang , Xu Zekuan , Li Guoxin , Yu Peiwu , He Hongyong , Shen Kuntang , Liu Fenglin , Sun Yihong
Published: September 2018

e15544

Background: The incidence rate of proximal gastric cancer has been rising steadily, and laparoscopic total gastrectomy (LTG) has been widely adopted. However, the safety of LTG still lacks solid evidence to prove. The aim of this study was to evaluate morbidity and mortality of LTG, and determine the risk factors associated with early postoperative complications. Methods: A retrospective multicenter study was carried out in China, and medical records of 109 gastric cancer patients receiving LTG during September 2014 and June 2016 were retrieved from the database. Patient characteristics, surgical outcomes, and postoperative morbidities and mortalities were analyzed. Results: Morbidity and mortality rates were 22.0% and 0% respectively. Pulmonary infection (13.8%, n = 15) was the most common complication. Most complications were grade II (15.5%, n = 17) according to the Clavien-Dindo classification. Multivariable analysis identified comorbidity, type of reconstruction method (TLTG) were independent risk factors of early postoperative complications. Comorbidity was the only independent risk factor of complications graded more than II. Diabetes mellitus was found correlated with surgical complication in subgroup analysis. Conclusions: LTG is safe and technically feasible in treating gastric cancer. Careful selection of patients without comorbidity and applying laparoscopy-assisted total gastrectomy instead of totally laparoscopic total gastrectomy may decrease postoperative complications.
Assessment of HER2 status in adenocarcinomas of the stomach or gastroesophageal junction in a Western population.
Authors: Martinez Lago Nieves , Padin Iruegas Maria Elena , Abdulkader Ihab , Santamaria Dora Insua , Carrera Juan Jose , Antunez Lopez Jose Ramón , López López Rafael
Published: September 2018

e15548

Background: HER2 status is a predictive biomarker to response to trastuzumab in metastatic adenocarcinomas of the stomach our gastroesophageal junction. However, relatively little is known about the role of HER2 in the non-metastatic disease in western population. Methods: This study included 106 patients with gastric cancer who underwent surgery between January 2007 and June 2014 at Universitary Hospital of Santiago de Compostela. Immunohistochemical expression of HER2 was analyzed using the DAKO-HercepTest™ and gene amplification using DAKO-DuoCISH kit; both was scored according to published reports. Correlations between HER2 status, clinicopathological characteristics, survival and relapse sites were retrospective analyzed. Results: HER2 expression rate by IHC was: 76 patients (71.7%) classificated as negative, 7 patients (6.6%) as positive and 23 patients (21.7%) as equivocal. HER2 gene amplification by DuoCISH was positive in 14 patients (13.2%). HER2 status was associated with intestinal subtype (p = 0.010), tumor grade (well-moderately differentiated, p = 0.008), lower tumor invasion (p 0.018) and distant relapse (p = 0.048). There was a significant interaction between HER2 status and significantly worse disease-free survival (DFS) (P = 0.039) and overall survival (OS) (P = 0.028), respectively. Conclusions: In our population, HER2 status appears to be associated with differentiated clinicopathological characteristic, worse OS and DFS and distant site of relapse in patients with resected gastric cancer.
Neutrophil-to-lymphocyte ratio (NLR) to predict the short-term and long-term outcomes of gastric cancer patients.
Authors: Miyamoto Ryoichi , Inagawa Satoshi , Sano Naoki , Tadano Sosuke , Yamamoto Masayoshi
Published: September 2018

e15560

Background: Preoperative NLR was well known as highly repeatable, cost-effective and widely available long-term postoperative prognostic marker of gastric cancer patients. However, the utility of preoperative NLR to predict short-term outcomes in gastric cancer patients remains unclear. In this study, we addressed whether the preoperative NLR is a predictive value of short-term outcome in gastric cancer patients. Methods: We retrospectively evaluated 154 consecutive gastric cancer patients. Mean NLR was calculated, and 3.5 was set as cut-off value. The patient characteristics and perioperative outcomes were respectively compared. In addition, median survival times (MSTs) were also compared. In terms of stage II/III (UICC 7th) gastric cancer patients, median disease-free survival times (MDFSTs) were compared between the two groups. Results: The patients were then divided into two groups: low-NLR group (n = 110) and high-NLR group (n = 44). Among low-NLR group and high-NLR group, significant differences were respectively observed in preoperative symptoms [56 (51%) vs. 31 (70%); p = 0.027] and perioperative outcomes including postoperative complications [3 (2.7%) vs. 5 (11.3%); p = 0.015], intraoperative blood loss (158 ± 168 g vs. 232 ± 433 g; p = 0.022), and intraoperative blood transfusion [0 vs. 3 (6.8%); p = 0.042]. MSTs and MDFSTs were significantly differed (812 vs. 594 days; p = 0.04, 848 vs. 475 days; p = 0.03, respectively). Conclusions: The present study indicated that preoperative NLR influenced not only long-term outcomes but also perioperative outcomes in gastric cancer patients. Preoperative NLR is also a useful predictive value of short-term outcomes in gastric cancer patients.
A study of thymidylate synthase gene expression as a biomarker for the treatment of esophageal adenocarcinoma.
Authors: Beamer Staci , Gatalica Zoran , Xiu Joanne , Jaroszewski Dawn E. , Stanton Melissa , Pai Rish , Krishna Murli , Thomas Mathew , Ross Helen J. , Ho Thai Huu
Published: September 2018

e15563

Background: Expression of thymidylate synthase (TS), a target of fluoropyrimidine-based (5-FU) chemotherapy, has prognostic value in colorectal adenocarcinoma. Its value as a biomarker in treatment of esophageal adenocarcinoma (EAC) is unknown. With widespread adoption of CROSS trial protocol for treatment of EAC, 5-FU is frequently omitted from regimens. We retrospectively analyzed the association between TS protein expression and clinical outcomes in EAC. Methods: TS expression levels were measured by immunohistochemistry in formalin-fixed paraffin-embedded specimens from 35 primary EAC patients from 2 institutions (range 5/2006-1/2016); at time of diagnosis and surgical resection (33 neoadjuvant chemoradiation and 2 surgery alone). TS expression higher than 1+, 5% was read as positive. Mean follow up was 1323 days (range 263-3677). TS expression correlated with treatment response and survival in patients treated with and without 5-FU therapy (log-rank test, Kaplan-Meier method). Results: In the cohort of 35 patients, 21 patients (60%) had pretreatment positive TS expression. Overall survival (OS) for TS negative patients was 1216 days versus 974 days for TS positive (p = 0.15). In the 23 patients treated with 5-FU, TS-negative patients had a trend towards longer overall survival compared to TS-positive patients, mean OS (1272 days versus 743 days, p = 0.08). In the group of 12 patients not treated with 5-FU, 2 patients showed negative TS staining. Neoadjuvant chemoradiation was performed in 33/35 patients. Downstaging was observed in 69% (9/13) of patients with negative pre-treatment TS levels versus 55% (11/20) in pre-treatment TS positive patients (p = 0.48). In 23 patients treated with 5FU, 9/12 (75%) were downstaged in the TS-negative cohort versus 6/11 (45%) in the TS-positive cohort (p = 0.21). In the 5FU treatment group, complete response was seen in 2 patients with negative TS staining. Conclusions: Low TS expression in EAC patients trended towards improved survival and tumor downstaging, particularly in patients treated with neoadjuvant 5-FU and platinum based therapy. Prospective data and greater patient numbers may be necessary to demonstrate statistical significance.
The characteristics of c-MET and HER2 expression in gastric carcinoma and its correlation with clinical-pathological parameters.
Authors: Stuebs Patrick , Dittmar Florian , Zierau Kathrin , Fahlke Joerg , Ridwelski Karsten , Geers Ann Kristin , Lessel Jana , Jechorek Doerthe
Published: September 2018

e15566

Background: The aim of this study was to determine whether overexpression of c-MET or HER2 had an effect on the clinical-pathological parameters and / or the prognosis of gastric carcinoma, as well as a direct correlation among those parameters. Methods: 134 gastric resectates were archived between 2007-2012 and retrospectively examined for c-MET and HER2 expression via immunohistochemistry (IHC). The HER2 status IHC2 + was additionally verified by means of Chromogenic in situ hybridization (CISH). Statistical data analysis was performed on the basis of the parameters acquired in the prospective multicentre observation study QCGC'07 / 09. Results: A total of 71 patients (53%) were found to express c-MET low and 63 patients (47%) expressed c-MET high, 122 patients (91%) were found to be HER2 negative and 12 persons (9%) were HER2 positive. C-MET high was significantly more pronounced in the Lauren intestinal type (63.8%, p = 0.001) and moderately to poorly differentiated tumour tissue (G2 50.9%, G3 43.9%, p = 0.038) as well es tissue with lymph vessel infiltration (L1 59.1%, p = 0.039). HER2 showed no significant effect on the clinical-pathological parameters. The median overall survival was shown to be shortened for the c-MET high-expressing (c-MET low 56 months, SD: ± 24.67; 95% CI: 7.65-104.36 vs. c-MET high 32 months, SD: ± (median-OS HER2 negative 38 months, SD: ± 14.11, 95% CI: 10.35-65, p = 0.839), and HER2 negative, 65, median-OS HER2 positive not reached, p = 0.305) patients. 8/134 resectates (5.97%, p = 0.135) were high and positive in both expression patterns, showing no significant difference to the OS (p = 0.393). Conclusions: In our studies, c-MET high or HER2 negative expression was associated with a poorer OS. However, no direct correlation between HER2 and c-MET could be demonstrated
Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumors.
Authors: Huang Jing , Mo Hongnan , Wu Dawei , Chen Xuelian , Ma Lanying , Lan Bo , Qu Dong , Yang Qing , Xu Binghe
Published: September 2018

e15572

Background: SHR-1210 is a humanized anti-PD-1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1. SHR-1210 binds to PD-1 with high affinity. Methods: This phase 1 study consisted of dose-escalation and expansion cohorts. We used a standard 3+3 design to assess safety in the dose escalation part. SHR-1210 was initially administered by intravenous (IV) infusion over 30 minutes on days 1 and 28, and repeated every 14 days thereafter. Based on pharmacologic models, disease-specific cohorts were enrolled to receive SHR-1210 at 200 mg IV every 2 weeks (Q2W). Results: Overall, a total of 58 patients were treated with SHR-1210 at 3 dose levels and schedules: 60 mg Q2W (12 patients); 200 mg Q2W (34 patients), and 400 mg Q2W (12 patients). 49/58 patients received > 2 cycles (each cycle was 28 days) while 36/58 patients were receiving ongoing treatment at the time of abstract preparation. No dose-limiting toxicity (DLT) was observed. The most common adverse events (AEs) related to SHR-1210 included: reactive capillary hemangiomas (79.3%), hypothyroidism (29.3%), pruritus (19.0%), elevated transaminase (13.8%), increased bilirubin (12.1%), fatigue (12.1%), fever (10.3%), and diarrhea (10.3%). Of the 46 cases of hemangiomas, only 5 patients were with grade 2, others were evaluated as grade 1. Of the 17 cases of hypothyroidism were asymptomatic and none exceeded grade 2 severity. Serious AEs suspected to be related to SHR-1210 included one grade 3 acute exacerbation of chronic obstructive pulmonary disease, one grade 3 elevated cardiac troponin I, one grade 4 thrombocytopenia and one grade 4 neutropenia. Overall, the objective response rate as assessed by central review was 31.0%, with a disease control rate of 46.5%. No patients achieved complete response. Eighteen patients had partial response, including 10 esophageal squamous cell carcinoma patients (10/29), three gastric cancer patients (3/8), one lung cancer patient (1/3), one nasopharynx cancer patient (1/3), one hepatocellular carcinoma patient (1/3), one colorectal carcinoma patient (1/3), and one bladder cancer patient (1/1). Conclusions: SHR-1210 was well-tolerated with encouraging antitumor activity and a safety profile. Clinical trial information: NCT02742935.
Effect of GPC1 on epithelial-to-mesenchymal transition and stemness and interaction with ITGB1 in gastric cancer.
Authors: Wang Shiqing , Wu Zhenzhen , Zhou Minyu , Liao Wangjun
Published: September 2018

e15580

Background: Gastric cancer is the fourth frequently diagnosed cancer worldwide and tumor metastasis plays an important role in its poor prognosis. EMT, which occurs during embryonic development and carcinoma progression, contributes to metastasis and regulates stemness. GPC1, a member of the heparan sulfate proteoglycans family, is overexpressed in many types of cancer, and associates with metastasis and tumor progression. However, it is unknown that the functions of GPC1 and its underlying mechanism in gastric cancer. Methods: Immunohistochemistry analysis was performed in 245 GC tissues to explore the relationship between GPC1 and tumor metastasis. Transwell migration and wound-healing assay were conducted to evaluate the effects of GPC1 on migration and invasiveness. Epithelial marker and mesenchymal markers expression in GC cells were detected by Western blot and immunofluorescence. GPC1 expression induced by TGF-β was detected by Western Blot. After GPC1 was knock downed, the metastatic effect and EMT markers induced by TGF-β were detected. Co-Immunoprecipitation was used to detect the interaction between ITGB1 and GPC1. Results: The expression of GPC1 was higher in GC tissues than in adjacent normal tissues and associated with poor prognosis. Knocking down GPC1 suppressed EMT and stemness which reduced metastasis in vivo and vitro by inhibiting Erk1/2 MAPK and FAK/Akt pathways. TGF-β stimulation significantly upregulated the expression of GPC1 whereas knocking down of GPC1 reversed TGF-β-mediated EMT and stemness. Moreover, we found that knocking down GPC1 could downregulate ITGB1 which was known to promote EMT in gastric cancer. Overexpression of ITGB1 counteracted the influence of knocking down GPC1 on EMT and stemness. Furthermore, GPC1 formed a complex with ITGB1, which indicated that the ability of GPC1 to stimulate EMT is ITGB1-dependent. Conclusions: We conclude that GPC1, through its interaction with ITGB1, plays an important role in regulating TGF-β-mediated EMT and stemness, and could be a potential future therapeutic target to prevent progression of gastric cancer.
A situation where hepatocellular carcinoma (HCC) may be more common in women than men: Clinical and genetic patterns of non risk-factored HCC.
Authors: El Dika Imane Hassan , Harding James J. , Capanu Marinela , Berger Michael F. , Rebibo Dafna , Rusek Matthew , Chou Joanne F. , O'Reilly Eileen Mary , Saltz Leonard , Abou-Alfa Ghassan K.
Published: September 2018

e15614

Background: Men are classically diagnosed with HCC three times more frequently than women. The gender difference persists after adjusting for confounding risk factors of viral hepatitis and alcoholic cirrhosis, presumably due to protective role of estrogens in women. In rare and unclear circumstances, HCC can arise in patients with no identified risk factor. Methods: Archival FFPE samples from patients with HCC and no underlying liver disease who consented to an IRB-approved protocol from 2014 onward were analyzed using the MSK-IMPACT platform, a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of > 400 key cancer genes. Tumor and matched normal libraries were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline. Demographic and treatment data was prospectively collected. Fisher’s exact tests were performed to look for associations between clinical characteristics and genetic alterations. Results: 16 patients were identified with 12 (75%) women affected versus 4 men only. Median age at diagnosis was 64 years. 5 (21%) patients had concomitant other malignancy, being melanoma, lymphoma, mesothelioma, rectal and prostate adenocarcinoma. 75% of patients underwent upfront surgery while only 12% presented with metastatic disease. Median number of genetic mutations was 4. Genetic sequencing did not reveal a specific molecular signature in this subgroup of patients; TERT and CTNNB1 were the most commonly mutated genes, found in 37% of cases. Median follow-up was 20 months and all patients were alive at last follow-up. Conclusions: In contrast to HCC in the general population, we found that HCC in the absence of risk factors is diagnosed more commonly in women than men in this small cohort. Patients in this cohort appear to live longer which can be attributed to normal underlying liver function or different disease biology. The pattern and number of genetic mutations reported herein are not different from those previously reported in risk-factored HCC. The study of a larger cohort of this non-previously defined non-risk factored HCC is warranted.
Benefit of second-line chemotherapy for advanced biliary tract cancer.
Authors: Moik Florian , Riedl Jakob M. , Winder Thomas , Bezan Angelika , Rossmann Christopher , Szkandera Joanna , Kasparek Anne-Katrin , Schaberl-Moser Renate , Pichler Martin , Stoger Herbert , Stotz Michael , Gerger Armin , Posch Florian
Published: September 2018

e15621

Background: Second-line chemotherapy (2LCTX) is increasingly applied in patients (pts) with advanced biliary tract cancer (aBTC), although no randomized trial has so far demonstrated the benefit of this intervention over best supportive care (BSC) alone. In the absence of randomized data, we thus conducted a comparative effectiveness analysis of survival outcomes in aBTC pts treated with BSC±2LCTX. Methods: In this single-center cohort study, we retrospectively included 80 pts with metastatic, recurrent, or inoperable aBTC who completed 1st-line CTX at our department between 2003 and 2016. Thirty-eight of these pts (48%) received 2LCTX+BSC (Fluoropyrimidine (FP) mono: n = 26 (68%), FP-based combination CTX: n = 9 (24%), Others: n = 3 (8%)). Primary endpoint was 18-month overall survival (OS). An inverse-probability-of-treatment-weighted analysis (IPTW) was implemented to rigorously account for imbalances in prognostic variables between the two study groups. Results: During a median follow-up of 14.8 months, we observed 49 deaths. Six-month, 12-month, and 18-month OS estimates were 77%, 53% and 23% in the BSC+2LCTX group, and 29%, 21%, and 14% in patients in the BSC group, for a univariable hazard ratio (HR) for OS of 0.36 (95%CI: 0.20-0.64, p = 0.001). However, pts receiving 2LCTX+BSC had a significantly higher prevalence of favorable prognostic variables, such as a higher Karnofsky Index (p = 0.0001), lower serum bilirubin (p = 0.03), higher hemoglobin (p = 0.002), and higher serum albumin (p = 0.0007). After careful adjustment for these imbalances using IPTW, 2LCTX+BSC was not associated with an OS benefit over BSC alone (Adjusted HR = 0.62, 95%CI: 0.30-1.29, p = 0.201). In IPTW analysis, 6-, 12-, and 18-month OS were 51%, 33% and 14% in the BSC+2LCTX group, and 35%, 29%, and 19% in patients in the BSC group. The beneficial association of 2LCTX with OS was highly time-dependent, with IPTW HRs of 0.07 (p = 0.002), 0.42 (p = 0.05), and 0.53 (p = 0.11) after 3, 6, and 12 months, respectively. Conclusions: Within the limitations of a non-randomized study, our data support the concept that 2LCTX is associated with a short-term OS benefit in pts with aBTC.
Immune cell surface proteins from tumor samples to predict patient clinical outcome.
Authors: Desai Jasmin Radhika , He Aiwu Ruth , Gusev Yuriy , Bhuvaneshwar Krithika , Smith Coleman , Kroemer Alexander H , Prins Petra
Published: September 2018

e15630

Background: The incidence and mortality of Hepatocellular carcinoma (HCC) are rapidly increasing in the US. Treatments for advanced HCC are limited despite best efforts to develop therapeutics that target the deregulated pathways of HCC. Recent studies reveal a direct causal relationship between cancer and immune dysfunction, whereby tumor cells and their microenvironment can evade immune attack by exploiting various immunoregulatory mechanisms in a process termed “cancer immune editing”. The objective is to determine the relationship between immune cell surface protein transcripts from tumor samples and the clinical outcome of pts by performing exploratory analyses of liver cancer data from the cancer genome atlas (TCGA). Methods: We analyzed RNAseq data from a cohort of 75 HCC samples in the TCGA collection. We explored the association of expression of a group of specific markers for infiltrating lymphocytes (several subtypes) with overall survival (OS) and these results were confirmed by IHC analysis of the same cell subtypes in HCC samples from patients at GUH. Results: Among the 75 HCC cases analyzed, 25 pts had Hepatitis C (HCV), 25 had Hepatitis B (HBV), and 25 had HCV and HBV co-infection. Fourteen of the 75 cases were found to express the CD8B isoform. The LOG RANK survival test showed a significant association between CD8B levels and OS (ChiSq = 5.2, 1df; p = 0.0222), as did the Cox proportional hazard model for survival. The latter test showed that pts with HCC that did not express CD8B were at a higher risk of death compared with those who had CD8B-expressing HCC. Additional immune cell subtype specific transcripts are being tested. Based on analysis of differentially expressed gene differences between immune cell subtype ‘low’ vs. ‘high’ groups, pathways highly relevant to lymphocyte signaling and immune response and infiltration were identified. Thus, 5 tumor-infiltrating immune cell subtypes were found to have wide variability among patients. Using IHC, these cell subtypes were assessed in HCC samples from patients and correlated to clinical outcome. Conclusions: Immune cell specific transcripts in tumor samples may serve as a predictor of response to treatments that target immune evasion in cancer patients.
Guidelines for management of urgent symptoms in cholangiocarcinoma (CC) patients (pts) with biliary stents or catheters using the modified RAND/UCLA Delphi process.
Authors: Iyer Renuka V. , Acquisto Susan G. , Bridgewater John A. , Choti Michael A. , Hong Theodore S. , Kis Bela , Mead Peter A , Roberts Lewis R. , Roberts Rebecca , Parikh Neehar D. , Sicklick Jason K. , Siegel Richard S. , Whisenant Jonathan R. , Cherepanov Dasha , Broder Michael , Valle Juan W.
Published: September 2018

e15641

Background: CC pts with biliary stents or catheters are prone to have obstruction/infection and studies show 20-40% present with fever/or jaundice requiring urgent treatment for which there is no uniform guideline. We aimed to develop an expert panel consensus on this topic using the modified RAND/UCLA Delphi process to rate treatment appropriateness. Methods: We recruited 13 physician experts from relevant specialty, geography, and practice settings. Patient scenarios were developed and panelists rated the therapies before and after a face-to-face discussion. The appropriateness of various therapies was rated on a 1-9 scale and classified as appropriate, inappropriate, or uncertain. Scenarios with > 2 ratings of 1-3 (inappropriate) and > 2 ratings of 7-9 (appropriate) were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists were from all US regions (92%) and the UK (8%); had practiced for a mean 16.5 years (4-33 years). Panelists rated 480 scenarios before the meeting, but re-rated only 288 clinical scenarios as they felt that ongoing treatment with chemotherapy did not influence decision-making. Disagreement decreased from 37.5% before the meeting to 10.4% after. Consensus statements are summarized in the table below. Conclusions: The Delphi process produced consensus guidelines to fill an unmet need in urgent management of ascending cholangitis in pts with CC. (Support: The Cholangiocarcinoma Foundation). [Table: see text]
Clinical and epidemiological features in 495 gastroenteropancreatic neuroendocrine patients in Mexico.
Authors: Medrano Guzman Rafael
Published: September 2018

e15687

Background: Data, incidence and/or prevalence about gastroenteropancreatic neuroendocrine tumors remains unknown in Mexico. Also there is no evidence about any Mexican multicenter study reporting information such as clinical presentation, diagnostic approach and treatment. The biggest problem is the lack of clinical and therapeutic management results so physicians can validate the proper patient protocols. Methods: To know the clinical, epidemiological and therapeutic characteristics of NET-GEP patients treated at the 5 biggest Concentration Mexican Medical Institutions.This paper was developed with the support of 5 Public Medical Institutions: Mexican Social Security Institute (IMSS), Institute for Social Security and Services for State Workers (ISSSTE), Secretary of the Mexican Navy, Petroleos Mexicanos (PEMEX), Ministry of Public Health 495 Patients from 6 hospitals where included: Oncology Hospital, CMN XXI Century, Hospital No. 25 25, Monterrey IMSS, National Cancer Institute (INCAN), National Medical Center November 20, Naval General Hospital of High Specialty and Private Institutions. This was a observational and retrospective academic paper . Results: :Of 495 patients, 59.7% (296) were women and 40.32% (200) were men, 26% of them had around 50 years old. Diagnosis symptoms included: abdominal pain 47.27% (234), gastrointestinal bleeding 18.58% (92) no-predominant symptoms 28.88% (143). Around 32.25% (160) had Carcinoid syndrome and 67.74% (336) were nonfunctioning. The predominant location was pancreas 33.27% (165) and stomach 28.02% (139). 36% resulted circumscribed neoplasia (179), features polypoid 26% (129) and infiltrative 15% (73). The size was > 2cm in 49% (242) > 1-2cm: 36% (180) 0.5 to 1 cm 9% (45) < 0.5 cm 6% (29). Grade: GI 64% (316), GII 13% (66), GIII 23% (114). Metastasis positive ganglioanres (6%) (31), negative (94%) (465). Only seven cases extra nodal metastases (liver (3), lung (2), spleen (2)) Conclusions:This is the first multi-center study in Mexico. Which reflects the clinical characteristics of the NET_GET. The results differ in their epidemiology from that reported in other countries. However, the clinical and therapeutic results are very similar.
Capecitabine and temozolomide (CAPTEM) in neuroendocrine tumor of unknown primary.
Authors: Chauhan Aman , Raajasekar Arun Kumar Arumugam , Myint Zin , Murray Leaundra , Anthony Lowell Brian
Published: September 2018

e15691

Background: Better diagnostics, recognition and knowledge of neuroendocrine tumors (NETs) have led to consistent growth in incidence and prevalence of the disease. Being an orphan disease, therapeutic options are limited. Scarce data exists regarding use of Capecitabine and Temozolomide (CAPTEM) in neuroendocrine tumors. There are no published data on use of CAPTEM in neuroendocrine tumors of unknown primary. NETs of unknown primary accounts for 10-15 % of NETs. Historically NETs with unknown primary are thought to be relatively aggressive, conferring a poorer prognosis. Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012-2016). Patients treated with CAPTEM regimen were analyzed for radiological response in first scan, time to progression on treatment and toxicity. IRB approval was obtained. Results: 56 patients with neuroendocrine tumors of unknown primary were identified. 12 patients were treated with CAPTEM. Median age of study cohort was 62 years. 6/12 were females. Seven patients were grade II, 4 were grade III and only one was grade I NET. CAPTEM was used as front line systemic therapy in 9 patients. Mean duration of treatment before progression was 10.8 months. 6 patients showed reduction in metastatic tumor volume at first q 3 monthly CT scan. 3 patients had stable disease and 3 patients showed disease progression at first surveillance scan. Following were the rates of common side-effects. Grade 2 thrombocytopenia (n = 4), Grade 1 lymphocytopenia (n = 3), hand/foot syndrome Grade 1 (n = 1), Grade 3(n = 1), Fatigue, Grade 1 (n = 6) Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.
Role of 92 gene cancer classifier assay in neuroendocrine tumor of unknown primary.
Authors: Chauhan Aman , Murray Leaundra , Raajasekar Arun Kumar Arumugam , Myint Zin , Anthony Lowell Brian
Published: September 2018

e15696

Background: Neuroendocrine tumor of unknown primary constitutes about 10-15 % of all neuroendocrine tumors. Identification of primary site can helps alter the management. Sunitinib is FDA approved for management of pancreatic neuroendocrine tumors, everolimus is approved for gastroenteropancreatic and bronchial NETs, immune checkpoint inhibitors are active in Merkel cell carcinoma and MIBG treatment is standard of care for pheochromocytoma. Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012-2016). Patient who underwent 92-gene reverse transcriptase polymerase chain reaction cancer classification assay (BioTheranostics Tissue Type ID) were analyzed. IRB approval was obtained. Results: 56 patients with neuroendocrine tumors with unknown primary were identified. Median age of cohort was 61 years. 28/56 patients were males. 92 gene cancer ID assay was used in 38 out of 56 patients. Primary site of tumor was identified with > 95% certainty in 36 out of 38 patients. The test reported pancreatic NET as the primary site for 10 patients, gastrointestinal NETs for 14 patients, bronchial carcinoid for 5, large call NEC for 3, Merkel cell carcinoma for two and pheochromocytoma in one patient. Conclusions: Tissue type ID was able to identify a primary site in NETs of unknown primary in majority (94.7%) of cases. The result had direct implication in management of patients with regards to FDA approved treatment options in 13/38 patients (pNETs, merkel cell and pheochromocytoma).
Molecular classification of neuroendocrine tumors: Clinical experience with the 92-gene assay in >24,000 cases.
Authors: Hendifar Andrew Eugene , Soifer Harris S , Israel Mason , Schnabel Catherine A.
Published: September 2018

e15700

Background: Histological diagnosis of metastatic neuroendocrine tumors (NET) can be straightforward, but identification of the specific NET tumor type/subtype is often challenging based on morphology alone. Accurate identification of tumor type/subtype in NETs of unknown primary has implications for grading, staging, and treatment decision-making as availability of targeted therapies increases. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes (including 7 NET subtypes) for patients with unknown/uncertain diagnoses. In this study, 92-gene assay results from cases submitted for clinical testing with molecular diagnoses of NET were evaluated. Methods: A de-identified database was created under an IRB approved protocol that contains clinical and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay with sufficient tissue for testing. In this analysis, patient demographics and distribution of molecular diagnoses were analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups. Results: Analysis included 24,484 patients. Median age was 65y (51% female). The 92-gene assay rendered a molecular diagnosis of NET in 6.3% of cases (n = 1551). Small/large cell lung carcinoma (50%) was the most common NET molecular diagnosis, followed by GI carcinoid (14%), islet cell (14%), Merkel cell (10%), and lung carcinoid (9%). In liver biopsies (39% of cases), all 7 NET subtypes were identified by the 92-gene assay. The proportion of molecular diagnoses classified as small/large cell lung NET increased with age, from 25% in < 40y to 45% in 40-65y and 55% in > 65y, and the proportion of islet cell NET decreased with age (p < 0.0001). Men had a higher proportion of molecular diagnoses that were small/large cell lung NET (53%) vs women (46%; p < 0.0001). Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.