bluuebunny/crossref_metadata_2025 huggingface dataset:
Gefitinb along with methotrexate as palliative therapy in PS 3 and above in metastatic esophagus squamous cell carcinoma with focus on Q-TWIST.
Authors: DUSI VIDYA SAGAR , C Obul Reddy , Attili Suresh VS , Palanki Satya Dattatreya
Published: February 2020

355

Background: Metronomic therapy is proven method for treatment of terminally ill patients with malignancy, who are not fit for chemotherapy. The median PFS was significantly superior in responders in previous Indian experiences. However most of them were done in head and neck cancers.The prognosis of patients with metastatic esophageal cancer remains poor with only option being symptomatic care. As the previous experiences show metronomic therapy is safe among various options and there is no study focusing on Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) in southern Indian population,we thought of evaluating the same. Methods: Details of 42 subjects with refractory or progressive metastatic squamous cell carcinoma esophagus having PS > 2 were evaluated. Case records between 2017 September and 2018 September were analyzed for TWIST and QOL. Patients received Gefitinib (250 mg/day), Methotrexate 15 mg IM weekly or in combination. Patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy based on physician/ patient preference. Metronomic therapy could be continued beyond disease progression- if there is TWIST/QOL improvement. Results: Out of 42 subjects, 29 had improvement in the PS and were continued later. 9 had stable PS and disease. 4 had worsening of PS. 34 subjects have clinically meaningful response (stable disease + complete + partial responses) and had symptomatic improvement. The median number of cycles was 6 (4–11). The median PFS was 198 days (95% CI, 174 to 214), and the median improvement in QOL was 6 points on a scale of 25. Grade II/IV toxicities were observed in 21 (50%) cases predominantly skin rash, stomatitis and diarrhea. Conclusions: Metronomic therapy is well tolerated and may have a role in the treatment of advanced cancers with poor performance status. 67% of the patients who are otherwise not eligible for any active therapy became eligible and had better QOL and longer PFS, which re-emphasizes role of metronomic therapy in advanced squamous cell carcinoma of esophagus.
Hyperprogressive disease during nivolumab chemotherapy in metastatic gastric cancer: Multicenter retrospective study in Japan.
Authors: Suzuki Takeshi , Aoki Masahiko , Shirasu Hiromichi , Takahashi Naoki , Nakatsuka Rie , Ando Takayuki , Kito Yosuke , Yamamoto Yoshiyuki , Kawakami Kentaro , Matsumoto Toshihiko , Shimozaki Keitaro , Nagase Michitaka , Yamaguchi Toshifumi , Negoro Yuji , Tamura Takao , Amanuma Yusuke , Esaki Taito , Miura Yuji , Nagashima Kengo , Boku Narikazu
Published: February 2020

377

Background: Nivolumab has demonstrated a survival benefit for advanced gastric cancer (AGC). However, hyperprogressive disease (HPD) has been reported in various cancers. Methods: The subjects of this retrospective study were AGC patients with measurable disease who received nivolumab, and their tumors were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. Tumor growth rates (TGR) during nivolumab were compared to those during prior therapy as reported (Champiat S, 2017). HPD was defined as an increase in TGR > 2-fold. Results: 218 patients were identified as the subjects. While 33 (15.1%) partial response (PR) were achieved, 130 patients (59.6%) showed progression disease (PD), 38 of whom were classified as HPD (17.4%) and 2 patients showed pseudo progression (1.0%). The median progression-free survival (PFS) was 1.9 months (95% CI: 1.9–2.4) and the median overall survival (OS) was 8.5 months (95% CI: 7.1–9.6) in all patients. While patients with PD showed shorter prognosis compared with non-PD patients (median PFS: 1.5 months vs 6.4 months, hazard ratio; 6.0 [95% CI: 4.3–8.4]; p < 0.0001; median OS: 4.7 months vs not reached, hazard ratio; 4.1 [95% CI: 2.8–6.3]; p < 0.0001), there were no differences either in PFS or OS between patients with HPD and those with PD other than HPD (median PFS: 1.5 months vs 1.6 months, hazard ratio; 1.3 [95% CI: 0.9–2.0]; p = 0.1194; median OS: 5.0 months vs 4.6 months, hazard ratio; 1.0 [95% CI: 0.6–1.5]; p = 0.8695). Histological type, liver metastases, carbohydrate antigen 19-9 (CA19-9) level were associated with HPD. Conclusions: HPD was observed 17.4% in AGC patients treated with nivolumab. There were no differences either in PFS or OS between patients with HPD and those with PD other than HPD. Clinicopathological characteristics might be a predict factor for HPD.
Palliative systemic chemotherapy with or without pressurized intraperitoneal aerosol chemotherapy with cisplatin and doxorubicin (PIPAC C/D) for gastric cancer with peritoneal metastasis: A propensity score analysis.
Authors: Khomiakov Vladimir , Meisner Christoph , Ryabov Andrey , Bolotina Larisa , Utkina Anna , Kolobaev Ilia , Sobolev Dmitry , Chayka Anna
Published: February 2020

380

Background: Gastric cancer (GC) with peritoneal metastasis (PM) has a dismal prognosis. Palliative systemic chemotherapy (SC), usually doublet combinations of platinum and fluoropyrimidines, is the standard of care. Pressurized IntraPeritoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin (PIPAC C/D) yields promising results. Here we aimed to compare overall survival (OS) between SC + PIPAC C/D vs. SC alone in patients with PM from GC. Methods: Prospective cohort of 95 consecutive patients with PM from GC treated in palliative intent at our institution from 2010 to 2018. Of these patients, 69 received SC + PIPAC C/D („PIPAC“), 26 SC alone („control“). Choice of treatment was not dictated by medical criteria, but by (non-) availability of the single-use medical devices needed for PIPAC in Russia. All patients received doublet or triplet chemotherapy with platinum together with fluoropyrimidines or capecitabin. A Cox proportional hazard model based on propensity score (PS) was used to assess the effect of PIPAC on OS and account for confounding factors. Results: The HR adjusted for PS for PIPAC vs. control was 0.396 (CI 5- 95% = 0.224-0.700, p-value 0.001). In the simple (unadjusted) Kaplan-Meier, median survival in the control group was 7.0 months (CI: 4.51 - 9.49) and in the PIPAC group 14.0 months (CI: 11.46-16.54). In the control group, all 26 patients died after 1-25 months. In the PIPAC group, 36 of 69 patients died after 4 to 20 months. The longest observed survival time in the PIPAC group was 27 months. Significance for the log-rank test after Mantel-Cox (not adjusted) was p < 0.0001. Conclusions: Compared with SC alone, intensified chemotherapy combining PIPAC C/D and SC doubled OS. These promising results need to be confirmed in a randomized trial.
Magnetic marking clip for easier laparoscopic localization of small gastrointestinal tumors.
Authors: Kim Sang Hoon , Keum Bora , Jeon Han Jo , Jang Se Hyun , Lee Kang Won , Kim Sanghyun , Choi Seong ji , Lee Jae Min , Choi Hyuk Soon , Kim Eun Sun , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck
Published: February 2020

386

Background: Laparoscopic surgery for gastrointestinal tumors requires fast and precise tumor localization. As tumor palpation is not possible during laparoscopic surgery, tumor identification is often difficult for some cases. Despite various methods, such as tattooing or endo-clipping, have been introduced for the localization of tumors, these methods own clear limitations. To overcome the drawbacks of these conventional marking methods, we designed a magnetic marking device linked to an endo-clip(MMC, Magnetic Marking Clip) for endoscopy. We performed preoperative endoscopic clipping with MMC and analyzed the intraoperative localization efficacy and safety during laparoscopic surgery. Methods: Study enrolled 30 patients with gastric and colorectal neoplasms scheduled to undergo endoscopic clipping before laparoscopic surgery at the Korea University Medical Center, Korea, between August 2017 and June 2019. A silicone-coated high-power neodymium marking device (ring or rod type) was fixed together with an endo-clip and applied on the center of the lesion during preoperative endoscopy. During laparoscopic surgery, a detecting magnetic body was inserted through a laparoscopic trocar and was used to localize the tumor that is marked with MMC. The time needed for endoscopists to place MMC at the lesion, laparoscopic clip detection time and success rate were studied. Results: Endoscopists placed MMC within 30 seconds. It was possible to find MMC in all cases of laparoscopic surgery. Time needed to find the MMC laparoscopically was relatively shorter than the time conventionally taken just with an endo-clip itself. There was no reported dislodgement of the clip before the surgery or any other adverse events associated with the MMC procedure. Conclusions: The MMC method enabled simple and fast tumor localization and showed excellent outcomes in efficacy of tumor localization. The MMC method may help surgeons localize GI tumor lesions easily and safely during laparoscopic surgery.
Real-world efficacy and biomarker of nivolumab for advanced gastric cancer.
Authors: Kawabata Ryohei , Kurokawa Yukinori , Hagi Takaomi , Omori Takeshi , Matsuyama Jin , Fujitani Kazumasa , Hirao Motohiro , Akamaru Yusuke , Takahashi Tsuyoshi , Yamasaki Makoto , Satoh Taroh , Doki Yuichiro
Published: February 2020

388

Background: Although nivolumab demonstrated survival benefit and a manageable safety profile in previously-treated advanced gastric cancer in a phase III trial (ATTRACTION-2), the efficacy of nivolumab in real-world and predictive factors of responses to nivolumab for advanced gastric cancer remain unclear. We evaluated the efficacy of nivolumab and compared clinicopathological characteristics with responses to nivolumab and long-term survivals in patients with gastric cancer. Methods: 205 patients with unresectable or recurrent gastric cancer who were treated with nivolumab as 3rd or more line treatment were enrolled from 23 institutions. Tissue specimens were collected in 199 patients. PD-L1 expression of tumor specimens defined as tumor positive score (TPS) and combined positive score (CPS) and mismatch repair (MMR) were analyzed by immunohistochemistry. Tumor responses were assessed according to RECIST version 1.1. Hyper progressive disease (HPD) was defined as ≥two folds increase in tumor growth rate. Results: 138 out of 205 enrolled patients had measurable lesions. Response rate and HPD rate were 16.7% (23/138) and 22.0% (29/132), respectively. Response rate was significantly higher in patients with performance status (PS) 0-1, non-peritoneal diseases, CPS ≥10, and MMR deficient patients. On the other hand, PS 2-3 and liver metastases were predictive factors of HPD. Patients with CPS≥10 and MMR deficiency showed significantly better progression-free (P = 0.005, P = 0.001) and overall survivals (P = 0.005, P = 0.002). TPS showed no significant association with any outcomes. Conclusions: Real-world efficacy of nivolumab was shown in previously-treated advanced gastric cancer. CPS and MMR could be the useful biomarkers for the efficacy of nivolumab treatment as well as PS and metastasis site. Clinical trial information: UMIN000032164.
Retrospective analysis for efficacy and safety of nivolumab in advanced gastric cancer patients (pts) with malignant ascites.
Authors: Sugaya Akinori , Ueyama Shunsuke , Suzuki Hirosumi , Yamada Takeshi , Yamamoto Yoshiyuki , Moriwaki Toshikazu , Hyodo Ichinosuke
Published: February 2020

392

Background: Nivolumab is a standard of care as the later-line therapy for advanced gastric cancer. However, there are few data about efficacy and safety of nivolumab for pts with malignant ascites. Methods: We conducted a multicenter retrospective study for pts with advanced gastric cancer who received nivolumab alone from Oct. 2017 to Feb. 2019. Pts were divided into two groups; high ascites burden (HAB) with moderate or massive ascites and non-HAB with none or a small amount of localized ascites at pelvis and/or liver surface. Results: A total of 72 pts (23 pts with HAB and 49 pts with non-HAB) were evaluable. The HAB group had more pts with young (median 62 vs 70 years), female (35 vs 14 %), no prior gastrectomy (63 vs 35 %) and poor performance status (PS > 1; 26 vs 10 %), compared to the non-HAB group. Disease control rate was 44% (95% CI 23-64%) in the HAB group and 57% (95% CI 43-71%) in the non-HAB group. Ascites decreased in 4 pts (17%) and completely disappeared in 2 pts (8.7%) in the HAB group. These 6 pts were all male and had prior ramucirumab treatment with a mean neutrophil-lymphocyte ratio 2.1 (from 0.85 to 3.7) at the initiation of nivolumab. After 5 months of follow up period, disease progression or death events for progression-free survival (PFS) occurred in 74% of the HAB group and 53% of the non-HAB group. Median PFS was 1.0 (95%CI 0.5-1.5) and 2.6 (95%CI 0.9-7.4) months in pts with HAB and non-HAB, respectively. PFS rates at 6 months were 31% in the HAB group and 33% in the non-HAB group. Immune-related adverse events occurred in 26% of the HAB group and 16% of the non-HAB group including one and two pts with grade 3 or 4 events, respectively. There was no treatment-related death in both groups. Conclusions: Although pts with HAB showed trends of worse outcomes compared with those with non-HAB, nivolumab was suggested to provide a survival benefit to some pts with HAB, and was tolerable in the HAB group.
Propensity score regression analysis of esophageal cancer treatment with surgery alone or neoadjuvant chemotherapy.
Authors: Lewis Wyn Griffith , Powell Arfon GMT , Christian Adam
Published: February 2020

405

Background: The aim of this study was to examine the outcomes of oesophageal adenocarcinoma (OC) treatment with either surgery alone (S), or with neoadjuvant chemotherapy (NAC) followed by surgery (NACS), by means of propensity score (PS) regression analysis, in order to examine whether the benefits reported in the MRC OE02 trial were reproducible in UK cancer network clinical practice. Methods: Consecutive patients undergoing potentially curative treatment for OC in a regional cancer network were studied. Multiple regression models, including PS were developed to account for confounding factors and the primary outcome measure was disease-free (DFS) and overall survival (OS). Results: A cohort of 440 patients was included in a regression analysis controlling for confounders (176 S, 264 NACS). NACS was associated with positive margin status (NACS vs. S, 42.4% vs. 26.7%, p<0.05), poor 5-year DFS (32.1% vs. 56.9, p<0.001), and poor 5-year OS (27.5% vs. 47.3%, p<0.001). On regression adjustment based on propensity scores, NACS was not associated with DFS (p=0.220) or OS (p=0.431). Mandard tumour regression grade (TRG) was significantly associated with DFS (hazard ratio (HR) 0.21,95% CI 0.07-0.70) and OS (HR 0.27 (95% CI 0.13-0.59). Five-year DFS and OS related to TRG was 63.6 and 61.5% vs. 8.0 and 8.6% (p<0.001) for good and poor responders respectively. Conclusions: Prescribing NAC to all OC patients risks delay in effective treatment of patients who are relatively chemo-resistant, given the variabilityin pathological response. Identifying OC patients who derive the most NAC benefit should be the focus.
Neoadjuvant chemotherapy (TPF regimen) followed with robotic surgery and its impact on outcome in management of esophageal cancers: Indian experience.
Authors: Somashekhar S.P. , C. Rohit Kumar , Rajgopal Ashwin K. , Rauthan Amit , Patil Poonam
Published: February 2020

407

Background: Neo-adjuvant chemotherapy coupled with robotic three stage esophagectomy have shown promising results in esophageal cancer. Methods: 136 patients diagnosed with squamous cell cancer esophagus were included to analyze the benefit of NACT with DCF (docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1, 5-FU 750mg/m2 per day 1-4) regimen 3 cycles followed by three stage robotic esophagectomy. Esophagus, assessed by EUS and PET-CT scan, pre-chemo and post-chemo, in biopsy proven Squamous cell Carcinoma Oesophagus. All the data pertaining to chemotherapy and surgery were prospectively maintained in a data base. Results: Median age 62.7 years, male to female 5.9:4.1. T2 4%, T3 90% & T4 6%. N0 10% & N+90%. Post NACT, Partial response of 50.8%, and a complete pathological response of 27.6% was observed with response rate of 66.3%. 20 pts. had mucositis, but none had grade 3 toxicity, neutropenia in 24 pts. and febrile neutropenia in 7 pt., vomiting and fatigue in 35 pts. Mean blood loss 256.5±85.8ml, duration of surgery 322.4±28.4min, ICU stay 1.5±0.8-day, hospital stay 10.5±2.1 day. Proximal and distal margin was negative for all whereas only 2 patients had a positive CRM. Mean Lymph node yield was 22.4±3.5 nodes. All patients had complete robotic surgery with no conversions and major intraoperative complication. Post-operatively Minor complication was noted in 5 patients temporary vocal cord palsy, 10 delayed gastric emptying, wound infection in 3 and minor lung infection 9. Major complication in form of leak (3), stenosis (5), chylous leak (4) was noted. 30-day mortality 4.5%. With the longest follow up of 50 months, 3 year DFS and OS was 75.4% & 68% respectively. Conclusions: Neoadjuvant chemotheraphy with TPF regimen showed excellent response rates with minimal G3 toxicity and is well tolerated in Indian patients. Combination of NACT with robotic esophagectomy has excellent outcome with low morbidity & mortality.
Gene mutations distinguishing gastric from colorectal and esophageal adenocarcinomas.
Authors: Hoang Tuyen , Hiyama Darryl , Dayyani Farshid
Published: February 2020

424

Background: Genetic analysis of gastrointestinal malignancies shows a great number of mutations. Most mutations found in gastric tumors are found in colorectal and esophageal tumors, and vice versa. The challenge remains to identify mutations that distinguish gastric from colorectal and esophageal cancers. Using open-access cancer genomics data, we sought to identify mutations that accounted for the unique phenotypic features of gastric tumors. Methods: Thirteen cancer genomics datasets with demographic, clinical, and genetic variables were analyzed. Each subject was flagged with or without a mutated gene. For each anatomical location, pathologic stage and histology were compared between subjects with and without a specific mutated gene, using two-sample t tests, adjusted for multiple gene testing. Results: Analysis included 1,915 subjects with valid pathologic stage and histology. Mean age was 68 years (SD=10). About 54% were female. The most common race was Caucasian (37%) while minorities were rare with high rate of missing data (44%). Pathologic stage: 20% stage I, 35% stage II, 31% stage III, and 14% stage IV. Anatomical location: 29.5% gastric, 59.5% colorectal, and 11.0% esophageal. Histology of gastric cancer: 61.4% intestinal, 23.2% diffuse, 14.9% others, and 0.5% missing. One gene–HEATR7B2–though rarely mutated, occurred only in stage IV of gastric tumors. Two mutated genes–CDH1, RHOA–distinguished diffuse from intestinal gastric histology. One mutated gene–CDH1–distinguished gastric from colorectal and esophageal tumors. Conclusions: This study confirmed the genes involved in the pathogenesis of gastric malignancies (CDH1, RHOA) and linked one novel gene to stage IV of gastric tumors (HEATR7B2). Future animal and human epidemiologic studies are needed to elucidate how this novel gene contributes to gastric malignancies.
Slug overexpression and association with clinicopathological features in gastric cancer.
Authors: Kim Joori , Kim In-Ho , Lee Han Hee , Lee Sung Hak , PARK Jae Myung
Published: February 2020

426

Background: Slug is a suppressive transcriptional factor of E-cadherin, acting as an activator of epithelial-mesenchymal transition(EMT). Its clinical relevance in gastric cancer(GC) is not fully known. Methods: Our study evaluated the expression patterns of EMT and cancer stem cell markers in GC patients who had clinical stage 2-3, underwent gastrectomy, D2 lymph node dissection (LND), adjuvant chemotherapy. Immunohistochemistry of E-cadherin, vimentin, CD133, ABCG2, NEDD9, SMAD4, XB130, Slug, Snail were investigated from 210 gastric cancer samples using tissue microarrays. The correlation between each markers expressed and the association with clinicopathological factors were analyzed. Results: Slug expression was more frequent in stage 3 than stage 2 (p=0.000), advanced T (p=0.007) and N stage (p=0.001), while histologic type did not make difference. Slug expression correlated with the expression of cancer stem cell marker CD133 (r=0.180, p=0.015) and CD133 expression was also related with ABCG2 (r=0.412, p=0.000). High Slug group showed shorter overall survival, compared to low Slug group (median OS 134 vs 124 months, p=0.044). The 2-year and 5-year disease-free (DF) rate for patients with high Slug and low Slug was 87.1% and 79.8%, 68.1% and 79.8%, respectively(p=0.038). The DFS curve reached an earlier plateau at 11-month in low Slug group, while in high Slug group took as long as 99 months. A multivariate analysis using the Cox proportional hazards regression model demonstrated Slug to be an independent prognostic factor for overall survival; hazard ratio 0.504 [95% CI 0.278-0.916] (p=0.025). Conclusions: In stage 2-3 GC patients who underwent gastrectomy with D2 LND and adjuvant chemotherapy, high Slug expression is associated with better disease-free and overall survival. Patients may benefit by testing Slug immunohistochemistry to predict prognosis after gastrectomy.
Correlation of radiomics of metastatic lesions in gastroesophageal adenocarcinoma (GEA) with tumoral DKK1 mRNA expression and other immune biomarkers in patients (pts) treated with DKN-01.
Authors: Sirard Cynthia A. , Klempner Samuel J. , Naik Girish S. , Kagey Michael , Nolte Zak , Hindosh Ziad , Burkett Andre , Korn Ronald Lee
Published: February 2020

429

Background: Dickkopf-1 (DKK1) modulates Wnt and PI3K/AKT signaling pathways and contributes to an immune suppressive tumor microenvironment. Recently, anti-DKK1 antibody (DKN-01) [D] plus pembrolizumab (P) in GEA tumors has demonstrated clinical activity. Radiomic Quantitative Texture Analysis (QTA) is a non-invasive method for imaging biomarker discovery that can predict molecular drivers of cancer from CT scans obtained during clinical trials. QTA may be a useful tool for predicting DKK1 expression and other immune biomarkers in metastatic lesions from GEA pts treated with DKN-01. Methods: 13 pts with GEA (12 M; 1F; age 37-81) enrolled in D+P Phase I/II trial with high vs low DKK1 RNA Scope H-Scores (H Score > 35; n = 6 vs H-Score < 35; n = 7) were identified. Metastatic Target lesions (TLs) from baseline CTs with IV contrast underwent additional QTA analysis (TexRAD, CE mark, Essex, UK) after RECIST analysis. ROIs were placed on the TLs and histogram frequency curves (HFC) of the metastatic tumor pixels were generated. First order tumor HFC statistical results (i.e. mean, Standard Deviation-SD, Skewness, Kurtosis, MPP) were correlated with tumoral DKK1 mRNA expression, baseline plasma DKK1 levels and other biomarkers (PD-L1 CPS and MDSCs) along with tumor shrinkage using Pearson’s r correlation (significance p < 0.05). Results: Tumor derived QTA parameter (QTA SD) of the largest metastatic TL from each subject was positively correlated with DKK1 RNAscope H-score (r = 0.661, p value = .014) meaning larger SD texture scores had greater DKK1 expression. Also, tumor derived QTA parameter (QTA MPP) was correlated with baseline plasma DKK1 (r = -0.461, p = 0.005). Finally, QTA SD was correlated with PD-L1 expression (r = 0.630, p = 0.028) and TL shrinkage (r = -0.590, p = 0.034). Conclusions: Radiomics of GEA tumor metastasis using QTA showed significant correlations between tumor texture, tumor DKK1 mRNA expression and baseline plasma DKK1 suggesting that tumor textures may provide a non-invasive tool for assessing DKK1. Although promising as a imaging biomarker, further studies are required to validate these findings. Clinical trial information: NCT02013154.
Effect of proton pump inhibitors on the occurrence and development of gastric cancer and the polarization of macrophages in the microenvironment to M2-type.
Authors: Lu Xiao-Qing , Zhang Shengxiao , Zhang Huan-Hu
Published: February 2020

437

Background: Long-term use of Proton pump inhibitors was associated with an increased gastric cancer(GC) risk in subjects even after HP eradication therapy. In contrast some basic research showed that PPI inhibited the growth of GC. In the tumor-microenvironment (TME), macrophages that are recruited around the tumor are activated to form the tumor-associated macrophages (TAMs), which are the most abundant mononuclear cells in the tumor infiltrating leukocytes. Many studies have shown that TAMs are associated with poor prognosis of tumors. Methods: Immunohistochemistry was used to detect the phenotype of macrophages in patients with gastric cancer treated with PPI or without PPI. Transcriptomics sequencing analyzed the signal pathways that were highly expressed in PPI-treated gastric cancer for further exploring the mechanism of PPI's main role in gastric cancer cells. In vitro, explore the effects of PPI on gastric cancer cells and the next step on macrophages. The effects of PPI on the growth of gastric cancer and the degree of infiltration and phenotype transformation of macrophages were verified by in vivo experiments. Results: In the gastric cancer tissues treated with PPI, the macrophage phenotype is mostly M2 type, thereby exerting a cancer promoting effects. Transcriptome results showed high expression of genes associated with endoplasmic reticulum stress in gastric cancer tissues after PPI treatment, compared with patients who were not treated with PPI. Among them, GRP78 is a classic marker of endoplasmic reticulum stress. It was not only highly expressed in gastric cancer treated by PPI, but also acted on macrophages through exosomes secreted by gastric cancer cells, and caused macrophage to polarize to M2. Conclusions: PPI caused GC cells to overexpress GRP78 which was secrete into the microenvironment through exosomes, thereby transforming macrophages into M2 type under the action of GRP78. Finally M2 type macrophages promoted the progression of gastric cancer.
Association of ascitic neutrophil to lymphocyte ratio with prognosis in patients with advanced gastric cancer
Authors: Kim Jae-Joon , Oh So Yeon , Park Kwonoh , Oh Sang-Bo
Published: February 2020

443

Background: Approximately 40% of metastatic gastric cancer patients develop peritoneal carcinomatosis, and this condition leads patients to grave prognosis. Blood neutrophil to lymphocyte ratio (NLR) is associated with prognosis in various solid tumors, such as non-small cell lung cancer, colorectal cancer, and gastric cancer. We performed this study to investigate the prognostic significance of NLR of ascitic fluid. Methods: This is retrospective study. Patients were consecutive included if they; 1) had histologically confirmed gastric adenocarcinoma, poorly cohesive carcinoma, or poorly differentiated carcinoma, 2) were relapsed after curative resection or initially metastatic, 3) had ascites due to peritoneal metastases of gastric cancer, 4) had received paracentesis at least once and the result of ascites exam is available. Patients with clinically active infection in the time of paracentesis is excluded. If multiple times of paracentesis was done, we used initial result. Results: From March 2012 to August 2018, total 157 patients who were visited in Pusan National University Yangsan Hospital met the inclusion criteria. Median age is 58 (29-86) years and male patients was 63% (n = 99). In 38.9% (n = 61) patients, gastric cancer was diagnosed in primary site and in ascites synchronously. At the time of first paracentesis, 47.1% (n = 74) of patients had already been received palliative chemotherapy due to metastatic gastric cancer. In the ascites, mean and median NLR is 2.2±6.8 and 0.3 (0-65). All except 3 patients were expired, and the median survival time form paracentesis was 47 (95% confidence interval 38.6-55.4) days. In the Kaplan-Meier survival analysis, patients with higher NLR (≥0.33) have shorter survival from paracentesis (39 days, 95% CI 32.5-45.4) in compared to lower NLR ( < 0.33) (61 days, 95% CI 29.4-92.6, log-rank p = 0.011). In the additional analyses, higher neutrophil count (41 vs 72 days, p = 0.045) and lower protein level (32 vs 61 days, p = 0.018) of ascites are also poor prognostic factor. Conclusions: High NLR of malignant ascites is poor prognostic factor in patients with gastric cancer. The role of neutrophil in the malignant ascites should be tested in a new perspective.
Predictive value of the modified systemic inflammation score in patients undergoing curative resection of squamous cell carcinoma of the esophagus.
Authors: Kanda Mitsuro , Koike Masahiko , Shimizu Dai , Tanaka Chie , Kobayashi Daisuke , Sonohara Fuminori , Takami Hideki , Inokawa Yoshikuni , Hattori Norifumi , Hayashi Masamichi , Yamada Suguru , Nakayama Goro , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2020

447

Background: Inflammation plays a critical role in the development and progression of cancers. Here we aimed to evaluate the clinical significance of the preoperative modified systemic inflammation score (mSIS) to predict long-term outcomes of patients with esophageal squamous cell carcinoma (ESCC). Methods: We included 443 patients who underwent curative resection of ESCC. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥4.0 g/dL and LMR ≥3.4), mSIS 1 (ALB < 4.0 g/dL or LMR < 3.4), and mSIS 2 ( ALB < 4.0 g/dL and LMR < 3.4). Results: Patients were categorized into preoperative mSIS 0 (n = 165), mSIS 1 (n = 183), and mSIS 2 (n = 95) groups. Preoperative mSIS was significantly associated with age, preoperative body mass index, and pathological disease stage. The disease-specific survival times of patients in preoperative mSIS 0, 1, and 2 sequentially shortened ( P = 0.009), and mSIS 2 was identified as an independent prognostic factor (hazard ratio 2.63, 95% confidence interval 1.33–5.27, P = 0.0053). In most patient subgroups, the mSIS was associated with greater risk of disease-specific death. A stepwise increase in the prevalence of hematogenous recurrences was directly proportion to the mSIS. When patients were subdivided by mSIS before neoadjuvant treatment, there were no significant differences in disease-specific survival. Conclusions: Our findings demonstrate that the preoperative mSIS may serve as a powerful prognosticator of ESCC that definitively stratifies clinical outcomes as well as a tool for selecting treatment strategies.
Tissue levels of steroid hormones and their receptors, prolactin, and SHBG in patients with gastric cancer.
Authors: Kit Oleg Ivanovich , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S.
Published: February 2020

448

Background: Hormones and their receptors are important effectors providing interconnection between the primary tumor and metastatic niches. The aim of the study was to determine levels of steroid hormones and their receptors, prolactin (PRL) and SSBG in tissues of gastric cancer (GC), omentum and peritoneum. Methods: Levels of steroid hormones and their receptors, PRL and SSBG were determined by ELISA in tissues of primary tumors, omentum and peritoneum in main groups: 1 (M0) – GC T3-4аN0-3M0 (n = 24) and 2 (M1) – GC T3-4аN0-3M1 (n = 21); in tissues of the stomach, omentum and peritoneum – in the control group (non-cancer patients, n = 17). Results: In GC (М1), estradiol was reduced in primary tumors, omentum and peritoneum by 4.2, 4.0 and 8.6 times, respectively; increased levels of free testosterone (by 18.9, 2.0 and 2.8 times) and PRL (by 8.0, 7.6 and 1.7 times) were observed (p < 0.05). GC (М0) was characterized by high levels of estrogen receptors (ER) α – by 1.2 times (p < 0.05), progesterone (PR) – by 3.5 times and SSBG – by 1.4 times (p < 0.05); tissues of the omentum and peritoneum showed increased levels of ERα – by 2.4 and 3.9 times, ERβ – by 1.5 (p < 0.05) and 2.5 times, РR – by 2.2 and 1.5 times (p < 0.05). GC (М1) had low ERα levels. Conclusions: Decreased levels of estradiol, together with elevated levels of free testosterone and prolactin, in tumor tissues can be considered marking for peritoneal metastases. Correlation between the content of these hormones in the omentum and peritoneum and the presence of metastasis in the organs confirms the “seed and soil” principle.
The comparisons of the outcomes between surgical resection and proton beam therapy for single primary hepatocellular carcinoma.
Authors: Tamura Shunsuke , Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ogi Katsuhisa , Murayama Shigeyuki , Uesaka Katsuhiko
Published: February 2020

482

Background: There are many treatment choices for hepatocellular carcinoma (HCC). Proton beam therapy (PBT) is considered a treatment option for HCC. The purpose of this study was to compare surgical resection (SR) and PBT in order to clarify the prognostic factors for operable HCC based on a single institution’s database. Methods: Patients with single primary nodular HCC ≤ 100 mm without vessel invasion on pretreatment imaging were divided into the SR group and PBT group. In the PBT group, the patients with unresectable HCC due to their liver function and/or performance status (PS) were excluded. Results: There were 314 and 31 patients who underwent SR and PBT, respectively. The median survival time in the SR group was significantly better than in the PBT group (104.1 vs. 64.6 months, p = 0.008). Regarding the relapse-free survival (RFS), there was no significant difference between the SR and PBT groups (33.8 vs. 14.0 months, p = 0.099). Conclusions: In RFS, the PBT group and the SR group were comparable. However, the PBT group was significantly worse than SR group in overall survival. SR may therefore be favorable as an initial treatment for HCC compared to PBT. Clinical trial information: 1856.
Biliary tract cancer (BTC) in the elderly: A real-world tertiary cancer center experience.
Authors: Salati Massimiliano , Caputo Francesco , Cerma Krisida , Spallanzani Andrea , Gelsomino Fabio , Santini Chiara , Bocconi Alessandro , Riggi Maria Laura , Luppi Gabriele , Casadei Gardini Andrea , Dominici Massimo
Published: February 2020

492

Background: Although BTC is mostly a disease of the elderly, only limited data ara available on the optimal management of this patient (pt) population. In fact, older pts are underepresented in clinical trials and results are seldom reported by age group. In this study, we aimed at evaluating pattern of care and treatment outcome in BTC aged ≥ 70 years and comparing them with their younger counterparts. Methods: Medical records of BTC followed at the Modena Cancer Centre from 2007 and 2019 were retrospectively reviewed.. Overall survival (OS) was estimated with the Kaplan-Meier curves and compared by log-rank test. Differences between categorical variables were assessed using the chi square test. Univariate and multivariate analyses were performed to assess the impact of covariates on survival. Results: A total of 120 BTC patients (49%) ≥ 70 were included in the analysis. 54% (64) were female, 47% (56) had iCCA, 41% (49) GBC, and 12% (15) eCCA. 68% (81) had unresectable locally advanced or metastatic disease. 32% (39) underwent surgical resection, 60% (72) were treated with first-line chemotherapy (1L), while 29% (21) of them went on to receive second-line (2L). No differences in terms of both chance to receive surgery (p=0.59) and survival (p=0.25) were recorded compared to youngers. In the advanced-disease setting, median OS was 8 months and was significantly worse than that of the younger counterparts (p<0.001). Older patients were less likely to receive 1L (p<0.001) and 2L (p<0.001) chemotherapy and doublet regimens (p<0.001). Female gender (p=0.031), ECOG PS 0 (p<0.001), stage III (p<0.001) and NLR>3 (p<0.001) were independently associated with a better prognosis in older BTC receiving 1L, with 1-year OS of 82% (95%CI 68-91, p=0.031). Conclusions: In this real-world study, no survival difference was found between older and non-older surgically-treated patients. Contrariwise, elderly BTC were less frequently treated with chemotherapy for advanced disease and their outcome is poorer than youngers. However, clinical and biochemical prognostic have been identified that may assist in selecting older pts more likely to benefit from systemic treatment, both in clinical trials and daily practice.
The adherence to The American Association for The Study of Liver Disease (AASLD) guidelines in treating patients with hepatocellular carcinoma: Institutional experience.
Authors: Manne Ashish , Escobar Daisy E. , Prodduturvar Pranitha , Henderson Phillip , Abdul-Rahim Osama , Hussain Zeiad , Liles Spencer , Fonseca Annabelle , Howard John Harrison , Mneimneh Wadad , Gilbert Robert , Pai Sachin Gopalkrishna , Khushman Moh'd M.
Published: February 2020

496

Background: The American Association for the Study of Liver Disease (AASLD) guidelines outline an algorithm regarding the treatment modality of choice for patients with hepatocellular carcinoma (HCC) based on Barcelona Clinic Liver Cancer (BCLC) stage. The AASLD guidelines have several limitations and the adherence rate has been reported to be low. The adherence to AASLD guidelines in treating patients with HCC was explored in this study. Methods: Between 2017 and 2019, 106 patients with HCC were identified. In our cohort, 70 patients (66%) were discussed in the multidisciplinary tumor board (MDTB) and their first-line treatment modality was selected based on consensus recommendations from the MDTB team members. The adherence rate of MDTB recommendations to AASLD guidelines was calculated. Results: Median age was 65 (range 42-90). Males represented 84% while females represented 16%. Caucasians, African Americans and Asians represented 69%, 30% and 1% respectively. BCLC stage 0, A, B, C and D represented 7%, 32%, 23%, 27% and 11% respectively. First-line treatment modality of choice recommended by MDTB is summarized in Table. The overall adherence rate of MDTB recommendations to AASLD guidelines is 60%. For BCLC stage 0, A, B, C and D, the adherence rate was 60%, 86%, 44%,58% and 25% respectively. Conclusions: Our MDTB recommendations adherence rate to AASLD guidelines was 60%. The reported low adherence rate to the guidelines suggest that AASLD guidelines would benefit from further refinement and periodic update.

[Table: see text]
Real-world experience of regorafenib in patients with hepatocellular carcinoma: A multicenter United Kingdom study.
Authors: Ross Paul J. , Ma Yuk Ting , Palmer Daniel H. , Lythgoe Mark Peter , Merrick Sophie , Samson Adel , Rao Ankit Rohit , Basu Bristi , Prasad Debi , Dhillon Tony , Lau David , Darby Suzanne , Orr James , Margetts Jane , Hubner Richard , Baijal Shobhit , Sharma Rohini , Faluyi Olusola Olusesan , Lee Lennard , Thillai Kiruthikah
Published: February 2020

499

Background: Regorafenib was the first treatment to demonstrate a survival benefit in patients with HCC after progression on sorafenib. The RESORCE trial found that regorafenib improved overall survival with acceptable toxicity, in patients with disease progression on sorafenib who tolerated ≥400mg sorafenib daily and had Child-Pugh A liver function. Methods: We performed a multicentre, retrospective, observational study of patients with HCC receiving regorafenib in the UK, following its availability in April 2018. Results: Data on a total of 104 patients were included from April 2018–August 2019, and 80.8% were male. Age was collected in 85 patients, with a median of 68 years (range 22–86). 23.5% had NAFLD, 21.2% had ALD, 12.9% had HBV, and 3.5% had HCV. Prior management included sorafenib (100%), TACE (30.8%), resection (12.9%). Duration of sorafenib treatment was evaluable in 99/104 patients, and reported a median of 8.7 months (range 1.8–76.6). Duration of regorafenib treatment was evaluable in 92/104 patients, and reported a median of 3.9 months (range 0.0–15.7). Following treatment with regorafenib, 6 patients (5.8%) achieved partial response, 37 (35.6%) achieved stable disease and 45 (43.3%) had progressive disease as the best response. 15 (14.4%) were not assessed and 1 (1.1%) had mixed response. Survival data is immature with 62/101 (61.4%) patients alive at the time of census with median survival currently 6.5 months. Fatigue was the most frequent AE, with 69/88 patients (85.2%) for all grades. 12/88 patients (14.8%) had Grade 3 fatigue. Other significant AEs include hand-foot syndrome (6/85 patients [7.3%] had Grade 3) and diarrhoea (4/83 patients [4.9%] had Grade 3). Conclusions: The population in our real-world experience of regorafenib for HCC had a similar duration of prior sorafenib to those in the RESORCE trial. However, there was different balance of aetiologies with a lower proportion of patients with HBV and HCV. The rate of partial response is similar to the RESORCE trial with fewer patients achieving stable disease. The incidence of fatigue was higher, but the incidence of hand-foot syndrome and diarrhoea were lower. Further expansion and follow-up of this population is warranted.
Eligibility of real-world patients with stage II/III colorectal cancer (CRC) in adjuvant chemotherapy (AC) trials.
Authors: Batra Atul , Kong Shiying , Cheung Winson Y.
Published: February 2020

50

Background: The results of AC trials in stage II/III CRC are often generalized to real-world patients. However, clinical trials have stringent inclusion and exclusion criteria, which can potentially lead to poor generalizability of results and slow accrual. This study was conducted to determine the proportion of real-world patients with stage II/ III CRC who would be eligible for AC trials based on common eligibility criteria and to compare the outcomes in eligible and ineligible patients. Methods: We identified all patients diagnosed with stage II/III CRC in 2004-2015 from the Alberta Cancer Registry. Patients meeting any one of the following criteria were considered ineligible: age >75 years, anemia, comorbid conditions (heart disease, uncontrolled diabetes, kidney disease, liver disease) and history of a prior malignancy or immunosuppression. Logistic regression was used to describe the likelihood of receiving AC and Cox regression models were constructed to determine overall survival (OS). Results: A total of 7841 patients with stage II/III CRC were identified, of whom 52% were men and median age at diagnosis was 71 years (IQR: 61-79 years). Approximately 59% patients were deemed trial-ineligible and the most common reasons for ineligibility were advanced age (36%), renal dysfunction (27%), and cardiac disease (17%), respectively. In the real-world, 54% of eligible patients received AC as compared to 23% of ineligible patients [odds ratio 3.89, 95% confidence interval (CI) 3.53-4.28, P< 0.0001]. The 5-year OS of trial-ineligible patients who received AC was significantly better than those treated with surgery alone (table). Conclusions: Majority of real-world patients with stage II/ III CRC are unable to participate in AC trials due to strict exclusion criteria, but a fair proportion of these patients still derive some benefit from AC. The eligibility criteria of AC trials in CRC should be broadened to be more representative of real-world patients.

[Table: see text]
A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117.
Authors: Kudo Masatoshi , Ikeda Masafumi , Motomura Kenta , Okusaka Takuji , Kato Naoya , Dutcus Corina E. , Hisai Takashi , Suzuki Mayumi , Ikezawa Hiroki , Iwata Takeyuki , Kumada Hiromitsu , Kobayashi Masahiro
Published: February 2020

513

Background: LEN, a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT with immunomodulatory activity, is approved in multiple countries for first-line treatment of uHCC. NIV is an anti-PD-1 monoclonal antibody approved in multiple countries as a second-line treatment for HCC. We report early results from a phase 1b trial of LEN + NIV in pts with uHCC. Methods: In this open-label study, pts with uHCC, BCLC stage B (not eligible for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS ≤ 1 received LEN (bodyweight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) PO QD and 240 mg NIV IV Q2W. The primary endpoint was tolerability and safety of the combination. Objective response rate (ORR; mRECIST by investigator) was a secondary endpoint. Tolerability was evaluated by assessing dose-limiting toxicities (DLTs) during the first cycle in pts for whom no other appropriate therapy was available (Part 1). Once tolerability was confirmed, additional pts with no prior systemic therapy for uHCC were enrolled (Part 2). Results: At data cutoff (May 17, 2019), 30 pts had received LEN + NIV (Part 1: n=6; Part 2: n=24). Pts had BCLC stage B (n=17) or C (n=13) and Child-Pugh scores of 5 (n=23) or 6 (n=7). 4 pts in Part 1 (66.7%) had received prior anticancer medications (3 pts had 1; 1 pt had ≥3). No DLTs were reported in Part 1. TEAEs leading to discontinuation of LEN were reported in 2 (6.7%) pts; 4 (13.3%) pts had TEAEs leading to discontinuation of NIV. TEAEs occurred in all 30 pts; the most common were palmar-plantar erythrodysesthesia (56.7%) and dysphonia (53.3%). Adverse events were manageable. Efficacy outcomes are reported (Table). Conclusions: LEN + NIV was well tolerated with encouraging anti-tumor activity in pts with uHCC. Clinical trial information: NCT03418922.

[Table: see text]
Optimal timing of radiotherapy for incomplete transarterial chemoembolization in BCLC stage B hepatocellular carcinoma.
Authors: Byun Hwa Kyung , Kim Nalee , Seong Jinsil
Published: February 2020

521

Background: Numerous studies have reported on the efficacy of radiotherapy (RT) after incomplete transarterial chemoembolization (TACE). However, the optimal timing of RT remains unclear. This study investigated the optimal time of initiating RT for incomplete TACE in patients with BCLC stage B hepatocellular carcinoma (BCLC-B HCC). Methods: Between 2001 and 2016, 116 lesions in 104 patients with BCLC-B HCC were treated with RT after TACE. The time interval between the last session of TACE and initiation of RT was obtained from medical records and analyzed retrospectively. The optimal cut-off time-interval that maximized the difference in local failure-free rate (LFFR) was determined using maximally selected rank statistics. Results: The median duration between TACE and RT was 26 (range: 2–165) days. Median number of TACE treatments on the target lesion before RT was 2; median tumor size was 7 cm. At a median follow-up of 18 (range: 3–160) months, the median overall survival was 18 months. The probability of local control increased as the time interval between TACE and RT decreased. The optimal cut-off value of the time interval was 5 weeks. With the cut-off of 5 weeks, 65 and 39 patients were classified into early and late RT groups, respectively. The early RT group had significantly poorer Child-Pugh class and higher alpha-fetoprotein levels. Most characteristics including tumor size (7 cm vs. 6 cm; P = .144) were not significantly different between the groups. One-year LFFR was significantly higher in the early RT group (94.6% vs. 70.8%; P = .005). On multivariate analysis, early RT was an independent predictor of favorable LFFR (hazard ratio: 3.82, 95% confidence interval: 1.64–8.88, P = .002). Conclusions: The optimal time for the administration of RT for incomplete TACE is within 5 weeks following TACE. Early administration of RT within 5 weeks after TACE was associated with better local control.