Predictive Roles of HER2 Gene Amplification and Neutrophil-to-Lymphocyte Ratio on Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab-Based Chemotherapy.

OBJECTIVES: Trastuzumab is used as an agent against human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). The aim of this study was to determine how HER2 gene amplification and neutrophil-to-lymphocyte ratio (NLR) could predict long-term survival in AGC patients that underwent trastuzumab-based chemotherapy. METHODS: We retrospectively reviewed medical records of 112 patients between 28 and 91 years old (median of 66 y) with AGC treated with first-line trastuzumab-based chemotherapy. The level of HER2 gene amplification was determined by the HER2/centromere enumerator probe 17 (CEP17) ratio and HER2 gene copy number (GCN). NLR was calculated as the neutrophil count divided by the lymphocyte counts. RESULTS: Median HER2/CEP17 ratio, HER2 GCN, and NLR values were 2.85, 7.1, and 2.81, respectively. Objective response rate in both high HER2/CEP17 ratio (59.4% vs. 28.1%, P=0.012) and HER2 GCN groups (62.1% vs. 33.3%, P=0.032) was higher than that of each group. High NLR correlated with significantly worse median overall survival (OS) (median OS, 8.2 vs. 18.9 mo, P=0.002) and progression free survival (PFS) (median PFS: 5.1 vs. 8.0 mo, P=0.005). However, median OS and PFS were not significantly different according to HER2/CEP17 ratio or HER2 GCN. In the multivariate analysis, high NLR, Eastern Cooperative Group performance status, and poorly differentiated/signet ring cell type were independent factors for OS. CONCLUSIONS: NLR was a significant predictor of long-term survival in AGC patients treated with first-line trastuzumab-based chemotherapy. Future validation of prospective trials with larger patient populations will be needed.

Patient preferences regarding bariatric/metabolic procedures: a survey of Korean obese candidates for surgery.

PURPOSE: The objective of this study was to survey potential candidates for bariatric/metabolic surgery for procedure preferences. METHODS: Questions asked were divided into 5 categories: (1) demographic and anthropometric data, comorbidities, and favored surgery; (2) awareness of safety, effectiveness, and complications of each type of surgery; (3) discordances in opinion between self-selected and medically recommended procedures; and (4, 5) reasons for/against particular surgery. RESULTS: From 1 October to 15 November 2018, 104 respondents adequately responded and were included in the analysis. The number (%) of female respondents was 79 (76.0%). The number (%) of respondents by decade was 17 (16.3%) in their 20s, 65 (62.5%) in their 30s, 19 (18.3%) in their 40s, and 3 (2.9%) in their 60s, respectively. Mean body mass index was 37.1 ± 6.3 kg/m2. Comorbidities were type 2 diabetes in 34 (32.7%) and hypertension in 35 (33.7%). The most favored procedure was sleeve gastrectomy (SG) in 78 (75.0%), adjustable gastric band (AGB) surgery in 12 (11.5%), Roux-en-Y gastric bypass (RYGB) in 6 (5.8%), and gastric plication (GP) in 8 (7.7%). Major reasons for choosing procedures were; "adjustable" for AGB, "stomach sparing" for GP, "excellent weight loss" for SG, and "comorbidity resolution" in RYGB. CONCLUSION: Candidates for bariatric/metabolic surgery favored SG followed by AGB, GP, and RYGB, and their choices were compatible with current evidence-based clinical practice.

Synchronous Peripancreatic Lymph Node Gastrinoma and Gastric Neuroendocrine Tumor Type 2.

A 34-year-old man was referred to our hospital with gastric polypoid lesions and biopsy-confirmed neuroendocrine tumor (NET). Computed tomography (CT) revealed a 3×3.5×8-cm retroperitoneal mass behind the pancreas, with multiple hepatic metastases. His serum gastrin level was elevated to 1,396 pg/mL. We performed a wedge resection of the stomach, a right hemi-hepatectomy, and a retroperitoneal mass excision. After careful review of the clinical, radiological, histopathological, and immunohistochemical findings, peripancreatic gastrinoma, and synchronous gastric NET were ultimately diagnosed. We reviewed a CT scan that had been performed 6 years previously after surgery for a duodenal perforation. There was no evidence of gastric or hepatic lesions, but the retroperitoneal mass was present at the same site. Had gastrinoma been detected earlier, our patient could have been cured using less invasive treatment. This case demonstrates how important it is to consider Zollinger-Ellison syndrome in patients with a recurrent or aggressive ulcer.

Low-dose capecitabine plus trastuzumab as first-line treatment in patients 75 years of age or older with HER2-positive advanced gastric cancer: a pilot study.

BACKGROUND: Single-agent chemotherapy is considered a good and safe treatment option for elderly patients with advanced gastric cancer (AGC). We investigated the efficacy and safety of trastuzumab plus low-dose capecitabine in elderly patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive AGC. METHODS: Patients aged 75 years or older with tumors having HER2 overexpression defined as either immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization-positive were eligible for inclusion. Patients received capecitabine (1000 mg/m(2)) orally twice daily on days 1-14 and trastuzumab (8 mg/kg for cycle 1, followed by 6 mg/kg) intravenously on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty patients were enrolled. The median age was 79 years (range 75-91). Nine patients (45 %) had ECOG performance status 2. Median PFS was 5.2 months (95 % CI 1.9-8.4 months), and median overall survival was 9.3 months (95 % CI 4.0-14.6 months). The confirmed response rate was 40 % (95 % CI 19-64 %) with disease control rate of 80 %. Grade 3-4 toxicities were anorexia (10 %), fatigue (5 %), stomatitis (5 %), and anemia (5 %). No treatment-related deaths or symptomatic congestive heart failure were observed. CONCLUSIONS: Low-dose capecitabine plus trastuzumab is effective and well tolerated in elderly patients with HER2-positive AGC.

A randomized phase II study of weekly docetaxel/cisplatin versus weekly docetaxel/oxaliplatin as first-line therapy for patients with advanced gastric cancer.

BACKGROUND: Docetaxel, in combination with cisplatin or oxaliplatin, has demonstrated efficacy in advanced gastric cancer (AGC). This randomized, non-comparative phase II trial evaluated two weekly docetaxel-based regimens to determine which is the most promising in terms of efficacy and safety as a front-line therapy in AGC. METHODS: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric adenocarcinoma were randomly assigned to receive docetaxel (35 mg/m(2)) weekly on days 1 and 8 of a 21-day cycle plus either cisplatin (60 mg/m(2) on day 1) (wDP) or oxaliplatin (120 mg/m(2) on day 1) (wDO). RESULTS: Of the 77 randomly assigned patients, 76 patients (38 per arm) received one of the study treatments. Overall, response rate (ORR) was 37 % for wDP and 41 % for wDO. Median progression-free survival (PFS) was 4.9 and 4.4 months for wDP and wDO, respectively, and median overall survival (OS) was 9.7 and 12.3 months, respectively. Exploratory analyses showed no significant difference between wDP and wDO in terms of ORR (P = 0.707), PFS (P = 0.324), or OS (P = 0.581). The main grade 3 or 4 toxicity in the wDP and wDO groups was neutropenia (47 % in both groups). wDO was less associated with nausea (66 vs. 82 %) and vomiting (39 vs. 63 %), but more associated with peripheral neuropathy (68 vs. 39 %) than wDP. Rates of overall grade 3 or 4 adverse events were similar (wDP 66 vs. wDO 68 %). CONCLUSIONS: wDP and wDO were found to be equally active and tolerable as front-line treatments in AGC.

Three-year experience of pouch dilatation and slippage management after laparoscopic adjustable gastric banding.

PURPOSE: Pouch dilatation and band slippage are the most common long-term complications after laparoscopic adjustable gastric banding (LAGB). The aim of the study is to present our experience of diagnosis and management of these complications. MATERIALS AND METHODS: The pars flaccida technique with anterior fixation of the fundus was routinely used. All band adjustments were performed under fluoroscopy. We analyzed the incidence, clinico-radiologic features, management, and revisional surgeries for treatment of these complications. We further presented the outcome of gastric plication techniques as a measure for prevention of these complications. RESULTS: From March 2009 to March 2012, we performed LAGB on 126 morbidly obese patients. Among them, 14 patients (11.1%) were diagnosed as having these complications. Four patients (3.2%) had concentric pouch dilatations, which were corrected by band adjustment. Ten (7.9%) had eccentric pouch with band slippage. Among the ten patients, there were three cases of posterior slippage, which were corrected by reoperation, and seven cases of eccentric pouch dilatation with anterior slippage. Three were early anterior slippage, which was managed conservatively. Two were acute anterior slippage, one of whom underwent a revision. There were two cases of chronic anterior slippage, one of whom underwent a revision. The 27 patients who underwent gastric plication did not present with eccentric pouch with band slippage during the follow-up period. CONCLUSION: The incidence of pouch dilatation with/without band slippage was 11.1%. Management should be individualized according to clinico-radiologic patterns. Gastric plication below the band might prevent these complications.

Laparoscopy Assisted versus Open Distal Gastrectomy with D2 Lymph Node Dissection for Advanced Gastric Cancer: Design and Rationale of a Phase II Randomized Controlled Multicenter Trial (COACT 1001).

PURPOSE: Laparoscopy-assisted distal gastrectomy for early gastric cancer has gained acceptance and popularity worldwide. However, laparoscopy-assisted distal gastrectomy for advanced gastric cancer is still controversial. Therefore, we propose this prospective randomized controlled multi-center trial in order to evaluate the safety and feasibility of laparoscopy assisted D2-gastrectomy for advanced stage gastric cancer. MATERIALS AND METHODS: Patients undergoing distal gastrectomy for advanced gastric cancer staged cT2/3/4 cN0/1/2/3a cM0 by endoscopy and computed tomography are eligible for enrollment after giving their informed consent. Patients will be randomized either to laparoscopy-assisted distal gastrectomy or open distal gastrectomy. Sample size calculation revealed that 102 patients are to be included per treatment arm. The primary endpoint is the non-compliance rate of D2 dissection; relevant secondary endpoints are three-year disease free survival, surgical and postoperative complications, hospital stay and unanimity rate of D2 dissection evaluated by reviewing the intraoperative video documentation. DISCUSSION: Oncologic safety is the major concern regarding laparoscopy-assisted distal gastrectomy for advanced gastric cancer. Therefore, the non-compliance rate of clearing the N2 area was chosen as the most important parameter for the technical feasibility of the laparoscopic procedure. Furthermore, surgical quality will be carefully reviewed, that is, three independent experts will review the video records and score with a check list. For a long-term result, disease free survival is considered a secondary endpoint for this trial. This study will offer promising evidence of the feasibility and safety of Laparoscopy-assisted distal gastrectomy for advanced gastric cancer. TRIAL REGISTRATION: NCT01088204 (international), NCCCTS-09-448 (Korea).

A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy.

BACKGROUND: The aim of this study was to evaluate the efficacy of irinotecan (CPT-11) monotherapy and CPT-11 plus 5-fluorouracil (5-FU)/leucovorin (LV) combination (mFOLFIRI) as second-line treatment in patients with advanced gastric cancer (AGC). METHODS: A total of 59 patients were randomly assigned to either CPT-11 (150 mg/m(2) iv on day 1) or mFOLFIRI (CPT-11 150 mg/m(2) plus LV 20 mg/m(2) on day 1 followed by 5-FU 2,000 mg/m(2) over 48 h), every 2 weeks. The primary end point was objective response rate (ORR). RESULTS: Following random assignment, 29 patients received CPT-11 and 30 patients mFOLFIRI. The ORR was 17.2 % [95 % confidence interval (CI) 3.4-30.9] and 20.0 % (95 % CI 5.6-34.3) for the CPT-11 and mFOLFIRI arms, respectively (P = 0.525). There was no significant difference in median progression-free survival: 2.2 months (95 % CI 0.2-4.3) for CPT-11 versus 3.0 months (95 % CI 2.0-3.7) for mFOLFIRI (P = 0.481) or in median overall survival: 5.8 months (95 % CI 3.0-8.7), compared with 6.7 months (95 % CI 5.3-8.2) (P = 0.514). Grade 3/4 toxicity was observed in 21 and 28 events in the CPT-11 and mFOLFIRI arms, respectively. CONCLUSIONS: Although this study had a small sample size and limited statistical power, CPT-11 monotherapy and mFOLFIRI appear to be equally active and tolerable as second-line chemotherapy for AGC. The addition of 5-FU/LV to CPT-11 did not significantly improve efficacy.

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer.

PURPOSE: This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC). MATERIALS AND METHODS: Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0-2, were enrolled in this study. A fixed dose of epirubicin (50 mg/m(2)) and oxaliplatin (130 mg/m(2)) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1-14. The S-1 dose was escalated according to the following schedule: level I, 35 mg/m(2); level II, 40 mg/m(2); level III, 45 mg/m(2); Level IV, 50 mg/m(2). Each cycle was repeated every 21 days. DLTs were evaluated during the first two cycles of treatment. RESULTS: Nineteen patients with a median age of 53 years (range, 40-71 years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5 days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5 % (95 % confidence interval (CI), 13.3-66.6 %). The median progression-free survival and overall survival of all patients was 6.8 months (95 % CI, 1.4-9.5 months) and 13.3 months (95 % CI, 1.9-24.6 months), respectively. CONCLUSION: The RD of the EOS regimen in patients with previously untreated AGC was 50 mg/m(2) of epirubicin and 130 mg/m(2) of oxaliplatin on day 1, with administration of 40 mg/m(2) of S-1 twice a day on days 1-14 for each 21-day cycle. The EOS regimen described produced promising results.

Quality of life in patients with advanced gastric cancer treated with second-line chemotherapy.

OBJECTIVE: Despite many trials of systemic chemotherapy in advanced gastric cancer, treatment after failure with first-line chemotherapy remains controversial. We prospectively assessed quality of life (QL) in gastric cancer patients treated with second-line chemotherapy. METHODS: Forty-three patients who received second-line chemotherapy for advanced gastric cancer completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and hospital anxiety and depression scale (HADS) at baseline and at regular intervals during and after chemotherapy. RESULTS: Compliance with QL questionnaire completion decreased to 72% after third cycle of treatment. In general, clinically meaningful improvements compared with baseline (change QLQ-C30 scores > or =10) were seen in a number of domains and items, including global health/QL, emotional function, cognitive function and all of the symptom scales and single items but appetite. There was no difference in QL between responders and non-responders (P = 0.473). At baseline, 27 (63%) patients were suspected to have anxiety or depressive disorder (HADS score > or =11), and this incidence decreased after chemotherapy (14.7 vs 9.5; P < 0.001). CONCLUSION: Improvements from baseline in QL measures and HADS scores were demonstrated in patients with advanced gastric cancer, treated with second-line chemotherapy.

A pilot study of cisplatin, irinotecan, leucovorin and 5-fluorouracil (PILF) combination chemotherapy for advanced gastric cancer.

PURPOSE: Irinotecan, in combination with leucovorin/5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. MATERIALS AND METHODS: Chemotherapy-naive AGC patients received irinotecan 150 mg/m(2) on day 1, and leucovorin 200 mg/m(2) and a 22-h infusion of FU 1000 mg/m(2) on days 1 and 2. Cisplatin 30 mg/m(2) was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. RESULTS: Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. CONCLUSION: This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.

Phase I dose-escalating study of docetaxel in combination with 5-day continuous infusion of 5-fluorouracil in patients with advanced gastric cancer.

BACKGROUND: Published data suggests that docetaxel combined with 5-fluorouracil (5-FU) may have synergistic activity in treating advanced gastric cancer. We performed a phase I study of docetaxel and 5-FU to determine the maximum tolerated dose (MTD), the recommended dose for phase II studies, and the safety of this combination. METHODS: Eligible patients had recurrent and/or metastatic advanced gastric cancer with normal cardiac, renal and hepatic function. Traditional phase I methodology was employed in assessing dose-limiting toxicity (DLT) and MTD. On day 1 every 3 weeks, docetaxel 75 mg/m2 (fixed dose) was infused over 1-h, followed immediately by 5-FU as a 5-day continuous infusion. RESULTS: Dose escalation schema was as follows: dose level (DL) 1 (5-FU 250 mg/m2/day), 2 (500), 3 (750), and 4 (1000). Three patients were enrolled on DL1, without DLT. On DL2, 1 DLT (grade 3 stomatitis) was developed in first 3 patients, and this cohort was expanded to 6 patients. Three patients had been enrolled on DL3. Because two out of 3 patients had DLTs, the MTD was reached at DL3. CONCLUSION: The recommended phase II dose of this combination is 75 mg/m2 docetaxel on day 1 immediately followed by a 5-day continuous infusion of 5-FU 500 mg/m2/day.

A phase II study of epirubicin, cisplatin and capecitabine combination chemotherapy in patients with metastatic or advanced gastric cancer.

OBJECTIVES: The purpose of this study was to evaluate the antitumor activity and safety of an epirubicin, cisplatin, and capecitabine (ECX) combination in patients with metastatic or advanced gastric cancer. PATIENTS AND METHODS: Patients with metastatic or advanced measurable gastric adenocarcinoma received ECX combination chemotherapy. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1 by intravenous injection. Capecitabine 1,000 mg/m2 twice daily was administered orally on day 1-14. The cycle was repeated every 3 weeks. RESULTS: Fifty-four patients were enrolled in this study. Fifty patients were assessable for responses and 53 for toxicity. A total of 250 cycles were administered. The overall best response rate by intent-to-treat analysis was 59% including 52% partial responses and 7% complete responses. Median response duration and time to progression was 5.8 and 6 months, respectively. Median survival for all patients was 9.6 months (95% CI, 8.7-10.5 months). The most common grade 3/4 hematological adverse event was neutropenia in 31% (76 cycles) including febrile neutropenia in 4.8% (11 cycles). Non-hematological toxicity was generally mild and reversible. Grade 3/4 nausea, vomiting and stomatitis occurred in 8, 9, and 8% of the patients, respectively. Hand-foot skin reactions developed in 51% of patients, but most were self-limited. Grade 3 occurred in only 4%. One patient died of neutropenic sepsis. CONCLUSIONS: ECX combination regimen showed high anti-tumor activity with a tolerable toxicity pattern as a front-line chemotherapy for patients with metastatic or advanced gastric cancer.

Down-regulation of organic anion transporter 2 mRNA expression by nitric oxide in primary cultured rat hepatocytes.

Role of nitric oxide (NO) on the expression of organic anion transporter 2 (OAT2) located in sinusoidal domain of hepatocytes has been investigated. Effect of NO generated in vivo in rat and delivered in vitro to hepatocytes was determined. Lipopolysaccharide (LPS) and spermine NONOate (SPER/NO) were selected as the NO donors for in vivo and in vitro experiments, respectively. Constitutive basal expression of rOAT2 mRNA was detected in the normal rat liver and the level of its expression was decreased by intraperitoneal administration of LPS. This LPS-induced decrement did not occur when aminoguanidine (AG), an inhibitor of iNOS, was co-administered with LPS. The expression of rOAT2 mRNA was detected in hepatocytes, but not in the nonparenchymal cells. In the primary cultured hepatocytes obtained from normal rats (normal hepatocytes), a time-dependent decline of rOAT2 mRNA expression was observed, but not in the hepatocytes obtained from rats pretreated with gadolinium chloride (GdCl3, Gd-hepatocytes), an inhibitor of Kupffer cell activation. The decline of rOAT2 mRNA expression observed in the normal hepatocytes was enhanced by LPS treatment, but not in the Gd-hepatocytes. The LPS-dependent enhancement in the decline of rOAT2 mRNA expression did not occur when the normal hepatocytes were treated with AG or actinomycin D. When the Gd-hepatocytes were treated with SPER/NO, an NO donor, the rOAT2 mRNA expression declined markedly. Combined, our results suggest that rOAT2 mRNA expression in hepatocytes is down-regulated by NO at least at the transcriptional step.

Epirubicin, cisplatin, and protracted venous infusion of 5-fluorouracil for advanced gastric carcinoma.

To evaluate the activity and safety of a combination chemotherapy with epirubicin, cisplatin, and a protracted venous infusion of 5-fluorouracil (ECF) in unresectable or metastatic gastric cancer, a phase II study was performed. Thirty-five chemotherapy-naive patients were given ECF. Epirubicin (50 mg/m(2) intravenous, i.v.) and cisplatin (60 mg/m(2) i.v.) were administered every three weeks during a continuous intravenous infusion of 5-fluorouracil (250 mg/m(2) /day) using infusion pump. One complete response and 19 partial responses (response rate=62%) were achieved. Eight patients remained stable, whereas in four patients the disease progressed. The median duration of response was 22 weeks (95% confidence interval, 18-27 weeks). The median survival for all patients was 10 months (95% confidence interval, 6-14 months), with a 1-yr survival rate of 40%. A total of 184 cycles of chemotherapy were administered. Grade 3 or 4 emesis occurred in 3%, mucositis in 2%, anemia in 10%, and leukopenia in 3% of the cycles. Central venous catheter complications that required line removal occurred in 37% (n=13) of the patients. No patient died of toxicity. Overall, the ECF regimen showed high anti-tumor activity with a tolerable toxicity pattern.