In the field of resectable gastric cancer, for instance, Taniguchi et al reported that a preoperative low psoas muscle index (PMI) measured by cross-sectional computed tomography (CT) at the ...umbilical level was a significant risk factor for postoperative pneumonia and an independent prognostic factor for recurrence-free survival in patients who underwent gastrectomy. 1 Hashimoto et al reported that patients with a low PMI had a higher incidence of hematological and nonhematological toxicities during preoperative chemotherapy for gastric cancer than those with a high PMI. 2 Sarcopenia may reduce the metabolic rate or the clearance of preoperative chemotherapeutic drugs, and may therefore result in higher concentrations of these drugs in the blood. In this issue of the Annals of Gastroenterological Surgery, Sugimura et al reported that the preoperative skeletal muscle index (SMI) measured with multifrequency bioelectrical impedance was associated with overall survival, but not with the incidence of postoperative complications after esophageal cancer surgery. 3 Interestingly, measurement of the preoperative 6-min walk distance (6MWD) as an indicator of physical performance significantly predicted both postoperative pneumonia and survival. Daitoku et al analyzed the association between the preoperative SMI measured with cross-sectional CT images at the L3 level and the densities of tumor-infiltrating lymphocytes (TILs) assessed by immunohistochemistry in patients who underwent colorectal cancer surgery, and reported that the preoperative SMI was significantly correlated with the density of CD3+ and CD8+ cells. 4 Although it remains unclear if sarcopenia is a cause or result of the low density of TILs, the close relationship may contribute to poor posttreatment outcomes in patients with both malignancies and sarcopenia.
Purpose
Prior to publication of the Clavien-Dindo classification in 2004, there were no grading definitions for surgical complications in either clinical practice or surgical trials. This report ...establishes supplementary criteria for this classification to standardize the evaluation of postoperative complications in clinical trials.
Methods
The Japan Clinical Oncology Group (JCOG) commissioned a committee. Members from nine surgical study groups (gastric, esophageal, colorectal, lung, breast, gynecologic, urologic, bone and soft tissue, and brain) specified postoperative complications experienced commonly in their fields and defined more detailed grading criteria for each complication in accordance with the general grading rules of the Clavien-Dindo classification.
Results
We listed 72 surgical complications experienced commonly in surgical trials, focusing on 17 gastroenterologic complications, 13 infectious complications, six thoracic complications, and several other complications. The grading criteria were defined simply and were optimized for surgical complications.
Conclusions
The JCOG postoperative complications criteria (JCOG PC criteria) aim to standardize the terms used to define adverse events (AEs) and provide detailed grading guidelines based on the Clavien-Dindo classification. We believe that the JCOG PC criteria will allow for more precise comparisons of the frequency of postoperative complications among trials across many different surgical fields.
Background
Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. ...We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers.
Methods
We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS).
Results
Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%,
P
< 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%,
P
= 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%,
P
= 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95;
P
= 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63;
P
= 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy.
Conclusions
Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.
The association between the tumor microenvironment (TME) and treatment response or survival has been a recent focus in several types of cancer. However, most study materials are resected specimens ...that were completely modified by prior chemotherapy; therefore, the unmodified host immune condition has not yet been clarified. The aim of the present study was to evaluate the relationship between TME assessed in pre–therapeutic biopsy samples and chemoresistance in esophageal cancer (EC). A total of 86 endoscopic biopsy samples from EC patients who received neoadjuvant chemotherapy (NAC) prior to surgery were evaluated for the number of intratumoral CD4+ lymphocytes (with/without Foxp3 expression), CD8+ lymphocytes (with/without PD‐1 expression), monocytes (CD14+) and macrophages (CD86+, CD163+ and CD206+) by multiplex immunohistochemistry (IHC). The number of tumor‐infiltrating CD206+ macrophages I significantly correlated with cT, cM, cStage and neutrophil/lymphocyte ratio (NLR), whereas the number of lymphocytes (including expression of Foxp3 and PD‐1) was not associated with clinico‐pathological features. The high infiltration of CD163+ or CD206+ macrophages was significantly associated with poor pathological response to NAC (P = 0.0057 and 0.0196, respectively). Expression of arginase‐1 in CD163+ macrophages tended to be higher in non–responders (29.4% vs 18.2%, P = 0.17). In addition, patients with high infiltration of M2 macrophages exhibited unfavorable overall survival compared to those without high infiltration of M2 macrophages (5‐year overall survival 57.2% vs 71.0%, P = 0.0498). Thus, a comprehensive analysis of TME using multiplex IHC revealed that M2 macrophage infiltration would be useful in predicting the response to NAC and long‐term survival in EC patients.
The present study confirmed that pre–therapeutic M2 macrophage infiltration would be a useful biomarker in predicting the response to NAC and unfavorable survival among a variety of immune cells in EC patients. Our results support the possibility of using immunotherapy, targeting M2 macrophages, alongside conventional neoadjuvant chemotherapy.
Background
Endoscopic resection has been limited to intestinal-type gastric cancer (cT1a) with a low risk of lymph node metastasis (T1a ≤2 cm, without ulcers). This single-arm confirmatory trial ...evaluated the efficacy and safety of endoscopic submucosal dissection (ESD) for >2 cm ulcer-negative and ≤3 cm ulcer-positive intestinal-type gastric cancer (cT1a).
Methods
The eligibility criteria included endoscopically diagnosed cT1a, a single primary intestinal-type gastric adenocarcinoma, an ulcer-negative lesion of any size or a ≤3 cm ulcer-positive lesion, cN0M0, and no prior treatment. If ESD resulted in noncurative resection, surgical resection was added. The primary endpoint was the 5-year overall survival (OS) (planned sample size was 470, with a one-sided alpha level of 2.5%). The threshold 5-year OS was 86.1%.
Results
We enrolled 470 early gastric cancer patients median tumor size, 25 (5–130) mm from 29 institutions between June 2007 and October 2010. These patients had 152 ulcer-negative lesions (>2 and ≤3 cm), 111 ulcer-negative lesions (>3 cm), and 207 ulcer-positive lesions (≤3 cm). The success rate for en block resection was 99.1% (466/470). Additional gastrectomy was conducted in 131 patients (28%) who did not fulfill the curative resection criteria. The 5-year OS of all patients was 97.0% (95% confidence interval, 95.0–98.2%), which was higher than the threshold 5-year OS (86.1%). The 317 patients who satisfied the curative resection criteria had no recurrence. There were no ESD-related grade 4 adverse events.
Conclusion
ESD for early gastric cancers that met the expanded criteria for intestinal-type gastric cancer (cT1a) was acceptable and should be the standard treatment instead of gastrectomy.
Background
Body weight loss (BWL) after gastrectomy is associated with not only a deteriorated quality of life but also a poor prognosis. Oral nutritional supplements (ONS) may be used to minimize ...BWL, which is observed in the first 3 months after gastrectomy and becomes stable thereafter, although the results of several randomized trials remain controversial.
Methods
We performed a multicenter, open-label randomized controlled trial including 1003 gastric cancer patients undergoing curative gastrectomy. Patients were assigned to the ONS group or the control group. In the former, 400 ml (400 kcal) per day for 12 weeks as enteral nutrition was planned, and the actual intake amount was recorded daily by patients themselves. The primary endpoint was BWL 1 year after gastrectomy.
Results
BWL data were available in 880 patients (ONS 437, control 443). BWL at 3 months was significantly lower in the ONS group than in the control group (7.1 ± 5.6% and 8.5 ± 5.8%,
p
= 0.0011). However, the difference gradually declined after 6 months and was not significant 1 year after surgery (9.3 ± 8.2% and 9.8 ± 8.7%,
p
= 0.37). In the ONS group, 50.4% of patients took more than 200 ml/day of ONS (average 301 ml) and showed significantly less BWL (8.2 ± 7.2%) at 1 year than the control (
p
= 0.0204).
Conclusion
The administration of ONS for 12 weeks after gastrectomy did not improve BWL at 1 year. However, the improvement in BWL remained until 1 year after surgery in patients who took more than 200 kcal/day of ONS.
Background
Several studies have shown that postoperative complications worsen the prognosis of patients with malignancies. However, our previous study showed that C-reactive protein (CRP) elevation ...over 12 mg/dL was a more reliable prognostic indicator than complication occurrence. This large-scale, multicenter validation study aimed to confirm the prognostic value of postoperative CRP elevation in resectable gastric cancer.
Methods
Data of 1456 patients with pT2–T4 gastric cancer who underwent R0 resection were collected from 21 institutions. The prognostic value of the highest postoperative serum level of CRP (CRP
max
) during hospitalization was evaluated using the Kaplan–Meier method. The prognostic independence of CRP
max
with assessed with a Cox multivariate analysis of recurrence-free survival (RFS).
Results
RFS in the high CRP
max
(≥ 12 mg/dL) group was significantly worse than that in the low CRP
max
(< 12 mg/dL) group (log-rank
P
= 0.002). The recurrence pattern showed that liver metastasis occurred more frequently in the high CRP
max
group (9.2%) than in the low CRP
max
group (4.7%) (
P
= 0.001). In patients without intra-abdominal infectious complications, the high CRP
max
group showed significantly worse RFS than the low CRP
max
group (log-rank
P
= 0.026). In patients with intra-abdominal infectious complications, the high CRP
max
group had worse RFS than the low CRP
max
group, but this difference was not significant (log-rank
P
= 0.075). Cox multivariate analysis with 13 covariables showed that CRP
max
(
P
= 0.043) was an independent prognostic factor, but postoperative complications were not (
P
= 0.387).
Conclusion
Postoperative CRP elevation was a better predictor of prognosis in patients with gastric cancer than the occurrence of intra-abdominal infectious complications.
Background
The Charlson Comorbidity Index (CCI), an indicator that objectively quantifies comorbidities, reduces nutritional status; however, the impact of the CCI on the postoperative nutrition ...indexes of patients with esophageal cancer remains unclear.
Methods
In total, 336 patients with esophageal cancer who underwent surgery between January 2011 and April 2017 were included in this study. We investigated the relationship between the CCI and postoperative nutrition indexes.
Results
Patients were divided into two groups: CCI ≤1 (low CCI group) and CCI ≥2 (high CCI group). A high CCI was significantly associated with shortened overall survival (OS; 3-year OS rate of 77.9% in the low CCI group versus 59.7% in the high CCI group;
p =
0.008). Nutritional indexes, such as the Prognostic Nutritional Index (PNI), at 1 month after esophagectomy were significantly lower in the high CCI group than in the low CCI group (
p =
0.031); however, the PNI at 6 months after surgery was similar between the high and low CCI groups. Multivariate analysis identified high CCI as an independent risk factor associated with PNI <45 in esophageal cancer patients at 1 month after esophagectomy (
p =
0.047).
Conclusion
This study showed that CCI ≥2 was significantly associated with poor PNI at 1 month after surgery for esophageal cancer, indicating that it is necessary to administer effective nutritional interventions for patients with postoperative malnutrition, especially those with multiple comorbidities.
Summary Background Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric ...cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients. Methods We did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20–75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m2 per day on days 1–21 and cisplatin 60 mg/m2 on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012. Findings Between Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7–42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2–34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7–19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8–16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78–1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients 18% vs two 3%), anorexia (22 29% vs nine 12%), nausea (11 15% vs four 5%), and hyponatraemia (seven 9% vs four 5%). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery). Interpretation Since gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours. Funding The Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.
Background
Despite improvements in gastric cancer treatment, the mortality associated with advanced gastric cancer is still high. The activation of β-adrenergic receptors by stress has been shown to ...accelerate the progression of several cancers. Accordingly, increasing evidence suggests that the blockade of β-adrenergic signaling can inhibit tumor growth. However, the effect of β-blockers, which target several signaling pathways, on gastric cancer remains to be elucidated. This study aimed to investigate the anti-tumor effects of propranolol, a non-selective β-blocker, on gastric cancer.
Methods
We explored the effect of propranolol on the MKN45 and NUGC3 gastric cancer cell lines. Its efficacy and the mechanism by which it exerts anti-tumor effects were examined using several assays (e.g., cell proliferation, cell cycle, apoptosis, and wound healing) and a xenograft mouse model.
Results
We found that propranolol inhibited tumor growth and induced G1-phase cell cycle arrest and apoptosis in both cell lines. Propranolol also decreased the expression of phosphorylated CREB-ATF and MEK-ERK pathways; suppressed the expression of matrix metalloproteinase-2, 9 and vascular endothelial growth factor; and inhibited gastric cancer cell migration. In the xenograft mouse model, propranolol treatment significantly inhibited tumor growth, and immunohistochemistry revealed that propranolol led to the suppression of proliferation and induction of apoptosis.
Conclusions
Propranolol inhibits the proliferation of gastric cancer cells by inducing G1-phase cell cycle arrest and apoptosis. These findings indicate that propranolol might have an opportunity as a new drug for gastric cancer.
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