To clarify the role of splenectomy in total gastrectomy for proximal gastric cancer.
Splenectomy in total gastrectomy is associated with increased operative morbidity and mortality, but its survival ...benefit is unclear. Previous randomized controlled trials were underpowered and inconclusive.
We conducted a multiinstitutional randomized controlled trial. Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not invading the greater curvature was eligible. During the operation, surgeons confirmed that R0 resection was possible with negative lavage cytology, and patients were randomly assigned to either splenectomy or spleen preservation. The primary endpoint was overall survival (OS) and the secondary endpoints were relapse-free survival, operative morbidity, operation time, and blood loss. The trial was designed to confirm noninferiority of spleen preservation to splenectomy in OS with a noninferiority margin of the hazard ratio as 1.21 and 1-sided alpha of 5%.
Between June 2002 and March 2009, 505 patients (254 splenectomy, 251 spleen preservation) were enrolled from 36 institutions. Splenectomy was associated with higher morbidity and larger blood loss, but the operation time was similar. The 5-year survivals were 75.1% and 76.4% in the splenectomy and spleen preservation groups, respectively. The hazard ratio was 0.88 (90.7%, confidence interval 0.67-1.16) (<1.21); thus, the noninferiority of spleen preservation was confirmed (P = 0.025).
In total gastrectomy for proximal gastric cancer that does not invade the greater curvature, splenectomy should be avoided as it increases operative morbidity without improving survival.
Background
Specific treatment strategies are sorely needed for scirrhous-type gastric cancer still, which has poor prognosis. Based on the promising results of our previous phase II study (JCOG0210), ...we initiated a phase III study to confirm the efficacy of neoadjuvant chemotherapy (NAC) in type 4 or large type 3 gastric cancer.
Methods
Patients aged 20–75 years without a macroscopic unresectable factor as confirmed via staging laparoscopy were randomly assigned to surgery followed by adjuvant chemotherapy with S-1 (Arm A) or NAC (S-1plus cisplatin) followed by D2 gastrectomy plus adjuvant chemotherapy with S-1 (Arm B). The primary endpoint was overall survival (OS).
Results
Between October 2005 and July 2013, 316 patients were enrolled, allocating 158 patients to each arm. In Arm B, in which NAC was completed in 88% of patients. Significant downstaging based on tumor depth, lymph node metastasis, and peritoneal cytology was observed using NAC. Excluding the initial 16 patients randomized before the first revision of the protocol, 149 and 151 patients in arms A and B, respectively, were included in the primary analysis. The 3-year OS rates were 62.4% 95% confidence interval (CI) 54.1–69.6 in Arm A and 60.9% (95% CI 52.7–68.2) in Arm B. The hazard ratio of Arm B against Arm A was 0.916 (95% CI 0.679–1.236).
Conclusions
For type 4 or large type 3 gastric cancer, NAC with S-1 plus cisplatin failed to demonstrate a survival benefit. D2 surgery followed by adjuvant chemotherapy remains the standard treatment.
Background
Nivolumab monotherapy has demonstrated superior efficacy in advanced unresectable gastric cancer (GC), but its impact on resectable GC remains unknown. This phase I study aimed to evaluate ...safety, feasibility, and potential biomarkers of neoadjuvant nivolumab monotherapy in resectable GC.
Methods
Untreated, resectable, cT2 or more advanced gastric adenocarcinomas with clinical stage I, II, or III were treated with two doses of nivolumab before gastrectomy. Patients were excluded if their tumors may be applicable to neoadjuvant chemotherapy. The primary endpoint was the incidence of adverse event (AE) categories of special interest.
Results
All of the 31 enrolled patients completed 2 doses of nivolumab monotherapy. While 30 (97%) patients underwent surgery with curative intent, 1 patient discontinued before the planned surgical intervention because of a newly emerging liver metastasis. Seven patients (23%) had nivolumab treatment-related AEs, and one patient had a treatment-related AE of grade 3–4. The incidences of treatment-related AE categories of special interest ranged from 0 to 6%. Notable surgical complications included two cases of grade 3 anastomotic leakage and two cases of pancreatic fistula. The major pathologic response (MPR) assessed by the independent pathology review committee was achieved in five (16%) patients, of which one patient had a pathologic complete response. The MPR was mostly observed in patients with positive PD-L1 expression, high microsatellite instability, and/or high tumor mutation burden.
Conclusions
Neoadjuvant nivolumab monotherapy is feasible with an acceptable safety profile and induces a MPR in certain patients with resectable GC. (Registration: clinicaltrials.jp, JapicCTI-183895).
Background
Neoadjuvant chemotherapy (NAC) followed by radical surgery is a promising strategy to improve survival of patients with stage III gastric cancer, but is associated with the risk of ...preoperative overdiagnosis by which patients with early disease may receive unnecessary intensive chemotherapy.
Methods
We assessed the validity of a preoperative diagnostic criterion in a prospective multicenter study. Patients with gastric cancer with a clinical diagnosis of T2/T3/T4, M0, except for diffuse large tumors and extensive bulky nodal disease, were eligible. Prospectively recorded clinical diagnoses (cT category, cN category) were compared with postoperative pathological diagnoses (pT category, pN category, and pathological stage). The primary endpoint was the proportion of pathological stage I tumors among those diagnosed as cT3/T4, which we expected to be 5% or less.
Results
Data from 1260 patients enrolled from 53 institutions were analyzed. The proportion of pathological stage I tumors in those with a diagnosis of cT3/T4 (primary endpoint) was 12.3%, which was much higher than the prespecified value. The positive predictive value and the sensitivity for pathological stage III tumors were 43.6% and 87.8% respectively. The sensitivity and specificity of contrast-enhanced CT for lymph node metastasis were 62.5% and 65.7% respectively. After exploring several diagnostic criteria, we propose, for future NAC trials in Japan, a diagnosis of “cT3/T4 with cN1/N2/N3,” by which inclusion of pathological stage I tumors was reduced to 6.5%, although its sensitivity for pathological stage III tumors decreased to 64.5%.
Conclusion
Clinical diagnosis of T3/T4 tumors was not an optimal criterion to select patients for intensive NAC trials because more than 10% of patients with pathological stage I disease were included. We propose the criterion “cT3/T4 and cN1/N2/N3” instead.
Some patients develop recurrence after curative resection and adjuvant chemotherapy. S-1, an oral fluoropyrimidine, is one of the standard regimens in adjuvant chemotherapy, and is also used in ...first-line treatment for advanced/metastatic gastric cancer. It is controversial as to whether the same treatment strategy can be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy. To investigate this issue, we compared the outcomes of patients who developed recurrences after treatment with or without adjuvant chemotherapy using the results of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC).
Patients who had confirmed recurrence in the ACTS-GC trial were analyzed. We defined 2 independent cohorts. Cohort 1 patients were divided by whether they received adjuvant chemotherapy (adjuvant S-1 group and surgery-only group). Cohort 2 patients were divided by whether they received a regimen including S-1 (IS) or not including S-1 (NIS) after recurrence.
A total of 375 patients experienced recurrence (160 in the adjuvant S-1 group and 215 in the surgery-only group). In cohort 1, the median time from recurrence to death (TFRD) was 11.4 months (95% confidence interval CI, 8.4-13.9) in the adjuvant S-1 group and 11.3 months (95% CI, 9.7-13.1) in the surgery-only group (hazard ratio HR, 1.05; 95% CI, 0.84-1.31). In cohort 2, 292 patients received chemotherapy after recurrence and were divided into the IS (n = 189) or the NIS group (n = 103). The median TFRD was 13.9 months (95% CI, 12.7-15.6) in the IS group and 8.1 months (95% CI, 6.6-9.7) in the NIS group (HR, 0.59; 95% CI, 0.45-0.76), and there was no significant interaction between the adjuvant S-1 group and surgery-only group.
Adjuvant chemotherapy with S-1 prolonged overall survival without influencing the TFRD. The same treatment strategy may be applied for patients who develop recurrence after adjuvant chemotherapy and those who did not receive adjuvant chemotherapy.
NCT00152217 . First Posted on September 9, 2005.
The dorsal spinal cord, which is essential for somatosensory transmission, comprises a heterogeneous population of neurons with distinct axonal lengths and projection patterns. Although the ...developmental origin of local‐circuit interneurons in the dorsal spinal cord has been well characterized, that of long‐range neurons extending axons over a long distance such as supraspinal projection neurons and propriospinal neurons is largely unknown. In this study, we performed birthdate and lineage analyses of these long‐range neurons in the mouse dorsal spinal cord. Unilateral injection of a retrograde neuronal tracer, cholera toxin B, into the brain or spinal cord efficiently labeled supraspinal projection neurons localized in Rexed's lamina I and the dorsolateral funiculus (DLF) and long‐range propriospinal neurons localized in the DLF, all of which had ipsi‐ and contralaterally projecting populations. Most of these neurons were born between E9.5 and E10.5, much earlier than in the case of the neurogenesis of local‐circuit neurons. Lineage analysis using an Lbx1‐Cre mouse line demonstrated that most long‐range neurons were derived from Lbx1‐positive neuronal progenitors, except in the case of the contralaterally projecting propriospinal neurons. Characterization of their neurotransmitter identity revealed that almost all of the supraspinal projection neurons were excitatory, whereas the long‐range propriospinal neurons comprised both excitatory and inhibitory populations. These results suggest that the supraspinal projection neurons were derived from the early‐born dI5 progenitor domain and that the long‐range propriospinal ones arose from several early‐born progenitor domains.
In this study, we performed birthdate and lineage analyses to examine the developmental origin of supraspinal projection neurons and long‐range propriospinal neurons in the superficial dorsal spinal cord in the mouse. Our analysis suggests that the supraspinal projection neurons are derived from the early‐born dI5 progenitor domain and that long‐range propriospinal ones arose from several early‐born progenitor domains.
Background
Recent studies have found a negative impact of postoperative complications on long-term survival outcomes, but it has not been confirmed by data obtained from a prospective study with a ...large sample size. This study investigated the impact of postoperative complications on long-term survival outcomes, and considered the optimal definition of complication, using data from JCOG1001, which compared bursectomy and non-bursectomy for patients with cT3/4a locally advanced gastric cancer.
Methods
This study included 1191 of 1204 patients enrolled in the JCOG1001 trial. Complications were graded by Clavien–Dindo (C-D) classification. Impact of the grade (≥ C-D grade II or ≥ grade III) or type (any or intra-abdominal infectious) of complication on survival outcome was evaluated by univariate and multivariable analyses using the Cox proportional hazard model.
Results
The incidence of any ≥ C-D grade II and ≥ grade III complication was 23.0% and 9.7%, respectively, and that of ≥ grade II and ≥ grade III intra-abdominal infectious complication was 13.4% and 6.9%, respectively. Multivariable analysis showed all four definitions of complications were independent prognostic factors for overall survival. Conversely, only any ≥ C-D grade III complication was found to be an independent prognostic factor for relapse-free survival (hazard ratio, 1.445; 95% confidence interval, 1.026–2.036;
P
= 0.035).
Conclusions
Postoperative complications adversely affect the long-term survival outcomes of patients with cT3/4a gastric cancer. Any ≥ C-D grade III complication seems to be the most suitable definition of complication for predicting negative long-term survival outcomes.
Background
Aldehyde dehydrogenase 2 (
ALDH2
; rs671, Glu504Lys) and alcohol dehydrogenase 1B (
ADH1B
; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde ...accumulation after alcohol drinking. To date, however, evidence for a significant
ALDH2
–alcohol drinking interaction and a mediation effect of
ALDH2
/
ADH1B
through alcohol drinking on gastric cancer have remained unclear. We conducted two case–control studies to validate the interaction and to estimate the mediation effect on gastric cancer.
Methods
We calculated odds ratios (OR) and 95% confidence intervals (CI) for
ALDH2
/
ADH1B
genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways.
Results
ALDH2
Lys alleles had a higher risk with increased alcohol consumption compared with
ALDH2
Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04–6.27;
P
for trend = 0.007), indicating a significant
ALDH2
–alcohol drinking interaction (
P
interaction
= 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38–2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76–0.92) of the
ALDH2
Lys alleles with the
ALDH2
–alcohol drinking interaction. No significant association of
ADH1B
with gastric cancer was observed.
Conclusion
The observed
ALDH2
–alcohol drinking interaction and the direct effect of
ALDH2
Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer.
Background
Preoperative chemotherapy with cisplatin plus S-1 (CS) followed by gastrectomy with D2 plus para-aortic lymph node (PAN) dissection is regarded as a standard treatment in Japan for ...advanced gastric cancer with bulky lymph node (BN) and/or PAN metastasis. In the JCOG1002, we added docetaxel to CS (DCS) to further improve long-term outcomes. However, the primary endpoint, clinical response rate (RR), did not reach the expected level (Ito et al. in Gastric Cancer 20:322–31, 2017). Herein, we report our long-term survival results.
Methods
Patients with BN and/or PAN metastasis received 2 or 3 cycles of DCS therapy (docetaxel at 40 mg/m
2
and cisplatin at 60 mg/m
2
on day 1 and S-1 at 80 mg/m
2
per day for 2 weeks, followed by a 2-week rest) followed by gastrectomy with D2 plus PAN dissection and postoperative S-1 for 1 year.
Results
Between July 2011 and May 2013, 53 patients were enrolled. Clinically, 17.0% had both PAN and BN metastasis, and the rest had either PAN (26.4%) or BN (56.6%) metastasis. Among all eligible patients, the 5-year overall survival was 54.9% (95% confidence interval 40.3–67.3%) at the last follow-up in May 2018. Among 44 eligible patients with R0 resection, the 5-year relapse-free survival was 47.7% (95% confidence interval 32.5–61.5%).
Conclusions
Adding docetaxel to CS in preoperative chemotherapy for extensive nodal metastasis improved neither short-term outcomes nor long-term survival. Preoperative chemotherapy with CS followed by D2 + PAN dissection and postoperative S-1 remains the standard of care for patients with extensive nodal metastasis.
Background
Few well-controlled studies have compared postoperative complications between Billroth I (B-I) and Roux-en-Y (R-Y). The aim of the present study was to compare the incidence of overall and ...severe postoperative complications by reconstruction method after distal gastrectomy.
Methods
We performed a multi-institutional dataset study of patients who underwent distal gastrectomy with B-I or R-Y reconstruction from 2010 to 2014. Using propensity scores to strictly balance the significant variables, we compared postoperative complications between the techniques.
Results
After matching, we enrolled 1014 patients (
n
= 507 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (29% vs 17%,
P
< 0.0001). The incidence of intra-abdominal abscess (4.3% vs 1.8%,
P
= 0.0177), bowel obstruction (2.6% vs 0.6%,
P
= 0.0203), and delayed gastric emptying (5.3% vs 1.0%,
P
< 0.0001) in the R-Y group was significantly higher vs the B-I group, respectively; we saw no significant difference in leakage (3.4% vs 4.1%,
P
= 0.5084). The incidence of grade ≥ III severe postoperative complications in the R-Y group was significantly higher vs the B-I group (13% vs 7.1%,
P
= 0.0013). Multivariable analysis showed that R-Y reconstruction was a strong independent risk factor for overall postoperative complications (odds ratio 1.58,
P
= 0.0044) and grade ≥ III severe postoperative complications (odds ratio 1.75,
P
= 0.0127). A forest plot revealed that R-Y reconstruction was associated with a greater risk of both overall and grade ≥ III severe postoperative complications in any subgroups.
Conclusions
R-Y reconstruction was associated with increasing overall postoperative complications, as well as severe postoperative complications.
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