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
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.
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.
Here, we assess the ability of metabolic tumor volume (MTV) as measured by F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) to evaluate neoadjuvant chemotherapy ...response for patients with locally advanced esophageal cancer (EC).
Optimal methods to evaluate treatment response for EC patients have not yet been established. Although previous studies have reported the value of standardized uptake value (SUV), the accuracy of predicting histological response or long-term survival in EC is limited.
In all, 102 EC patients without distant metastasis who underwent F-FDG PET/CT both before and after the preoperative chemotherapy series were analyzed.
The median primary tumor MTV values before and after preoperative chemotherapy were 22.55 (range 0.4-183.1) and 2.75 (0-52.9), respectively, and the median MVT reduction rate was 86.5%. We found the most significant difference in survival between PET responders and nonresponders with a cut-off value of 60% MTV reduction, using a 10% stepwise cut-off analysis 2-year progression-free survival (PFS): 79.2 vs 44.4%; hazard ratio (HR) 3.397; P < 0.0001). With this cut-off value, histological response (P = 0.0091), tumor location (P = 0.0102), pT (P = 0.0011), and pN (P = 0.0110) were significantly associated with PET response. Univariate analysis of PFS indicated a correlation between PFS and tumor size, cT, decrease of primary lesion by CT, SUVmax reduction rate, MTV reduction rate, pT, pN, and pM. Multivariate analysis further identified pM (HR 3.063; P = 0.0279) and MTV reduction rate (HR 2.471; P = 0.0263) to be independent prognostic predictors, but not decrease of primary lesion by CT or SUVmax reduction rate.
MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.
It is commonly perceived that surgery in obese patients is associated with worse outcomes than in nonobese patients. Because of the increasing prevalence of obesity and colonic diseases in the world ...population, the impact of obesity on outcomes of laparoscopic colectomy remains an important subject. The aim of this review was to evaluate the feasibility and safety of laparoscopic colectomy for colorectal diseases in obese patients compared with nonobese patients.
We conducted a comprehensive review for the years 1983-2010 to retrieve all relevant articles.
A total of 33 studies were found to be eligible and included 3 matched case control studies and 1 review article. Obesity, often accompanied by preexisting comorbidities, was associated with longer operative times and higher rates of conversion to open procedures mainly because of the problem of exposure and difficulties in dissection. Although some studies showed obesity was associated with increased postoperative morbidity including cardiopulmonary and systemic complications, or ileus leading to longer hospital stay, there was no evidence about the negative impact of obesity on intraoperative blood loss, perioperative mortality, and reoperation rate. Whether obesity is a risk factor for wound infection after laparoscopic colectomy remains unclear. Though sometimes in obese patients, additional number of ports were necessary to successfully complete the procedure laparoscopically, obesity did not influence the number of dissected lymph nodes in cancer surgery. Lastly, the postoperative recovery of gastrointestinal function was similar between obese and nonobese patients.
Laparoscopic colorectal surgery appears to be a safe and reasonable option in obese patients offering the benefits of a minimally invasive approach, with no evidence for compromise in treatment of disease.
Background
Sarcopenia and obesity are associated with outcomes after surgery. However, few studies have investigated which more accurately predicts postoperative complications or prognosis in ...patients with gastric cancer.
Methods
A total of 567 consecutive patients with gastric cancer who underwent gastrectomy between 2010 and 2015 were retrospectively reviewed. Psoas muscle mass index (PMI) and visceral fat area (VFA) were measured by CT scan. Patients were divided into two groups based on PMI (PMI-H group: male ≥ 6.36 cm
2
/m
2
, female ≥ 3.92 cm
2
/m
2
; and PMI-L group: male < 6.36 cm
2
/m
2
, female < 3.92 cm
2
/m
2
) and two groups based on VFA (VFA-H group: ≥ 100 cm
2
; VFA-L group: < 100 cm
2
). The incidence of postoperative complications and the recurrence-free survival (RFS) were compared between the two groups.
Results
The incidence of postoperative complications was significantly higher in the VFA-H group than in the VFA-L group (35.1% vs. 20.3%;
P
< 0.001), whereas there was no significant difference between the PMI-H and PMI-L groups. Multivariate analysis showed that PMI-L and VFA-H were independent risk factors for pneumonia (odds ratio, 4.49;
P
= 0.018) and intra-abdominal abscess (odds ratio, 5.19;
P
= 0.004), respectively. While there was no significant difference in RFS between the VFA-H and VFA-L groups, the PMI-L group showed significantly worse RFS than the PMI-H group (
P
< 0.001).
Conclusions
PMI and VFA were useful predictive factors for postoperative pneumonia and intra-abdominal abscess, respectively. PMI might be a useful prognostic factor in patients with gastric cancer, but VFA is not.
To investigate the residual pattern of esophageal cancer in the esophageal wall after neoadjuvant chemotherapy (NAC) and its clinical significance.
NAC is a standard treatment for locally advanced ...esophageal cancer; however, residual tumor patterns in resected specimens after NAC and their clinico-pathological characteristics remain unknown.
One hundred twenty consecutive patients with cT3 or deeper esophageal cancer underwent curative esophagectomy after NAC and achieved grade 2 histological responses between 2000 and 2016. Hematoxylin-eosin staining of residual tumor sections revealed 4 remnant categories: Type 1: shallow, Type 2: central, Type 3: deep, and Type 4: diffuse. We examined associations between these Types and clinico-pathological factors, including prognosis.
Forty-five (38%) specimens had no residual tumor cells in the mucosal layer. The adventitia layer displayed the lowest residual tumor cell frequency (18%) among all layers. Types 1, 2, 3, and 4 residual tumor patterns were found in 49 (41%), 33 (28%), 9 (8%), and 29 (24%) patients, respectively. Type 4 showed the maximum standard uptake value after NAC; Types 3 and 4 had higher ratios of venous invasion than Type 1 or 2. Patients with Type 3 or 4 more frequently developed pleural dissemination or distant metastasis than patients with Type 1 or 2. Survival was similar among the 4 Types.
After NAC for locally advanced esophageal cancer, the shallow residual tumor pattern was most common, but approximately 40% of specimens showed no tumor cells in the mucosal layer. Deep and diffuse remnant patterns were associated with high risks of pleural dissemination and distant metastasis.
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