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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVE:The aim of this study was to evaluate primary tumor (PT) and lymph node (LN) responses to neoadjuvant chemotherapy (NACT) for predicting long-term survival in patients with metastatic ...esophageal cancer (EC).
BACKGROUND:In evaluating NACT responses in patients with EC, imaging modalities typically target the PT in the esophagus, which is unmeasurable. Targeting measurable organs, like positive LNs, might provide more accurate assessments.
METHODS:We enrolled 251 patients with EC and clinically positive LNs that underwent curative resections, after triplet NACT. The percent reduction of PT area was measured with bidimensional computed tomography. The LN response was defined as the percent reduction of the sum of the short diameters in all positive LNs.
RESULTS:NACT reduced PTs and LNs by (median, range) 58.0% (38.1–94.9) and 34.5% (46.2–68.2), respectively. Based on the receiver-operating characteristic analyses for predicting a histological response and a 10% stepwise cutoff analyses of recurrence-free survival (RFS), responder/nonresponder cutoff values were ≥60% for PT area reductions and ≥30% for LN size reductions. 39.6% of patients showed discordant PT and LN responses. Compared with PT-responders, LN-responders had significantly less advanced pN (P < 0.0001) and pM (P = 0.015) in addition to less advanced pT (P < 0.0001) and better histological responses (P < 0.0001), and closer correlations to lymphatic, distant metastases and dissemination. A multivariate analysis of RFS identified 2 independent prognostic factorsthe LN response hazard ratio (HR) = 2.51, 95% confidence interval (CI) = 1.63–3.95, P < 0.0001 and the pN (HR = 2.72, 95% CI = 1.44–5.64, P = 0.0016), but not the PT response.
CONCLUSIONS:The LN response to NACT predicted long-term survival more precisely than the PT response in patients with metastatic EC.
OBJECTIVES:To investigate the residual pattern of esophageal cancer in the esophageal wall after neoadjuvant chemotherapy (NAC) and its clinical significance.
BACKGROUND: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.
METHODS: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 categoriesType 1shallow, Type 2central, Type 3deep, and Type 4diffuse. We examined associations between these Types and clinico-pathological factors, including prognosis.
RESULTS: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.
CONCLUSIONS: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.
Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a ...new therapy for PDAC.
We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo.
GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice.
GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong ...expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared with 9 of 24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the antiapoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation. Ectopic STAT3 expression increased radioresistance, whereas expression of the STAT3 negative regulator SOCS1 via an adenoviral vector improved radioresponse. Inhibiting the STAT3-Mcl-1 axis by SOCS1 enhanced DNA damage after irradition and induced apoptosis. Combining SOCS1 with radiotherapy enhanced antitumor responses in a murine xenograft model compared with the individual therapies. Tumor repopulation occurred transiently after treatment by irradiation but not the combination SOCS1/radiotherapy. Tumors subjected to this combination expressed high levels of γH2AX and low levels of Ki-67, which was maintained after cessation of treatment. Overall, we demonstrated that inhibiting the STAT3-Mcl-1 signaling axis by ectopic SOCS1 improved radiosensitivity by inducing apoptosis and enhancing DNA damage after radiotherapy, offering a mechanistic rationale for a new ESCC treatment.
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Gastric cancer is one of the most common malignant tumors. Although improvement in chemotherapy has been achieved, the clinical prognosis of advanced gastric cancer remains poor. Therefore, it is ...increasingly important to predict the prognosis and determine whether patients should or should not receive neoadjuvant or adjuvant chemotherapy. Leucine‐rich α2‐glycoprotein‐1 (LRG1) is overexpressed during inflammation and is associated with various malignancies. In this study, we assessed LRG1 expression in cancer specimens and in the sera of patients with cancer to clarify the usefulness of LRG1 as a biomarker in gastric cancer. This study enrolled 239 (for immunohistochemical staining; IHC) and 184 (for ELISA) patients with gastric cancer. Results of IHC showed that LRG1 expression was significantly associated with histological type, lymphatic and venous invasion, tumor and node factors, and disease stage. Overall survival was significantly worse in the high LRG1 expression group than in the low LRG1 group (P = 0.0003). Cox multivariate analysis of overall survival revealed that LRG1 expression was an independent prognostic factor (P = 0.0258). Serum LRG1 was significantly higher in gastric cancer patients than in healthy volunteers, and increased as the pathological stage progressed. Furthermore, a significant correlation was revealed between serum LRG1 level and LRG1 expression with IHC (P < 0.0001). Inhibition of LRG1 significantly decreased cell proliferation in vitro (migratory and invasive capacity of gastric cancer cells). These results suggest that LRG1 expression in tumors and serum may be a useful prognostic marker in gastric cancer patients.
Expression of leucine‐rich α2‐glycoprotein‐1 (LRG1) with both preoperative serum and resected specimen is a significant prognostic factor in gastric cancer. Inhibiting LRG1 decreases cell growth in gastric cancer cell lines. In gastric cancer, LRG1 expression has a critical role progression and may be a clinical therapeutic target.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
Anastomotic stricture after esophagectomy is a major cause of long-term morbidity and a poor quality of life. The aim of this study was to identify the risk factors for the development of ...anastomotic stricture after esophagectomy.
Methods
The study subjects were 213 patients who underwent esophagectomy for squamous cell carcinoma of the esophagus between 2012 and 2014. Anastomotic stricture was defined as stenosis at the site of anastomosis that required endoscopic dilation. Refractory stricture was defined as that requiring more than four sessions of dilations. Univariate and multivariate logistic regression analyses were used to identify the potential risk factors for the development of anastomotic stricture.
Results
In this retrospective study, 29 patients (13.6%) developed anastomotic stricture within a median period of 108 postoperative days and required a median of 2 dilations. Tumors located in the upper part of the esophagus (
p
= 0.004), the presence of cardiovascular disease (
p
= 0.024) and anastomotic leakage (
p
= 0.002) were identified as independent risk factors for the development of anastomotic stricture. The time to the diagnosis of refractory stricture (85 ± 33 days) was significantly shorter than that of non-refractory stricture (171 ± 22 days,
p
= 0.038).
Conclusions
Patients with squamous cell carcinoma in the upper esophagus with cardiovascular disease who develop postoperative anastomotic leakage should be carefully monitored to prevent the development of benign anastomotic stricture.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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