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
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.
Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a ...compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiological manner. Here we use a rational approach to isolate CD4(+)FOXP3(+) regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human faecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, we isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory molecules--including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)--in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.
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.
Intraoperative electrocorticography (iECoG) is widely performed to identify irritative zones in the cortex during brain surgery; however, several limitations (e.g., short recording times and the ...effects of general anesthesia) reduce its effectiveness. The present study aimed to evaluate the utility of iECoG for localizing epileptogenic zones. We compared the results of iECoG and chronic electrocorticography (cECoG) in 25 patients with refractory epilepsy. Subdural electrodes were implanted with iECoG under general anesthesia (2% sevoflurane). cECoG recordings were performed for 3-14 days. The distribution of iECoG spikes was compared with cECoG spike, seizure onset zone, and resection areas. The concordance patterns of each distribution were classified into four patterns: Group 1: No spike in iECoG, Group 2: concordant (2a: iECoG smaller, 2b: iECoG larger, Group 3: discordant >50%). The concordance rate of interictal spikes, seizure onset zones, and resection areas were 88.0% (Group 2a: 72.0%, Group 2b: 16.0%), 70.0% (Group 2a: 25.0%, Group 2b: 45.0%), and 81.0% (Group 2a: 42.9%, Group 2b: 38.1%), respectively. The resection of iECoG spike areas significantly correlated with good surgical outcomes. The indication and limitations of iECoG need to be realized, and the complementary use of iECoG and cECoG may enhance clinical utility.
Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of ...the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8
T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8
T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8
T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.
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 evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC.
The pathological response to preoperative treatment is commonly ...evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery.
We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III, <10%; and IV, 0%. We analyzed the correlation of grade with clinico-pathological parameters.
Among 319 patients with clinically positive LNs, pathological LN regression grades were I/II/III/IV in 115/51/58/95 patients, and 191 patients (59.9%) showed discordance between the PT and LN pathological regression grades. LN regression grade significantly correlated with cN positive number, ypTNM, lymphovascular invasion, and clinical/pathological PT response. Multivariate analysis for recurrence-free survival revealed that LN regression grade hazard ratio (HR) = 2.25, P < 0.001, ypT (HR = 1.65, P = 0.005), and ypT (HR = 1.62, P = 0.004) were independent prognostic factors, but not pathological PT regression grade (P = 0.67).
Compared to PT response, pathological LN response better predicted long-term survival in EC patients who received NAC plus curative surgery.
Backgrounds
Since the prognosis of patients with adenocarcinoma of the esophagogastric junction (AEG) remains poor, more intensive treatments, including neoadjuvant chemotherapy (NAC), should be ...developed. We retrospectively examined whether neoadjuvant docetaxel, oxaliplatin, and S‑1 (DOS) combination chemotherapy resulted in a favorable clinical response and acceptable toxicity in patients with AEG.
Methods
This retrospective cohort study included 36 consecutive patients with cStage IIB–IV AEG (Siewert types I–III). Regarding stage IV disease, patients with resectable distant lymph node metastasis (M1-LYM) were eligible. Patients underwent three 3-week cycles of docetaxel (40 mg/m
2
) and oxaliplatin (100 mg/m
2
) on day 1 plus oral S-1 (80–120 mg according to body surface area) from day 1 to 14. Surgical resection was performed within 2–4 weeks after completion of NAC.
Results
Three cycles of neoadjuvant DOS were completed in 28 (78%) patients. Grade 3–4 neutropenia, anorexia, and diarrhea were observed in 26 (72%), 7 (19%), and 4 (11%) patients, respectively. Febrile neutropenia occurred in six (17%) patients. There were no treatment-related deaths. R0 resection was achieved in 35 (97%) patients, and postoperative morbidities of Clavien–Dindo grade III or higher were observed in 6 (17%) patients. Pathological complete response was observed in 11 (31%) of 36 patients. Pathological response rates of grade ≥ 2 and grade ≥ 1b were 47 and 72%, respectively. Two-year progression-free and overall survival rates were 60.1 and 81.2%, respectively.
Conclusions
Neoadjuvant DOS therapy for AEG produced high pathological response rates with an acceptable safety profile, and may be a promising treatment strategy.
PDF
