Background
Controlling Nutritional Status (CONUT), as calculated from serum albumin, total cholesterol concentration, and total lymphocyte count, was previously shown to be useful for nutritional ...assessment. The current study investigated the potential use of CONUT as a prognostic marker in gastric cancer patients after curative resection.
Methods
Preoperative CONUT was retrospectively calculated in 416 gastric cancer patients who underwent curative resection at Kumamoto University Hospital from 2005 to 2014. The patients were divided into two groups: CONUT-high (≥4) and CONUT-low (≤3), according to time-dependent receiver operating characteristic (ROC) analysis. The associations of CONUT with clinicopathological factors and survival were evaluated.
Results
CONUT-high patients were significantly older (
p
< 0.001) and had a lower body mass index (
p
= 0.019), deeper invasion (
p
< 0.001), higher serum carcinoembryonic antigen (
p
= 0.037), and higher serum carbohydrate antigen 19-9 (
p
= 0.007) compared with CONUT-low patients. CONUT-high patients had significantly poorer overall survival (OS) compared with CONUT-low patients according to univariate and multivariate analyses (hazard ratio: 5.09, 95% confidence interval 3.12–8.30,
p
< 0.001). In time-dependent ROC analysis, CONUT had a higher area under the ROC curve (AUC) for the prediction of 5-year OS than the neutrophil lymphocyte ratio, the Modified Glasgow Prognostic Score, or pStage. When the time-dependent AUC curve was used to predict OS, CONUT tended to maintain its predictive accuracy for long-term survival at a significantly higher level for an extended period after surgery when compared with the other markers tested.
Conclusions
CONUT is useful for not only estimating nutritional status but also for predicting long-term OS in gastric cancer patients after curative resection.
Background
Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study was performed to evaluate the prognostic significance of skeletal ...muscle depletion in patients with resectable stage I–III colorectal cancer (CRC).
Methods
We conducted a retrospective analysis of 220 consecutive patients with stage I–III CRC who underwent curative resection. The skeletal muscle cross-sectional area was measured by preoperative computed tomography. The lowest sex-specific quartile of skeletal muscle mass was classified as sarcopenia. Factors contributing to recurrence-free survival (RFS) were analyzed by univariate and multivariate Cox proportional hazard models.
Results
Of 220 patients who met our inclusion criteria, 55 (25 %) had sarcopenia. The median follow-up duration was 41.4 months. Patients with sarcopenia were younger and had higher carcinoembryonic antigen levels than patients without sarcopenia. RFS and overall survival (OS) were significantly shorter in patients with sarcopenia than those without (5-year RFS, 56 vs. 79 %, log-rank
p
= 0.006; 5-year OS, 68 vs. 85 %, log-rank
p
= 0.015). Multivariate Cox regression analysis revealed that sarcopenia was independently associated with shorter RFS (hazard ratio HR 2.176; 95 % confidence interval CI 1.200–3.943;
p
= 0.010) and OS (HR 2.270; 95 % CI 1.147–4.494;
p
= 0.019). The influence of sarcopenia on patient outcome was modified by age at surgery (
p
value for interaction = 0.026); sarcopenia was associated with a poor prognosis, especially in young patients (log-rank
p
< 0.001).
Conclusions
Sarcopenia negatively impacts survival in patients undergoing curative resection for stage I–III CRC.
Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12‐chemokine (CCL2, ‐3, ‐4, ‐5, ‐8, ‐18, ‐19, ‐21, CXCL9, ‐10, ‐11, ‐13) signature ...status from tumor tissue and the TLS expression. However, the potential significance of 12‐chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12‐chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12‐chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12‐chemokine signature status had a significant shorter relapse‐free survival in discovery cohort (HR: 1.61, 95% CI: 1.11–2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33–10.08, p = 0.0087). High 12‐chemokine signature status had significant associations with right‐sided tumor, high tumor‐localized TLS expression, BRAF mutant, CIMP‐high status and MSI‐high status. Furthermore, RNA‐seq based analysis showed that high 12‐chemokine signature status was strongly associated with inflammation‐related, immune cells‐related and apoptosis pathways (using gene set enrichment analysis), and more tumor‐infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP‐counter analysis). We investigated a promising effect of 12‐chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.
What's new?
Chronic inflammation at tumor sites is linked to the emergence of ectopic formations known as tertiary lymphoid structures (TLSs), which combat tumor progression. Here, analyses of human colorectal cancer (CRC) tissue show that high expression of a previously identified 12‐chemokine signature predicts high TLS expression at tumor sites and is associated with increased presence of tumor infiltrating immune cells and reduced CRC recurrence rate. High 12‐chemokine signature status was further linked to key clinicopathological and molecular features of CRC. The findings indicate that the 12‐chemokine signature is informative for host immune status and may have a prognostic role in CRC.
Background
A nutritional indicator suitable for predicting complications after esophagectomy has not been confirmed. The nutritional screening tool CONUT is a potential candidate.
Methods
We ...retrospectively analyzed 352 patients who underwent elective esophagectomy with lymphadenectomy for esophageal cancer between April 2005 and December 2014. Patients were divided into three groups according to the malnutrition degree in controlling nutritional status (CONUT): normal, light malnutrition, moderate or severe malnutrition.
Results
The numbers of patients assigned to the normal, light malnutrition, and moderate or severe malnutrition groups were 205, 126, and 21, respectively. One hundred forty-seven (41.8 %) patients were considered malnourished. Patients with moderate or severe malnutrition had a significantly high incidence of any morbidity, severe morbidities, and surgical site infection. Hospital stay in patients with moderate or severe malnutrition was significantly longer. Logistic regression analysis suggested that moderate or severe malnutrition was an independent risk factor for any morbidity hazard ratio (HR) 2.75, 95 % confidence interval (CI) 1.081–7.020;
p
= 0.034 and severe morbidities (HR 3.07, 95 % CI 1.002–9.432;
p
= 0.049).
Conclusions
CONUT was a convenient and useful tool to assess nutritional status before esophagectomy. Patients with moderate or severe malnutrition according to CONUT are at high risk for postoperative complications.
Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study evaluated the prognostic significance of skeletal muscle status before and ...after chemotherapy in patients with unresectable colorectal cancer (CRC).
We conducted a retrospective analysis of 215 consecutive patients with unresectable CRC who underwent systemic chemotherapy. Skeletal muscle cross-sectional area was measured by computed tomography. We evaluated the prognostic value of skeletal muscle mass before chemotherapy and the rate of skeletal muscle change in cross-sectional area after chemotherapy.
One-hundred-eighty-two patients met our inclusion criteria. There were no significant differences in progression-free survival (PFS) or overall survival (OS) associated with skeletal muscle mass before chemotherapy. However, 22 patients with skeletal muscle loss (>5%) after chemotherapy showed significantly shorter PFS and OS compared with those without skeletal muscle loss (PFS, log-rank p = 0.029; OS, log-rank p = 0.009). Multivariate Cox regression analysis revealed that skeletal muscle loss after chemotherapy (hazard ratio, 2.079; 95% confidence interval, 1.194-3.619; p = 0.010) was independently associated with OS.
Skeletal muscle loss after chemotherapy was an independent, negative prognostic factor in unresectable CRC.
Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. ...However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.
What's new?
The presence in the tumor stroma of cancer‐associated fibroblasts (CAFs) may be an indication of imminent tumor invasion and metastasis. CAFs appear to function through the stimulation of CXCL12/CXCR4 signaling, though precisely how these chemokines contribute to cancer progression is uncertain. Here, in gastric cancer cells, CXCL12/CXCR4 activation by CAF2 was found to enhance the clustering of integrin β1 at the cell surface and thereby promote gastric cancer cell invasiveness and motility. Increased invasiveness was suppressed by treatment with the CXCR4 antagonist, AMD3100, which blocked interactions between integrin β1 and the extracellular matrix.
Purpose
Pulmonary complications after esophagectomy are still common and are a major cause of mortality. The aim of this study was to clarify the risk factors for the occurrence of pulmonary ...complications after esophagectomy.
Methods
The clinical courses of 299 patients who underwent elective subtotal esophagectomy with lymph node dissection for esophageal cancer were retrospectively analyzed. Group I included patients who had pulmonary complications (
n
= 53), and group II included patients who did not (
n
= 246). The clinicopathological factors, surgical procedures and surgical results were compared between the groups.
Results
The frequency of any pulmonary complication was 17.7 %. Pneumonia (
n
= 26; 8.7 %) and respiratory failure that needed initial ventilatory support for 48 h or reintubation (
n
= 16; 5.4 %) were the major morbidities. The results of the logistic regression analysis suggested that smoking with a Brinkman index ≥800, salvage esophagectomy after definitive chemoradiotherapy and the amount of blood loss/body weight were independent factors associated with the occurrence of pulmonary complications.
Conclusion
Pulmonary complications after esophagectomy remain common despite advances in perioperative management. Cases with a history of heavy smoking, preoperative definitive chemoradiotherapy, and high blood loss during surgery require more careful postoperative pulmonary care.
Highlights • Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. • A field for cancerization, or a field defect, is formed by the ...accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. • A better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention.
A recent large‐scale phase III study (the ToGA trial) demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2‐positive gastric cancer. Although ...trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. However, it is unclear whether similar mechanisms of trastuzumab resistance are involved in gastric cancer (GC). The aim of the current study was to identify a novel micro‐RNA (miR)/gene pathway that regulates the sensitivity of HER2‐positive GC cells to trastuzumab. We focused on F‐box and WD repeat domain‐containing 7 (FBXW7), which is one of the major causes of drug resistance. We also identified miR‐223, which can regulate FBXW7, using miR quantitative reverse transcription‐PCR array analysis using by resistance cell line, which we established. Overexpression of miR‐223 decreased FBXW7 expression and the sensitivity of GC cells to trastuzumab, while suppression of miR‐223 restored FBXW7 expression and the sensitivity of GC cells to trastuzumab. Moreover, overexpression of miR‐223 significantly suppressed trastuzumab‐induced apoptosis. This study is the first report to reveal that the miR‐223/FBXW7 pathway regulates the sensitivity of a HER2‐positive GC cell line to trastuzumab through the modulation of apoptosis. These findings suggest that this pathway can be crucial for the mechanism of trastuzumab resistance in GC, which may lead to the development of individualized treatment in clinical practice.
What's new?
The monoclonal antibody trastuzumab is effective against HER2‐positive gastric cancers (GCs). However, as with breast cancer, many GCs develop resistance to this drug. In this study, the authors found that a microRNA called “miR‐233” interacts with a gene called “FBXW7” to regulate the sensitivity of HER2‐positive GC cells to trastuzumab, by altering apoptosis. These results suggest that the miR‐223/FBXW7 pathway may be a valuable therapeutic target to decrease resistance of GC to trastuzumab.
Background
Various systemic inflammatory and nutritional scores have been reported to predict postoperative outcomes. This study aimed to investigate the best systemic inflammatory and nutritional ...scores in colorectal cancer (CRC) patients who underwent potentially curative resection.
Method
We evaluated 468 consecutive CRC patients in this study. Comparisons of systemic inflammatory and nutritional scores, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), prognostic nutritional index (PNI), and modified Glasgow prognostic score (mGPS), were performed using univariate/multivariate analyses for patient survival.
Results
The PNI and mGPS, but not the NLR, PLR, and PI, were significantly associated with overall and relapse-free survival. The mGPS, but not the PNI, was strongly correlated with TNM stage (
P
< 0.001). Cox multivariate analysis showed that both the PNI and mGPS were exclusive independent prognostic factors for both overall and relapse-free survival (
P
< 0.001). Furthermore, the PNI status predicted patient survival more clearly than the mGPS in combination with TNM stage.
Conclusions
This study suggests that the PNI and mGPS are useful predictive scores in CRC patients who undergo potentially curative resection, especially the PNI in combination with TNM stage. Routine evaluation of the host status using the scores may be useful in CRC treatment.
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