Claudin-18 status and its correlation with HER2 and PD-L1 expression in gastric cancer with peritoneal dissemination.

BACKGROUND: Gastric cancer with peritoneal dissemination (PD) has a dismal prognosis, and current treatments have shown little efficacy. CLDN18.2-targeted therapies have shown promising efficacy against gastric cancers that express high levels of CLDN18. Because of the limited information regarding CLDN18.2 status in PD, we analyzed PD-positive gastric cancers for CLDN18 status in both primary and PD, along with HER2 and PD-L1 combined positive score (CPS). METHODS: Immunohistochemical analyses were performed on 84 gastric cancer cases using paired primary and PD tissue samples. RESULTS: At 40% cut-off, CLDN18 was positive in 57% (48/84) primary tumors and in 44% (37/84) PDs. At 75% cut-off, 28.6% (24/84) primary tumors and 20.2% (17/84) PDs were CLDN18-positive. The concordance rate between primary tumors and PD was 79.8% at 40% cut-off and 75% at 75% cut-off. When comparing biopsy and surgical specimens, the concordance rates were 87.5% at 40% cut-off and 81.3% at 75% cut-off. Within a tumor, the superficial area tended to have a higher CLDN18-positive rate than the invasive front (P = 0.001). Although HER2 -positivity was only 11.9% in this cohort, CLDN18 positivity in HER2-negative tumors (n = 74) was relatively high: 60.8% at 40% cut-off and 28.4% at 75% cut-off. Among double-negative (HER2 - and PD-L1 CPS < 1) tumors, CLDN18 positivity was 67.6% at 40% cut-off and 26.5% at 75% cut-off. CONCLUSIONS: CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer.

Prognostic Impact of Serum SCC Antigen in the 566 Upfront Surgery Group of Esophageal Squamous Cell Carcinoma: A Multi-Institutional Study of the Japan Esophageal Society.

PURPOSE: This study aimed to determine the clinicopathologic and prognostic significance of squamous cell carcinoma antigen (SCC-Ag) in patients with esophageal SCC who underwent radical surgery without neoadjuvant therapy. METHODS: This study included 566 patients with primary esophageal SCC who underwent radical resection without neoadjuvant therapy at 15 Japanese hospitals between 2008 and 2016. The cutoff value of SCC-Ag was 1.5 ng/mL based on the receiver operating characteristic curves. Preoperative SCC-Ag and postoperative SCC-Ag were analyzed to evaluate clinicopathological and prognostic significance. Survival curves were compared between the SCC-Ag-positive group and the SCC-Ag-negative group. The prognostic impact of SCC-Ag was evaluated using univariate and multivariate analyses. RESULTS: The preoperative SCC-Ag-positive rate was 23.5% (133/566). SCC-Ag-positive status was significantly associated with old age (p = 0.042), tumor depth (p <0.001), and tumor stages (p <0.001). The preoperative SCC-Ag-positive group had significantly poorer overall survival than the SCC-Ag-negative group (p = 0.030), but it was not an independent predictor of poor prognosis. Postoperative SCC-Ag-positive status was an independent risk factor for poor overall survival (p = 0.034). CONCLUSION: Both pre- and postoperative SCC-Ag-positive statuses were significantly associated with poor prognosis. Postoperative SCC-Ag-positive status was an independent risk factor for predicting overall survival.

Preoperative NUn score serves as a robust predictor of overall and disease-specific survivals following radical surgery for gastric cancer.

PURPOSE: Methods to preoperatively stratify oncological risks associated with gastric cancer (GC) are limited. Host inflammatory parameters, i.e., serum C-reactive protein (CRP) and albumin levels, are known to be associated with outcomes. We examined the relationships between disease-specific mortality and four CRP-albumin-based indices (CRP-albumin ratio [CAR], modified Glasgow prognostic score [mGPS], Osaka prognostic score [OPS], and NUn score) preoperatively measured in cases with resectable GC. METHODS: Survival outcomes of 1290 consecutive GC patients with oncological gastrectomy were reviewed. Predictive significances of preoperative CAR, mGPS, OPS, and NUn scores were assessed with time-dependent receiver operating characteristic curves and Cox regression analyses. RESULTS: Median follow-up was 107 months. Area under the curve for predicting overall and disease-specific survivals (OS/DSS) for the preoperative NUn score was clearly superior to those of the other parameters. On univariate Cox regression analysis, preoperative CAR, mGPS, OPS, and the NUn score all correlated significantly with OS/DSS. On multivariate Cox regression analysis, the preoperative NUn score, as a continuous variable, showed an independent relationship with OS (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.16-1.50, per 1-unit increase, P < 0.001) and even DSS (HR 1.23, 95% CI 1.02-1.49, P = 0.032). The other three markers failed to maintain independence for DSS. CONCLUSIONS: Preoperative NUn scores are stably associated with outcomes, including disease-specific mortality, possibly serving as a simple measure to define the likelihood of progression to systemic disease after meticulous surgery for GC, which may contribute to identifying patients who would benefit from additional modalities.

Percent vital capacity predicts postoperative sarcopenia after esophagectomy in initially nonsarcopenic esophageal cancer patients: a retrospective cohort study.

PURPOSE: The development of sarcopenia after esophagectomy is reported to affect the outcomes of patients with esophageal cancer (EC); however, the characteristics of patients likely to be predisposed to postoperative sarcopenia have not been defined. This study explores the associations between preoperative respiratory function and surgery-induced sarcopenia in EC patients confirmed as nonsarcopenic preoperatively. METHODS: The subjects of this retrospective review were 128 nonsarcopenic patients who underwent esophagectomy for EC. We took body composition measurements and performed physical function tests 3 and 6 months postoperatively, to establish whether sarcopenia was present, according to the 2019 Asian Working Group for Sarcopenia guideline. We defined patients with surgery-induced sarcopenia as those with evidence of the development of sarcopenia within 6 months postoperatively or those with documented sarcopenia at 3 months but who could not be evaluated at 6 months. RESULTS: Surgery-induced sarcopenia developed in 19 of the 128 patients (14.8%), which correlated significantly with the preoperative %VC value (p < 0.01), but not with the preoperative FEV1.0% value. We set the lower quartile %VC value (91%) as the cut-off for predicting surgery-induced sarcopenia. A low %VC was independently associated with surgery-induced sarcopenia (odds ratio: 5.74; 95% confidence interval: 1.99-16.57; p < 0.01). CONCLUSIONS: Based on the findings of this study, %VC was a simple but valuable factor for predicting sarcopenia induced by esophagectomy.

The importance of ethnic-specific cut-offs of low muscle mass for survival prediction in oncology.

BACKGROUND & AIMS: While skeletal muscle index (SMI) is the most widely used indicator of low muscle mass (or sarcopenia) in oncology, optimal cut-offs (or definitions) to better predict survival are not standardized. METHODS: We compared five major definitions of SMI-based low muscle mass using an Asian patient cohort with gastrointestinal or genitourinary cancers. We analyzed 2015 patients with surgically-treated gastrointestinal (n = 1382) or genitourinary (n = 633) cancer with pre-surgical computed tomography images. We assessed the associations of clinical parameters, including low muscle mass by each definition, with cancer-specific survival (CSS) and overall survival (OS). RESULTS: During a median follow-up period of 61 months, 303 (15%) died of cancer, and 147 died of other causes. An Asian-based definition diagnosed 17.8% of patients as having low muscle mass, while the other Caucasian-based ones classified most (>70%) patients as such. All definitions significantly discriminated both CSS and OS between patients with low or normal muscle mass. Low muscle mass using any definition but one predicted a lower CSS on multivariate Cox regression analyses. All definitions were independent predictors of lower OS. The original multivariate model without incorporating low muscle mass had c-indices of 0.63 for CSS and 0.66 for OS, which increased to 0.64-0.67 for CSS and 0.67-0.70 for OS when low muscle mass was considered. The model with an Asian-based definition had the highest c-indices (0.67 for CSS and 0.70 for OS). CONCLUSIONS: The Asian-specific definition had the best predictive ability for mortality in this Asian patient cohort.

Alterations in Intratumoral Immune Response before and during Early-On Nivolumab Treatment for Unresectable Advanced or Recurrent Gastric Cancer.

We investigated the tumor immune response in gastric cancer patients receiving third-line nivolumab monotherapy to identify immune-related biomarkers for better patient selection. Nineteen patients (10 males, median age 67 years) who received nivolumab as a third- or later-line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR; objective response rate, OS; overall survival, PFS; progression-free survival) to previous trials. The immunograms of individual subjects displayed no significant changes before or early in the treatment, except for the regulatory T cell (Treg) score. Moreover, there were no consistent alterations observed among cases experiencing DCB. The intratumoral immune response was suppressed by previous treatments in most third- or later-line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in early-on-treatment tumors, but clonal replacement did not impact efficacy. High T cell/Treg ratios and a low UV-radiation-response gene signature were linked to DCB and treatment response. This study emphasizes the tumor immune response's importance in nivolumab efficacy for gastric cancer. High T cell/Treg ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. The tumor-infiltrating immune response was compromised by prior treatments in third-line therapy, implying that, to enhance immunotherapeutic outcomes, commencing treatment at an earlier stage might be preferable. Larger cohort validation is crucial to optimize immune-checkpoint inhibitors in gastric cancer treatment.

Laparoscopic and endoscopic cooperative surgery as palliative treatment for elderly patients with gastric cancer.

Oncological gastrectomy, despite remaining a mainstay of gastric cancer treatment, is reportedly associated with high morbidity and mortality in elderly patients. Less invasive modalities suitable for senior gastric cancer patients with insufficient surgical tolerance are thus needed. We adopted laparoscopic and endoscopic cooperative surgery as an alternative for elderly gastric cancer cases unsuitable for aggressive gastrectomy. To date, we have experienced three cases (80-86 years old) undergoing palliative laparoscopic and endoscopic cooperative surgery. Postoperative courses were uneventful in two cases, while sutural leakage occurred in the other, which was managed conservatively. Postoperative loss of body weight and skeletal muscle mass appeared to be minimal according to bioelectrical impedance analyses. No gastric cancer recurrence was detected in any of our three cases. As to the balance between radicality and safety, laparoscopic and endoscopic cooperative surgery is potentially a viable option for geriatric gastric cancer patients in whom conventional gastrectomy is contraindicated.

Prior treatment with oxaliplatin-containing regimens and higher total bilirubin levels are risk factors for neutropenia and febrile neutropenia in patients with gastric or esophagogastric junction cancer receiving weekly paclitaxel and ramucirumab therapy: a single center retrospective study.

BACKGROUND: Weekly paclitaxel + ramucirumab (wPTX + RAM) therapy is recommended as the standard second-line chemotherapy regimen for unresectable advanced/recurrent gastric cancer (GC) or esophagogastric junction cancer. Recent subgroup analysis of the RAINBOW trial revealed a higher frequency of severe neutropenia due to wPTX + RAM in Japanese compared to Western patients. However, no risk factors for severe neutropenia have been identified. METHODS: This retrospective observational study included patients with advanced/unresectable gastric or esophagogastric junction cancer who received wPTX + RAM after failure to respond to platinum and fluoropyrimidine doublet chemotherapy between June 2015 and April 2020. We conducted multivariable logistic regression analyses to identify the risk factors associated with grade 4 neutropenia and febrile neutropenia (FN). In addition, we investigated the relationship between the number of risk factors and overall survival (OS) and progression-free survival (PFS). RESULTS: Among 66 patients who met the inclusion criteria, grade 4 neutropenia and FN occurred in 21 (31.8%) and 12 (18.2%) patients, respectively. Prior treatment with oxaliplatin-containing regimens was identified as an independent risk factor for developing grade 4 neutropenia (odds ratio (OR) 20.034, 95% confidence interval (95% CI) 3.216-124.807, P = 0.001). Total bilirubin of > 1.5 mg/dL (OR 31.316, 95% CI 2.052-477.843, P = 0.013) and prior treatment with oxaliplatin-containing regimen (OR 12.502, 95% CI 1.141-137.022, P = 0.039) were identified as independent risk factors for developing FN. Next, we classified patients with 0, 1, 2 risk factor(s) as RF-0, RF-1, and RF-2 subgroups, respectively, and compared the PFS and OS among the three subgroups. PFS was not significantly different among the three subgroups, whereas OS was significantly shorter in the RF-2 subgroup (median 1.4 month, 95% CI 0.0-5.3 month) than in the RF-0 subgroup (median 10.2 month, 95% CI 6.8-13.5 month, P < 0.01 vs RF-2) and RF-1 subgroup (median 13.3 month, 95% CI 10.9-15.7 month, P < 0.01 vs RF-2). CONCLUSIONS: Careful monitoring for grade 4 neutropenia and FN is needed for patients receiving wPTX + RAM therapy who have a history of treatment with oxaliplatin-containing regimens and higher total bilirubin levels.

Lymphatic flow mapping using near-infrared fluorescence imaging with indocyanine green helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer not treated with neoadjuvant chemotherapy.

BACKGROUND: Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for the intraoperative prediction of lymph node metastasis in esophageal or esophagogastric junction cancer. However, a consistent method that yields sufficient diagnostic quality is yet to be confirmed. This study explored the diagnostic utility of our newly established lymphatic flow mapping protocol for predicting lymph node metastasis in patients with esophageal or esophagogastric junction cancer. METHODS: We injected 0.5 mL of ICG (500 µg/mL) into the submucosal layer at four peritumoral points on the day before surgery for 54 patients. We performed lymphatic flow mapping intraoperatively using NIR imaging. After determining the NIR status and presence of metastases, evaluable lymph node stations on in vivo imaging and all resected lymph nodes were divided into four categories: ICG+meta+ (true positive), ICG+meta- (false positive), ICG-meta+ (false negative), and ICG-meta- (true negative). RESULTS: The distribution of ICG+ and meta+ lymph node stations differed according to the primary tumor site. Sensitivity and specificity for predicting meta+ lymph nodes among ICG+ ones were 50% (95% CI 41-59%) and 75% (73-76%), respectively. Predicting meta+ lymph node stations among ICG+ stations improved these values to 66% (54-77%) and 77% (74-79%), respectively. Undergoing neoadjuvant chemotherapy was an independent risk factor for having meta+ lymph nodes with false-negative diagnoses (odds ratio 4.82; 95% CI 1.28-18.19). The sensitivity of our technique for predicting meta+ lymph nodes and meta+ lymph node stations in patients who did not undergo neoadjuvant chemotherapy was 79% (63-90%) and 83% (61-94%), respectively. CONCLUSION: Our protocol potentially helps to predict lymph node metastasis intraoperatively in patients with esophageal or esophagogastric junction cancer undergoing esophagectomy who did not undergo neoadjuvant chemotherapy.

Effects of the preoperative use and dosage of steroids on postoperative complications of gastric cancer surgery.

PURPOSE: To investigate the effects of preoperative steroid administration, including dosage, on complications after gastrectomy for gastric cancer. METHODS: We reviewed patients who underwent gastrectomy for gastric and esophagogastric junctional adenocarcinoma between 2013 and 2019 at the Department of Gastrointestinal Surgery, The University of Tokyo. RESULTS: Among the total 764 patients eligible for inclusion in the study, 17 were on steroid medication preoperatively (SD group) and 747 were not (ND group). The hemoglobin, serum albumin levels, and respiratory functions were significantly lower in the SD group than in the ND group. The incidence of postoperative complications classified as Clavien-Dindo (C-D) ≥ 2 was significantly greater in the SD group than in the ND group (64.7% vs. 25.6%, p < 0.001). Intra-abdominal infection (35.2% vs. 9.6%, p < 0.001) and anastomotic leakage (11.8% vs. 2.1%, p < 0.001) occurred more frequently in the SD group than in the ND group. On multiple logistic regression analysis for C-D ≥ 3 postoperative complications, the odds ratio for oral steroid use ≥ 5 mg per day as prednisolone had the highest value, of 13.0 (95% confidence interval 2.46-76.2, p < 0.01). CONCLUSION: Preoperative oral steroid use was identified as an independent risk factor for postoperative complications after gastrectomy for gastric cancer. Furthermore, the complication rate appears to increase as the oral steroid dosage is increased.

PD-L1 and HLA-class I expression status and their therapeutic implication in oesophageal small-cell carcinoma.

AIMS: Oesophageal small-cell carcinoma is a rare and highly aggressive subtype of oesophageal cancer with a dismal prognosis. To explore the potential applicability of immunotherapy, we investigated the expression status of programmed death ligand 1 (PD-L1) and human leukocyte antigen (HLA)-class I and the degree of tumour-infiltrating lymphocytes (TILs) in oesophageal small-cell carcinoma. METHODS AND RESULTS: PD-L1 and HLA-class I expression levels were evaluated in 10 pure small-cell carcinomas and five mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). The combined positive score (CPS) and tumour proportion score (TPS) were used for PD-L1 assessment. Immunohistochemistry for mismatch repair (MMR) proteins was also performed. PD-L1 immunohistochemistry demonstrated CPS ≥1 in nine (60%), CPS ≥10 in five (33%), and TPS ≥1 in five (33%) cases. Overall survival was significantly longer in patients with CPS ≥1 than in those with CPS <1. HLA-class I deficiency (>50% tumour cells) was noted in five cases (33%), with no significant correlation with PD-L1 expression status. Among the five MiNENs, HLA-class I expression was decreased in the small-cell carcinoma component of three cases. HLA-class I deficiency was significantly associated with higher TNM stage and reduced TIL levels. MMR deficiency was not observed in any case. CONCLUSION: Given that a significant subset (40%) exhibited PD-L1 CPS ≥1 with preserved HLA-class I expression and high levels of TIL, the PD-1/PD-L1 pathway is a potential therapeutic target for oesophageal small-cell carcinoma.

Low pretherapy skeletal muscle mass index is associated with an increased risk of febrile neutropenia in patients with esophageal cancer receiving docetaxel + cisplatin + 5-fluorouracil (DCF) therapy.

PURPOSE: Docetaxel + cisplatin + 5-fluorouracil (DCF) therapy, a frequently prescribed regimen for esophageal cancer, is associated with a high risk of febrile neutropenia (FN). This study investigated whether a low skeletal muscle mass index (SMI) is an independent risk factor for FN. METHODS: This retrospective, observational study investigated the SMI of patients with esophageal cancer who received DCF therapy between March 2018 and July 2020. Based on the Asian sarcopenia criteria, patients were divided into two groups: high and low SMI (SMI of < 7.0 and 5.7 kg/m2 for males and females, respectively). The incidence of FN was then compared between the two groups. RESULTS: Thirty-nine patients (20 and 19 in the high- and low-SMI groups, respectively) were included in this study. The incidence of FN was significantly higher in the low-SMI group (63.2% vs. 20.0%, P = 0.006). Univariable and multivariable logistic regression analyses revealed that a low SMI was an independent risk factor for FN (odds ratio, 7.178; 95% confidence interval, 1.272-40.507; P = 0.026). In addition, the frequency of dose reduction in DCF therapy was significantly higher in the low-SMI group (68.4% vs. 35.0%, P = 0.037). CONCLUSION: Low SMI is an independent risk factor for FN in patients with esophageal cancer receiving DCF therapy.

Aberrant Cadherin11 expression predicts distant metastasis of gastric cancer.

The prognosis of gastric cancer (GC) is significantly affected by distant metastases and postoperative recurrences. Bone metastasis is one of the worst prognostic metastases in GC; however, its molecular mechanisms and predictive biomarkers remain elusive. In prostate and breast cancers, it has been reported that overexpression of Cadherin 11 (CDH11), a mesenchymal cell-cell contact factor, is known to be correlated with bone metastasis. Overexpression of CDH11 mRNA in bulk GC tissues has also been reported to be associated with a worse prognosis. However, a more precise evaluation of CDH11 expression in GC cells is necessary to establish a robust link between CDH11 and metastatic features of GC. We performed immunohistochemical analysis of CDH11 expression in 342 GC cases, of which specimens were obtained at the time of surgery, with a special focus on its aberrant membranous expression in GC cells. The correlations between aberrant CDH11 expression and distant metastases and the prognosis of GC cases were statistically investigated. Approximately half of the GC cases investigated showed aberrant expression of CDH11 in the GC cells of primary lesions. Aberrant CDH11 expression was statistically associated with bone metastasis of GCs. Moreover, metastases to the liver and distant lymph nodes were also statistically correlated with CDH11 expression. Aberrant CDH11 expression in GC cells in primary tumor lesions was shown to be a predictive biomarker of distant metastases in GC. GCs with CDH11 expression require preventive clinical attention for the detection of metastatic lesions.

Significance of dissection in each regional lymph-node station of esophageal cancer based on efficacy index and recurrence patterns after curative esophagectomy.

BACKGROUND: The optimal extent of lymph-node (LN) dissection in esophageal cancer has not been established. Although the frequency and patterns of recurrence in each regional LN station after radical dissection are important in determining the regional LNs of thoracic esophageal cancer to be routinely dissected, this information has not been investigated sufficiently. We studied the significance of dissection at each LN station based on their recurrence patterns. METHODS: Six hundred and twelve patients with esophageal cancer who underwent curative esophagectomy were studied. The incidence and pattern of recurrence (systemic or non-systemic) at each regional LN station were analyzed. To compare the significance of dissection among regional LNs, the efficacy index (EI) was also calculated. RESULTS: Regional LN recurrence was diagnosed in 101 (16.5%) patients. Among the regional LNs, recurrent laryngeal nerve, paraesophageal, and perigastric LNs showed higher EIs (3.1-6.7). Pretracheal and posterior thoracic para-aortic LNs showed low EIs (0-0.2). Supraclavicular LNs had moderate EIs (1.7-2.0). The recurrence rate was highest in the pretracheal LN, followed by the supraclavicular LNs. The majority (81.8%) of the pretracheal LN had a systemic recurrence, while about half (right: 60.0%, left: 43.8%) of the supraclavicular LNs had a systemic recurrence. CONCLUSION: Due to the high incidence of systemic recurrence or low EI for pretracheal and posterior thoracic para-aortic LNs, we suggest that these LN stations be regarded as non-regional LNs and be excluded from routine dissection. Supraclavicular LNs may also be excluded from routinely dissected stations.

Elevation of serum plasminogen activator inhibitor-1 predicts postoperative delirium independent of neural damage: a sequential analysis.

Older adult surgical patients are susceptible to developing delirium. Early intervention can be initiated if a potential biomarker associated with delirium can be identified during the acute phase of surgery. Therefore, we investigated the changes in the levels of serum inflammatory mediators responsible for delirium. Serum biomarkers were measured preoperatively to postoperative day 3 in 96 patients who underwent esophageal cancer surgery and compared between patients who did and did not develop delirium. Serum concentrations of the brain-derived phosphorylated neurofilament heavy subunit remained at higher levels throughout the entire perioperative period in patients with delirium (n = 15) than in those without delirium (n = 81). The interaction between delirium and non-delirium was significant for plasminogen activator inhibitor-1 (including age as a covariate, F = 13.360, p < 0.0001, η2 p = 0.134, observed power 1.000) during the perioperative periods. Plasminogen activator inhibitor-1 level discriminated between patients with and without clinically diagnosed delirium with significantly high accuracy (area under curve, 0.864; sensitivity, 1.00: negative predictive value, 1.000; p = 0.002). Rapid increases in the levels of serum plasminogen activator inhibitor-1 may enable clinicians to identify patients at risk of developing postoperative delirium and initiate early prevention and intervention.

Combining nutritional status with TNM stage: a physiological update on gastric cancer staging for improving prognostic accuracy in elderly patients.

BACKGROUND: The tumor-node-metastasis (TNM) staging system does not take the patient's physiological status into consideration, reportedly making it insufficient for predicting survival outcomes in frail cancer patients. We assessed the prognostic values of several nutrition- and inflammation-based markers in combination with pTNM stage in gastric carcinoma (GC) patients. METHODS: In total, 1166 patients undergoing GC surgery were studied. The prognostic capabilities of 3 nutritional and 3 systemic inflammatory parameters were examined. We developed new staging systems by adding these markers, individually, to the pTNM stage. We then compared the prognostic capabilities of our new systems with that of pTNM stage alone. We also assessed the prognostic values of these systems by dividing our patient cohort into elderly (≥ 65 years) and non-elderly groups. RESULTS: Our novel staging systems had greater predictive capabilities for overall survival (OS) than pTNM alone. Most notably, survival discrimination was significantly increased for pTNM when it was combined with albumin-based nutritional indices (geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI)). Our new staging systems incorporating GNRI or PNI into pTNM had significantly better predictive capability for OS, especially non-GC mortality, than pTNM alone in elderly GC patients. In the non-elderly patients, the predictive capabilities of the new staging systems for OS differed minimally from that of pTNM. CONCLUSIONS: The predictive capability of pTNM stage was particularly enhanced when this parameter was combined with nutritional markers. Our new approach aids in predicting survival outcomes, especially non-GC-related death, in elderly GC patients.

Implications of Liver-Directed Therapy for Postoperative Hepatic Metastasis from Esophageal Cancer.

Background: Distant recurrence of esophageal cancer (EC), even after radical resection, is common, and the most frequent site of EC metastasis is the liver. However, a multidisciplinary treatment strategy for postoperative liver metastasis (LM) from EC has yet to be established; in particular, the role of liver-directed therapy (LDT) remains uncertain. We investigated the clinicopathological features and outcomes of patients undergoing post-esophagectomy LM with versus without LDT to explore its therapeutic implications. Methods: Among 624 consecutive patients undergoing R0/R1 esophagectomy for EC, 30 were identified in whom LM had developed as the initial recurrence. Their characteristics were retrospectively reviewed. Results: Six of the 30 subjects underwent LDT for metachronous LM. Five of those 6 also received systemic chemotherapy. A comparison between the 6 LDT and 24 non-LDT cases revealed no significant differences in major clinicopathological and operative factors, except for concurrent metastasis to extrahepatic organs (1/6 vs. 15/24, p=0.044). Twenty-nine of the 30 patients died during the study period, whereas 1 who had received multimodal treatment with LDT remained alive more than 200 months after multiple LM had been detected. Kaplan-Meier analysis for survival after LM demonstrated significantly prolonged survival in LDT cases compared to non-LDT cases treated with systemic chemotherapy alone (p=0.014). Even when the analysis was limited to patients without extrahepatic metastasis, this significant prognostic advantage of LDT was maintained (p=0.047). Conclusion: Multimodal treatment combined with LDT might be beneficial for patients with metachronous LM from EC and should therefore be considered a potential treatment option.

Optimal settings of near-infrared fluorescence imaging with indocyanine green for intraoperative detection of lymph node metastasis in esophageal cancer.

Lymphatic flow mapping using near-infrared fluorescence (NIR) imaging with indocyanine green (ICG) has been used for intraoperative diagnosis of lymph node metastasis (LNM) in various cancers. Accurate prediction of LNM intraoperatively may allow minimization of the extent of lymphadenectomy. However, a consistent method and diagnostic ability, allowing application of NIR-guided lymphatic flow mapping to esophageal cancer (EC), have not been established due to the multidirectional and complex characteristics of lymphatic flow in the esophagus. Herein, we present a novel NIR-guided surgical technique for predicting lymph node stations potentially containing LNM in EC with high diagnostic accuracy derived from appropriately adjusting the ICG injection setting.