Squamous cell carcinoma-derived G-CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients.

Tumor-derived G-CSF is a well-known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G-CSF in squamous cell carcinoma (SCC). High expression of G-CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR-S1M cells produce considerable amount of G-CSF, which expression is correlated with its metastatic potentials. Deletion of G-CSF in NR-S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR-S1M tumors in the mice. Mechanistically, G-CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR-S1M tumor-bearing mice, accumulation of plasma G-CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8+ T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G-CSF produced by NR-S1M cells facilitates tumor progression in mice through bi-functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G-CSF expression.

Multiplex Intraoperative Rapid Immunohistochemistry with Noncontact Antibody Mixing for Distinguishing the Histologic Phenotype of Lung Cancer.

INTRODUCTION: Determining a surgical strategy for early-stage lung cancer requires an accurate histologic diagnosis. Immunohistochemistry (IHC) enables reliable diagnosis of histological types but requires more time and more tumor tissue slides than hematoxylin and eosin staining. We aimed to assess the clinical validity of a new rapid multiplex IHC technique utilizing alternating current (AC) mixing for intraoperative lung cancer diagnosis. METHODS: Forty-three patients who underwent radical resection of lung cancers were enrolled in a retrospective observational study. Frozen sections were prepared from lung tumor samples, and rapid IHC employing AC mixing was implemented alongside a multiplex IHC protocol targeting thyroid transcription factor-1 + cytokeratin 5, desmoglein 3 + Napsin A, and p63 + tripartite motif containing 29. We then evaluated the concordance between intraoperative diagnoses derived from rapid multiplex IHC and final pathology. RESULTS: The concordance rate between the pathological diagnosis made with added rapid multiplex IHC and the final pathology was 93.0% (Cohen's 𝜅 coefficient = 0.860 and 95% CI: 0.727-0.993). When considering only adenocarcinoma and squamous cell carcinoma, the diagnoses were in agreement for all cases. CONCLUSIONS: We suggest rapid multiplex IHC as a promising tool for determining surgical strategies for lung tumors.

Pretreatment periodontitis is predictive of a poorer prognosis after esophagectomy for esophageal cancer.

BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.

Preoperative inspiratory muscle weakness as a risk factor of postoperative pulmonary complications in patients with esophageal cancer.

OBJECTIVE: We examined whether preoperative inspiratory muscle weakness (IMW) is a risk factor for postoperative pulmonary complications (PPCs) in patients with esophageal cancer who underwent subtotal esophagectomy. METHODS: This single-center retrospective cohort study enrolled patients with esophageal cancer who underwent a scheduled subtotal esophagectomy between June 2020 and May 2022. Maximal inspiratory pressure (MIP) was measured as inspiratory muscle strength using a respiratory dynamometer, and we defined IMW as MIP < 80% of the predicted value. Our primary outcome comprised overall PPCs. We investigated the relationship between IMW and PPCs using the Bayesian logistic regression model. RESULTS: After exclusion, 72 patients were included in this study. IMW was identified in 26 patients (36%), and PPCs developed in 28 patients (39%). Among patients with IMW, 15 (58%) developed PPCs. Preoperative IMW was associated with PPCs (mean odds ratio [OR]: 3.58; 95% credible interval [95% CrI]: 1.29, 9.73) in the unweighted model. A similar association was observed in the weighted model adjusted for preoperative and intraoperative contributing factors (mean OR: 4.15; 95% CrI: 2.04, 8.45). CONCLUSIONS: Preoperative IMW was associated with PPCs in patients with esophageal cancer who underwent subtotal esophagectomy. This association remained after adjusting for preoperative and intraoperative contributing factors.

Validity of the 30-Second Chair-Stand Test to Assess Exercise Tolerance and Clinical Outcomes in Patients with Esophageal Cancer: A Retrospective Study with Reference to 6-Minute Walk Test Results.

This retrospective study aimed to investigate the validity of a 30-sec chair stand test (CS-30) as a simple test to assess exercise tolerance and clinical outcomes in 53 Japanese patients with esophageal cancer. There was a strong correlation between the results of CS-30 and the 6-min walk test (6MWT), the gold standard for assessing exercise tolerance (r=0.759). Furthermore, fewer patients whose CS-30 score was greater than 16 (the cutoff value defined based on 6MWT) experienced pneumonia in their postoperative course. These results suggest that exercise tolerance could be assessed using CS-30, and its cutoff value may be useful in predicting postoperative pneumonia risk.

Does Esophagectomy Provide a Survival Advantage to Patients Aged 80 Years or Older? Analyzing 5066 Patients in the National Database of Hospital-based Cancer Registries in Japan.

OBJECTIVE: To determine whether esophagectomy provides a survival advantage in octogenarians with resectable thoracic esophageal cancer. SUMMARY BACKGROUND DATA: Elderly patients with thoracic esophageal cancer do not always receive the full standard treatment; however, advanced age alone should not preclude the use of effective treatment that could meaningfully improve survival. METHODS: We retrieved the 2008 to 2011 data from the National Database of Hospital-based Cancer Registries from the National Cancer Centerin Japan, divided the patients into a ≥75 group (75-79 years; n = 2935) and a ≥80 group (80 years or older; n = 2131), and then compared the patient backgrounds and survival curves. A multivariable Cox proportional hazards regression model was developed to compare the effects of esophagectomy and chemoradiotherapy in the 2 groups. RESULTS: A significantly greater percentage of patients were treated with esoph-agectomy in the ≥75 group (34.6%) than the ≥80 group (18.4%). Among patients who received esophagectomy, the 3-year survival rate was 51.1% in the ≥ 75 group and 39.0% in the ≥80 group (P < 0.001). However, among patients who received chemoradiotherapy, there was no difference in survival curve between the 2 groups (P = 0.17). Multivariable Cox proportional hazard analysis revealed that esoph-agectomy for clinical Stage ii-iii patients was significantly associated to better survival (adjusted HR: 0.731) (95%CI: 0.645-0.829, P < 0.001) in the ≥75 group but not the ≥ 80 group when compared with chemoradiotherapy. CONCLUSIONS: Many octogenarians do not necessarily get a survival benefit from esophagectomy. However, patients should be evaluated based on their overall health before ruling out surgery based on age alone.

PET-Uptake Reduction into Lymph Nodes After Neoadjuvant Therapy is Highly Predictive of Prognosis for Patients Who have Thoracic Esophageal Squamous Cell Carcinoma Treated with Chemoradiotherapy Plus Esophagectomy.

BACKGROUND: Patients with 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)-positive lymph nodes before treatment have a poor prognosis after esophagectomy. This study investigated whether FDG uptake into lymph nodes on FDG-PET (PET-N) during the pre- or posttreatment stage is more predictive of survival for thoracic esophageal squamous cell carcinoma (TESCC) patients who received neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy. METHODS: Of 129 TESCC patients with clinical lymphatic metastasis who underwent curative-intent esophagectomy after NACRT between 2010 and 2018, 97 who received PET before and after NACRT were enrolled in the study. The study defined lymph nodes with a maximum standardized uptake value (SUVmax) greater than 2.5 on FDG-PET before NACRT as cPET-N(+) and after NACRT as CRT-cPET-N(+). Both the cPET-N(+) and CRT-cPET-N(-) patients were defined as PET-N responders. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: No significant difference in survival was detected between the cPET-N(+) and cPET-N(-) patients. However, the CRT-cPET-N(-) patients had significantly better 5-year overall survival (OS) and disease-specific survival (DSS) than the CRT-cPET-N (+) patients. The PET-N responders had significantly better 5-year OS and DSS than the PET-N non-responders, and PET-N response was an independent prognostic factor for 5-year DSS. CONCLUSION: The PET-N response is a highly predictive prognostic marker for TESCC patients who undergo NACRT followed by esophagectomy. The PET-N response may help clinicians to establish a strategy for perioperative treatments that improves survival for patients with lymph node metastasis in TESCC.

Association between ABCC2 polymorphism and hematological toxicity in patients with esophageal cancer receiving platinum plus 5-fluorouracil therapy.

BACKGROUND: Platinum agents are taken up into cells by copper transporter (CTR) 1 (gene code: SLC31A1) and are excreted from cells by copper-transporting P-type adenosine triphosphatase (ATP7B) and multidrug resistance-associated protein (MRP) 2 (gene code: ABCC2). In addition, glutathione S transferase (GST) P1 is involved in the metabolism of platinum agents. The present study aimed to determine whether the rate of grade 3-4 hematological toxicity associated with platinum plus 5-fluorouracil (5-FU) therapy in 239 patients with esophageal cancer was affected by the SLC31A1 rs10981694A>C and rs12686377G>T, ATP7B rs9535828A>G, GSTP1 rs1695A>G, and ABCC2 -24C>T polymorphisms. METHODS: Chemotherapy consisted of protracted infusion of 5-FU (800 mg/m2/day) on days 1-5 and cisplatin or nedaplatin (80 mg/m2/day) on day 1. RESULTS: A total of 82 of 239 patients developed grade 3-4 hematological toxicity after chemotherapy. Univariate analysis showed that ABCC2 -24C/T + T/T genotypes (P = 0.038), radiation therapy (P = 0.013), baseline white blood cell count < 6000/µL (P = 0.003), and baseline neutrophil count < 3900/µL (P = 0.021) were statistically significant predictors of grade 3-4 hematological toxicity. Multivariate analysis revealed that ABCC2 -24C/T + T/T genotypes (P = 0.036), radiation therapy (P = 0.005), and baseline white blood cell count < 6000/µL (P < 0.001) were significant risk factors. CONCLUSIONS: We determined that ABCC2 -24C>T is significantly associated with grade 3-4 hematological toxicity after platinum plus 5-FU therapy. These findings might contribute to improved treatment strategies for patients with esophageal cancer.

Differences in treatment and survival between elderly patients with thoracic esophageal cancer in metropolitan areas and other areas.

To address the major issue of regional disparity in the treatment for elderly cancer patients in an aging society, we compared the treatment strategies used for elderly patients with thoracic esophageal cancer and their survival outcomes in metropolitan areas and other regions. Using the national database of hospital-based cancer registries in 2008-2011, patients aged 75 years or older who had been diagnosed with thoracic esophageal cancer were enrolled. We divided the patients into two groups: those treated in metropolitan areas (Tokyo, Kanagawa, Osaka, Aichi, Saitama, and Chiba prefectures) with populations of 6 million or more and those treated in other areas (the other 41 prefectures). Compared were patient backgrounds, treatment strategies, and survival curves at each cancer stage. In total, 1236 (24%) patients from metropolitan areas and 3830 (76%) patients from nonmetropolitan areas were enrolled. Patients in metropolitan areas were treated at more advanced stages. There was also a difference in treatment strategy. The 3-year survival rate among cStage I patients was better in metropolitan areas (71.6% vs. 63.7%), and this finding mainly reflected the survival difference between patients treated with radiotherapy alone. For cStage II-IV patients, there were no differences. Multivariable Cox proportional hazard analysis including interaction terms between treatment areas, cStage, and the first-line treatments revealed that treatments in the metropolitan areas were significantly associated with better survival among patients treated with radiotherapy alone for cStage I cancer. Treatment strategies for elderly patients with thoracic esophageal cancer and its survival outcomes differed between metropolitan areas and other regions.

m6 A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N6 -methyladenosine (m6 A) of mRNA, is an abundant post-transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of m6 A modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of m6 A demethylase ALKBH5 correlated with poor prognosis and that ALKBH5 was an independent prognostic factor of the survival of patients. There was no correlation between the other demethylase FTO and prognosis. siRNA knockdown of ALKBH5 but not FTO significantly suppressed proliferation and migration of human ESCC cells. ALKBH5 knockdown delayed progression of cell cycle and accumulated the cells to G0/G1 phase. Mechanistically, expression of CDKN1A (p21) was significantly up-regulated in ALKBH5-depleted cells, and m6 A modification and stability of CDKN1A mRNA were increased by ALKBH5 knockdown. Furthermore, depletion of ALKBH5 substantially suppressed tumor growth of ESCC cells subcutaneously transplanted in BALB/c nude mice. Collectively, we identify ALKBH5 as the first m6 A demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients.

Verification of the Optimal Interval Before Esophagectomy After Preoperative Neoadjuvant Chemoradiotherapy for Locally Advanced Thoracic Esophageal Cancer.

BACKGROUND: The interval between preoperative chemoradiotherapy and surgery reportedly affects perioperative outcomes and survival; however, the optimal interval in esophageal cancer patients remains uncertain. OBJECTIVE: Our aim was to determine whether a prolonged interval between preoperative neoadjuvant chemoradiotherapy (NACRT) and esophagectomy affects the outcomes of esophageal cancer patients. METHODS: A total of 131 patients with esophageal cancer received curative surgery following NACRT at Akita University Hospital between 2009 and 2017. We divided these patients into two groups based on the median interval from NACRT to esophagectomy, and compared the rates of pathological complete response (pCR), surgical outcomes, and survival. RESULTS: The median interval from NACRT to esophagectomy was 39 days (range 21-95). Of the 131 patients, 70 (53%) received esophagectomy after 39 days or more from completion of NACRT. There were no significant differences in the clinicopathological features, including pCR rates, between the two groups. Prolongation of the interval from NACRT to esophagectomy was significantly associated with an increased rate of anastomotic leakage and recurrent laryngeal nerve palsy (p = 0.0225 and p = 0.0022, respectively); however, no association with overall survival was detected. CONCLUSIONS: A prolonged interval between NACRT and esophagectomy had no impact on pCR rates or survival. However, delaying esophagectomy may increase the likelihood of surgical complications such as anastomotic leakage and recurrent laryngeal nerve palsy.

Patterns and timing of recurrence in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy plus esophagectomy.

BACKGROUND: Tumor regression grade (TRG) after neoadjuvant therapy is reportedly predictive of prognosis in esophageal cancer patients, as lack of a response to neoadjuvant therapy is associated with a poor prognosis. However, there is little information available on the timing and pattern of recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC) that takes into consideration TRG after neoadjuvant chemoradiotherapy (NACRT). Here, in an effort to gain insight into a treatment strategy that improves the prognosis of NACRT non-responders, we evaluated the patterns and timing of recurrence in TESCC patients, taking into consideration TRG after NACRT. METHODS: A total of 127 TESCC patients treated with NACRT and esophagectomy between 2009 and 2017 were enrolled in this observational cohort study. TRGs were assigned based on the proportion of residual tumor cells in the area (TRG1, ≥1/3 viable cancer cells; 2, < 1/3 viable cancer cells; 3, no viable cancer cells). We retrospectively investigated the timing and patterns of recurrence and the prognoses in TESCC patients, taking into consideration TRG after NACRT. RESULTS: The 127 participating TESCC patients were categorized as TRG1 (42 patients, 33%), TRG2 (56 patients, 44%) or TRG3 (29 patients, 23%). The locoregional recurrence rate was higher in TRG1 (36.4%) patients than combined TRG2-3 (7.4%) patients. Patients with TRG3 had better prognoses, though a few TRG3 patients experienced distant recurrence. There were no significant differences in median time to first recurrence or OS among patients with locoregional or distant recurrence. There was a trend toward better OS in TRG2-3 patients with recurrence than TRG1 patients with recurrence, but the difference was not significant. CONCLUSIONS: NACRT non-responders (TRG1 patients) experienced higher locoregional recurrence rates and earlier recurrence with distant or locoregional metastasis. TRG appears to be useful for establishing a strategy for perioperative treatments to improve TESCC patient survival, especially among TRG1 patients. (303 words).

IGF2BP3 Expression Correlates With Poor Prognosis in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Insulin-like growth factor-II mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein normally involved in cell growth and migration during the early stages of embryogenesis. However, it is also expressed in various cancers, and the relationship between IGF2BP3 and the clinicopathological features and prognosis of esophageal squamous cell carcinoma patients is not fully understood. Our aim in this study was to determine whether IGF2BP3 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma. METHODS: The IGF2BP3 expression statuses of 177 patients treated with esophagectomy without preoperative therapy were evaluated immunohistochemically using tissue microarray analysis. The relationships between IGF2BP3 expression status and clinicopathological features and survival were then assessed using appropriate statistics. RESULTS: Among 177 esophageal tumors, 122 (68.9%) expressed high levels of IGF2BP3. In patients undergoing surgery alone, IGF2BP3-high expression was significantly associated with a poorer prognosis. By contrast, there were no significant associations between IGF2BP3 expression and clinicopathological features or outcomes in patients treated with surgery plus postoperative adjuvant chemotherapy. CONCLUSIONS: IGF2BP3 positivity in advanced thoracic esophageal squamous cell carcinoma is associated with adverse clinical outcomes in patients treated with surgery alone.

SUVmax reduction predicts long-term survival in patients of non-pCR both in the tumor and lymph nodes after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma.

BACKGROUND: A pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) ensures long-term survival in esophageal squamous cell carcinoma (ESCC) patients following esophagectomy, but pCR patients are a minority. The aim here was to identify prognostic factors in patients with non-pCR ESCC after NACRT. METHODS: This is a retrospective study. Investigated were 5-year overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) among non-pCR ESCC patients divided into pT0N0, primary site pCR (pT0N+), lymph node pCR (pT+N0), and non-pCR in both the tumor and lymph node (pT+N+) subgroups after NACRT and esophagectomy. Focusing on the SUVmax reduction rate in the primary tumor in 88 patients who underwent FDG-PET before and after NACRT, we used univariate and multivariate Cox proportional hazard models to identify prognostic factors. RESULTS: Although there were no significant survival differences among non-pCR ESCC patients with pT0N+, pT+N0, or pT+N+, survival rate among pT+N+patients was the poorest. After setting a 60% cutoff for the SUVmax reduction rate in the tumor, RFS curves for non-pCR patients significantly differed between patients above the cutoff and those below it. For pT+N+ patients, the SUVmax reduction rate (<60% vs ≥ 60%) was an independent prognostic factor of OS, DSS, and RFS. CONCLUSION: Because ESCC patients with SUVmax reduction rates of <60% in the tumor after NACRT and categorized as pT+N+ after NACRT had significantly poorer prognoses, even after esophagectomy, a change in treatment strategy may be an option to improve survival.

Approaches to resection of recurrent solitary mediastinal lymph nodes after esophagectomy.

Esophageal cancer recurrence in solitary mediastinal lymph node that may possibly been left behind in the first surgery differs from other recurrence patterns because it is still local disease and offers the possibility of complete cure through resection, but it is technically difficult. We resected recurrent mediastinal lymph nodes in six cases. A left transthoracic approach was used in three patients. Other approaches were left thoracoabdominal, right open transthoracic and transcervical. R0 resections were achieved in five patients without severe surgical stress or postoperative complications. Overall survival after resection of recurrent lymph nodes was 43 (16-82) months. Approaches to resection of recurrent solitary mediastinal lymph nodes after esophagectomy should be consider to perform curative treatment safely and less invasively.

Development of a Novel One-Step Automated Rapid in situ Hybridization for Anaplastic Lymphoma Kinase Rearrangement Using Non-Contact Alternating-Current Electric-Field Mixing.

Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (ALK) fusion gene rearrangement is a key driver mutation in non-small cell lung cancer (NSCLC). Although Break-Apart ALK fluorescence in situ hybridization (FISH) is a reliable diagnostic method for detecting ALK gene rearrangement, it is also costly and time-consuming to use as a routine screening test. Our aim was to evaluate the clinical utility of a novel one-step, automated, rapid FISH (Auto-RaFISH) method developed to facilitate hybridization. This method takes advantage of the non-contact mixing effect of an alternating-current electric field. Ten representative specimens from 85 patients diagnosed at multiple centers with primary lung cancer with identified ALK-FISH status were collected. The specimens were all tested using FISH, RaFISH, and Auto-RaFISH. With both RaFISH protocols, the ALK test was completed within 4.5 h, as compared to the 20 h needed for the standard protocol. We found 100% agreement between the standard FISH, RaFISH, and new Auto-RaFISH based on the ALK status, and all methods stained equally well. These findings suggest that Auto-RaFISH could potentially serve as an automated clinical tool for prompt determination of ALK status in NSCLC.

Decreases in the Psoas Muscle Index Correlate More Strongly with Survival than Other Prognostic Markers in Esophageal Cancer After Neoadjuvant Chemoradiotherapy Plus Esophagectomy.

BACKGROUND: Despite wide acknowledgement of the importance of sarcopenia and prognostic markers such as the neutrophil-to-lymphocyte ratio, the impact on cancer patient survival of the timing of sarcopenia's emergence and its severity is not well understood, nor is the association between sarcopenia and prognostic markers. The aim of this study, therefore, was to investigate the effect of the severity and timing of changes in the psoas muscle index (PMI) on survival of advanced esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (NACRT) plus esophagectomy and the association between PMI and known prognostic markers. METHODS: Included in this study were 113 ESCC patients who underwent NACRT followed by esophagectomy. PMI and prognostic markers were measured at their initial visit, just before surgery (after NACRT), and 3 months postoperatively. RESULTS: All patients were classified into four groups according to the percent decrease in PMI after NACRT and after NACRT plus esophagectomy. Patients exhibiting a larger PMI decrease (≥20%) after NACRT plus esophagectomy had significantly poorer overall survival than those showing a smaller PMI decrease. Furthermore, multivariable analysis showed that a larger decrease in PMI after NACRT plus esophagectomy was a significant risk factor for overall (P < 0.0001) and recurrence-free (P = 0.0097) survival. Neither pretherapeutic PMI nor a decrease in PMI after NACRT significantly affected survival. PMI also showed weak, but significant, correlations with several prognostic markers postoperatively. CONCLUSIONS: Decreased PMI after NACRT plus esophagectomy is a strong prognostic indicator in ESCC patients.

Evaluation of metastatic lymph nodes in cN0 thoracic esophageal cancer patients with inconsistent pathological lymph node diagnosis.

BACKGROUND: Preoperative clinical diagnosis of lymph node (LN) metastasis and subsequent pathological diagnosis are often not in agreement. Detection of false-negative LNs is essential in selecting an optimal treatment strategy, and most importantly, the presence of false-negative LN is itself a significant prognostic indicator. Therefore, at present, there is an urgent need to establish more accurate and individualized evaluation methods for LN metastasis. METHODS: Of 213 cN0 patients who underwent curative esophagectomy without preoperative neoadjuvant treatment, 60 (28%) had LN metastasis diagnosed pathologically. There were 129 false-negative LNs, of which 85 were detectable by preoperative computed tomography (CT). We retrospectively investigated the distribution, frequency, and characteristics of pathologically positive nodes in patients with clinically N0 esophageal cancer. RESULTS: The paracardial region was the most frequent region of false-negative LNs, accounting for 26% (22 LNs) of the total incidence. False-negative LNs distributed widely from the neck to the abdomen in patients with a primary tumor in the middle thoracic esophagus. In patients with a primary tumor in the lower thoracic esophagus, four false-negative LNs were detected in the superior mediastinum. When the short-axis diameter, shape, and attenuation patterns of the LNs were used as criteria for metastasis diagnosis, they were insufficient for an accurate diagnosis. However, false-negative LNs in the most frequently occurring sites are characterized by smaller short-axis, suggesting that accurate diagnosis cannot be made unless the diagnostic criteria for the short-axis are reduced in addition to shape and attenuation. CONCLUSIONS: Although restrictive to the most frequent regions of false-negative LNs occur, reducing size criterion and consideration of their shape and attenuation may contribute to improved diagnosis.

High TLR4 expression predicts a poor prognosis after esophagectomy for advanced thoracic esophageal squamous cell carcinoma.

BACKGROUND: Poor oral health is an independent risk factor for upper aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). The pattern recognition receptor Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide in the cell walls of Gram-negative periodontal pathogens associated with the development and progression of ESCC. It is, therefore, plausible that TLR4 plays a crucial role in the pathogenesis of ESCC. METHODS: We used an ESCC tissue microarray to confirm expression of TLR4 in patients with ESCC and to determine whether TLR4 expression status correlates with the clinicopathological features of these patients or their prognosis after esophagectomy. We also tested whether the combined expression statuses of TLR4 and TLR3 better correlate with prognosis in these patients than either parameter alone. RESULTS: Clinical ESCC samples from all 177 patients tested showed expression of TLR4. Moreover, high TLR4 expression (3 + and 2 +) correlated with poorer 5-year overall survival after esophagectomy than lower TLR4 expression (1 +) (p = 0.0491). Patients showing high TLR4 expression tended to have a poorer prognosis whether treated with surgery alone or with surgery and adjuvant chemotherapy. Univariate and multivariate analyses showed TLR4 expression status to be an independent prognostic factor affecting 5-year overall survival. Patients exhibiting high TLR4 expression with low TLR3 expression had a much poorer prognosis than other patients (p = < 0.0001). CONCLUSION: High TLR4 expression predicts a poor prognosis in advanced thoracic ESCC patients after esophagectomy.

Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma.

PURPOSE: To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma. METHODS: Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model. RESULTS: Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group. CONCLUSIONS: S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.