Intratumour Fusobacterium nucleatum and immune response to oesophageal cancer.

BACKGROUND: Experimental evidence suggests a role of intratumour Fusobacterium nucleatum in the aggressive behaviour of gastrointestinal cancer through downregulating anti-tumour immunity. We investigated the relationship between intratumour F. nucleatum and immune response to oesophageal cancer. METHODS: Utilising an unbiased database of 300 resected oesophageal cancers, we measured F. nucleatum DNA in tumour tissue using a quantitative polymerase chain reaction assay, and evaluated the relationship between the abundance of F. nucleatum and the densities of T cells (CD8 + , FOXP3 + and PDCD1 + ), as well as lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoural lymphocytic reaction, stromal lymphocytic reaction and tumour-infiltrating lymphocytes) in oesophageal carcinoma tissue. RESULTS: F. nucleatum was significantly and inversely associated only with the peritumoural lymphocytic reaction (P = 0.0002). Compared with the F. nucleatum-absent group, the F. nucleatum-high group showed a much lower level of the peritumoural lymphocytic reaction (univariable odds ratio, 0.33; 95% confidence interval, 0.16-0.65; P = 0.0004). A multivariable model yielded a similar finding (multivariable odds ratio, 0.34; 95% confidence interval 0.16-0.69; P = 0.002). CONCLUSIONS: Intratumour F. nucleatum is associated with a diminished peritumoural lymphocytic reaction, providing a platform for further investigations on the potential interactive roles between intratumour F. nucleatum and host immunity.

C-Reactive Protein Levels After Esophagectomy are Associated with Increased Surgical Complications and Poor Prognosis in Esophageal Squamous Cell Carcinoma Patients.

BACKGROUND: C-reactive protein (CRP) levels are reported to predict complications and survival after surgery in various cancers. However, the relationship between postoperative CRP levels and short- and long-term outcomes of esophageal squamous cell carcinoma (ESCC) patients after esophagectomy is unclear. METHOD: We reviewed the records of 543 ESCC patients who underwent subtotal esophagectomy with gastric conduit reconstruction at Kumamoto University Hospital between August 2010 and July 2021. Blood tests for CRP were done on postoperative days (PODs) 1, 3, 5 or 6, and 7 or 8. RESULTS: The mean CRP levels on day 1, day 3, day 5/6, and day 7/8 were 6.68 ± 0.13 mg/dL, 11.49 ± 0.27 mg/dL, 7.48 ± 0.26 mg/dL, and 5.38 ± 0.22 mg/dL, respectively. Mean CRP levels were highest on day 3, and CRP levels after day 3 correlated with grade >2 complications based on the Clavien-Dindo classification. Receiver operating characteristic curve analysis established the optimal cut-off value for CRP day 3 levels to be 12.19 mg/dL. Multivariate logistic regression analyses found that high CRP day 3 levels significantly correlated with grade >2 complications (odds ratio [OR] 3.77, 95% confidence interval [CI] 2.56-5.35; p < 0.001). Moreover, high day 7/8 CRP levels (>3.52) correlated with postoperative survival, and based on multivariate logistic regression analyses, were significantly associated with poor prognosis (hazard ratio 1.67, 95% CI 1.14-2.43; p = 0.008). CONCLUSION: Our findings suggest CRP day 3 levels as a potential biomarker for predicting postoperative complications and that CRP day 7/8 levels have potential prognostic value for ESCC patients after esophagectomy.

Prognostic Significance of Systemic Inflammation Indices by K-ras Status in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Systemic inflammation markers are useful prognostic indicators for metastatic colorectal cancer. However, the influence of K-ras genotypes on these markers in patients with metastatic colorectal cancer is unclear. OBJECTIVE: This study aimed to evaluate the associations between systems of evaluating pretreatment systemic inflammation and outcomes according to K-ras genotypes in patients with metastatic colorectal cancer. DESIGN: This was a retrospective study. SETTINGS: This study was conducted at a university hospital. PATIENTS: This study included a total of 272 patients ( K-ras wild type: K-ras mutant = 169:103) who received first-line systemic chemotherapy for metastatic colorectal cancer. MAIN OUTCOME MEASURES: We retrospectively calculated 8 systemic inflammation indices: neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, lymphocyte/monocyte ratio, prognostic nutritional index, Glasgow prognostic score, Naples prognostic score, systemic inflammation score, and systemic immune-inflammation index. Patients were categorized into high or low groups for each index. The prognostic relevance of these indices for overall survival was evaluated according to the K-ras genotype. RESULTS: Kaplan-Meier survival analyses showed that median overall survival significantly differed between the high and low groups for all indices in the K-ras wild-type group but not in the K-ras mutant group, except for Glasgow prognostic score and lymphocyte/monocyte ratio. Multivariate Cox regression analyses identified all indices as independent prognostic factors. In the K-ras wild-type group, all indices except platelet/lymphocyte ratio had strong prognostic effects, but not in the K-ras mutant group. Interaction tests indicated that K-ras genotype significantly influenced the prognostic impacts of the neutrophil/lymphocyte ratio ( p = 0.042), prognostic nutritional index ( p = 0.048), Naples prognostic score ( p < 0.001), and systemic immune-inflammation index ( p = 0.004). LIMITATIONS: A major limitation of this study is the lack of external validation. CONCLUSIONS: The prognostic significance of systemic inflammation indices is more useful in patients with K-ras wild-type metastatic colorectal cancer than those with K-ras mutant cancer. See Video Abstract at http://links.lww.com/DCR/B921 . IMPORTANCIA PRONSTICA DE LOS NDICES DE INFLAMACIN SISTMICA POR ESTADO DE KRAS EN PACIENTES CON CNCER COLORRECTAL METASTSICO: ANTECEDENTES:Los marcadores de inflamación sistémica son indicadores de pronósticos útiles para el cáncer colorrectal metastásico. Sin embargo, la influencia de los genotipos KRAS en estos marcadores en pacientes con cáncer colorrectal metastásico no está clara.OBJETIVO:Evaluamos las asociaciones entre los sistemas de evaluación de la inflamación sistémica previa al tratamiento y los resultados según los genotipos K-ras en pacientes con cáncer colorrectal metastásico.AJUSTE:Este estudio se realizó en un hospital universitario.DISEÑO:Este fue un estudio retrospectivo.PACIENTES:Un total de 272 pacientes (K-ras wildtype [K-raswt]:mutant [K-rasMut] = 169:103) que recibieron quimioterapia sistémica de primera línea para el cáncer colorrectal metastásico.PRINCIPALES MEDIDAS DE RESULTADO:Calculamos retrospectivamente 8 índices de inflamación sistémica: proporción de neutrófilos/linfocitos, proporción de plaquetas/linfocitos, proporción de linfocitos/monocitos, índice nutricional pronóstico, puntuación de pronóstico de Glasgow, puntuación de pronóstico de Nápoles, puntuación de inflamación sistémica e índice de inmunoinflamación sistémica. Los pacientes se clasificaron en grupos altos o bajos para cada índice. La relevancia pronóstica de estos índices para la supervivencia global se evaluó según el genotipo K-ras.RESULTADOS:Los análisis de supervivencia de Kaplan-Meier mostraron que la mediana de la supervivencia general difería significativamente entre los grupos alto y bajo para todos los índices en el grupo K-raswt pero no en el grupo K-rasMut, excepto para la puntuación de pronóstico de Glasgow y la proporción de linfocitos/monocitos. Los análisis de regresión multivariable de Cox identificaron todos los índices como factores pronósticos independientes. En el grupo K-raswt, todos los índices, excepto el cociente plaquetas/linfocitos, tuvieron fuertes efectos pronósticos, pero no en el grupo K-rasMut. Las pruebas de interacción indicaron que el genotipo K-ras influyó significativamente en los impactos pronósticos de la proporción de neutrófilos/linfocitos (p = 0,042), el índice nutricional pronóstico (p = 0,048), la puntuación pronóstica de Nápoles (p < 0,001) y el índice de inflamación inmunológica sistémica (p = 0,004).LIMITACIÓN:Una limitación importante de este estudio es la falta de validación externa.CONCLUSIÓNES:La importancia pronóstica de los índices de inflamación sistémica es más útil en pacientes con cáncer colorrectal metastásico K-raswt. Consulte Video Resumen en http://links.lww.com/DCR/B921 . (Traducción-Dr. Yolanda Colorado ).

Postoperative respiratory morbidity can adversely affect prognosis in thoracoscopic esophagectomy for esophageal cancer: a retrospective study.

BACKGROUND: Esophagectomy for esophageal cancer is associated with frequent respiratory morbidities, which may deteriorate postoperative survival outcomes. Thoracoscopic esophagectomy (TE) is less invasive and is associated with fewer respiratory morbidities than open esophagectomy. However, the relationship between post-TE respiratory morbidity and prognosis has not been well established. METHODS: This study included 378 patients who underwent TE for esophageal cancer between May 2011 and November 2020. Patients were divided into two groups based on the presence of respiratory morbidity. Short-term and long-term outcomes of the groups were retrospectively compared. RESULTS: Respiratory morbidity was significantly associated with heavy past smoking habits (Brinkman index, p = 0.0039), short duration of smoking cessation (p = 0.0012), worse American Society of Anesthesiologists physical status (p = 0.016), frequent cardiovascular comorbidities (p = 0.0085), and long hospital stay (p < 0.001). Respiratory morbidity significantly deteriorated overall survival (OS) (p = 0.011) and relapse-free survival (p = 0.062) and could be an independent prognostic factor for OS (hazard ratio = 1.90, 95% confidence interval = 1.093-3.311, p = 0.023) along with clinical stage. CONCLUSION: Respiratory morbidity can adversely affect prognosis after TE. Various prophylaxes for respiratory morbidity are required to improve the short-term and long-term outcomes of TE for esophageal cancer.

Prolonged door-to-antibiotics time is associated with high hospital mortality in patients with perforated colorectal peritonitis.

PURPOSE: Colorectal perforation is a fatal disease that presents with generalized peritonitis, leading to sepsis and septic shock. Recently, the association between prolonged door-to-antibiotics time and increased mortality in sepsis has been widely reported. In this study, we investigated the prognostic impact of a prolonged door-to-antibiotics time in patients with perforated colorectal peritonitis undergoing emergency surgery. METHODS: This retrospective study included 93 patients with perforated colorectal peritonitis who underwent emergency surgery at our institution between April 2015 and August 2019. Patients were divided into two groups depending on the door-to-antibiotics time (< 162 min or ≥ 162 min). The primary outcome was in-hospital mortality. The secondary outcomes were the length of hospital stay and severe complication rate. The logistic regression analysis was used to estimate the odds ratio for in-hospital mortality. RESULTS: We identified 38 patients who presented with an extended door-to-antibiotics time (≥ 162 min) and 55 patients who presented with a shortened door-to-antibiotics time (< 162 min). We found a strong association between the door-to-antibiotics time ≥ 162 min and in-hospital mortality. There were no significant differences between the two groups regarding the length of hospital stay and postoperative complication rate. However, in multivariate analysis, extended door-to-antibiotics time was an independent prognostic factor for in-hospital mortality (odds ratio = 244; 95% confidence interval, 11 -23,885). CONCLUSION: A prolonged door-to-antibiotics time (≥ 162 min) worsened hospital mortality rates in patients with perforated colorectal peritonitis.

PD-L1 and PD-L2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma.

Immune checkpoint inhibitors have shown efficacy in various cancers. Although programmed death ligand 1/2 (PD-L1/L2) expressions have been demonstrated as predictive biomarkers of response to immune checkpoint inhibitors and prognostic markers, whether PD-L1/L2 expression is altered in esophageal squamous cell carcinoma during the therapeutic course is unclear. Whether PD-L1/L2 expression in metastatic or recurrent lesions is consistent with that in primary tumors is also unknown. This study included 561 surgically resected esophageal squamous cell carcinomas and PD-L1/L2 expression was evaluated by immunohistochemistry. We investigated the influence of chemotherapeutic drugs (cisplatin and fluorouracil) on PD-L1/L2 expression and PD-L1/L2-related pathways in vitro. We also examined PD-L1/L2 expression in 18 surgically resected lymph node metastases and 10 recurrent lesions compared with primary lesions. The positive rate of PD-L1 was significantly higher in patients with preoperative chemotherapy than in those without preoperative therapy. The positive rate of PD-L2 expression showed no significant difference between patient groups. Cisplatin increased PD-L1 expression in cancer cell lines in vitro, but decreased PD-L2 in some cell lines. The effects of cisplatin on phosphorylated signal transducer and activator of transcription 1/3 (pSTAT1/3) also differed depending on cell lines. Fluorouracil increased PD-L1 and PD-L2 expression. PD-L1/L2 expression in lymph node metastases and recurrent lesions did not always match expression in primary lesions. PD-L1/L2 expression may be altered by preoperative chemotherapy, and PD-L1 /L2 expression in primary lesions does not always match that of metastatic/recurrent lesions. Thus, one-time evaluation is not sufficient to evaluate PD-L1/L2 expression as a biomarker in esophageal cancer.

Comprehensive Analysis of Multiple Primary Cancers in Patients With Esophageal Squamous Cell Carcinoma Undergoing Esophagectomy.

OBJECTIVE: The aim of this study was to elucidate the latest epidemiology and risk factors for multiple primary cancers (MPCs), and the association between neoadjuvant chemotherapy (NAC) and postoperative metachronous cancer (PMC) in patients with esophageal squamous cell carcinoma (ESCC) who underwent esophagectomy. SUMMARY OF BACKGROUND DATA: Background data to derive appropriate screening strategies are insufficient. METHODS: This study consisted of 3 retrospective investigations. A total of 766 consecutive patients with ESCC who underwent esophagectomy between April 2005 and December 2019 were eligible for epidemiological analysis. Of these, 688 patients without missing data were analyzed for the risk of MPCs. In total, 364 patients who underwent NAC (115) and no preoperative treatments (249) were investigated for the association between NAC and PMC. RESULTS: Of 766 patients, 288 (38%) patients experienced 357 MPCs in their life. PMCs identified after the completion of 5-year postoperative follow-up were significantly more advanced (P = 0.019). Male sex [hazard ratio (HR) = 3.04, P = 0.038], older age (HR = 2.39, P < 0.001), and diabetes mellitus (HR = 1.76, P = 0.034) were risk factors for preoperative metachronous cancers. Heavy smoking (HR = 1.70, P = 0.014) and drinking (HR = 1.61, P = 0.029) were risk factors for synchronous cancers. NAC significantly reduced PMC incidence ( P = 0.043). NAC showed a trend to contribute to improved survival via reduced deaths from PMCs, although this did not reach significance ( P = 0.082). CONCLUSIONS: ESCC is associated with a high risk of MPCs. Continuing follow-up for PMCs after the completion of 5-year postoperative follow-up is important. NAC may reduce PMCs, representing a novel mechanism for improving survival in patients with locally advanced ESCC.

Clinical Significance of Pretreatment Red Blood Cell Distribution Width as a Predictive Marker for Postoperative Morbidity After Esophagectomy for Esophageal Cancer: A Retrospective Study.

BACKGROUND: Clinical significance of red blood cell distribution (RDW) as a predictive marker for the incidence of postoperative morbidity after esophagectomy for esophageal cancer has not been established. METHODS: This study included 634 consecutive patients who underwent three-incisional esophagectomy with lymphadenectomy for esophageal cancer between April 2005 and November 2020. Correlation between pretreatment RDW and patient background, cancer background, and short-term outcome after esophagectomy were retrospectively investigated. RESULTS: Eighty patients (12.6%) had a high pretreatment RDW (> 14.2), which correlated with malnutrition estimated by body mass index, hemoglobin, total lymphocyte count, albumin, and total cholesterol. High pretreatment RDW was an independent risk factor for postoperative severe morbidity of grade IIIb or higher based on the Clavien-Dindo classification (hazard ratio [HR] 3.90, 95% confidence interval [CI] 1.707-8.887; p = 0.0012) and reoperation (HR 4.39, 95% CI 1.552-12.390; p = 0.0053) after open esophagectomy (OE). However, RDW was not associated with postoperative morbidity incidence after minimally invasive esophagectomy (MIE). CONCLUSIONS: Pretreatment RDW may be a surrogate marker for nutritional status and could be a predictive marker for postoperative severe morbidity, reoperation, and possibly pneumonia after OE. On the contrary, the lower invasiveness of MIE may have reduced the effect of pretreatment malnutrition on morbidity incidence, which could explain the insignificant relationship between RDW and poor short-term outcomes in MIE.

Preoperative Smoking Cessation and Prognosis After Curative Esophagectomy for Esophageal Cancer: A Cross-Sectional Study.

BACKGROUND: Several cohort studies have reported that post-esophagectomy morbidities may worsen prognosis. Smoking cessation is an effective prophylactic measure for reducing post-esophagectomy morbidity; however, whether smoking cessation can contribute to the improvement of prognosis is unknown due to the absence of reliable databases covering the cessation period. This study aimed to elucidate whether sufficient preoperative smoking cessation can improve prognosis after esophageal cancer surgery by reducing post-esophagectomy morbidity. METHODS: This study included 544 consecutive patients who underwent curative McKeown and Ivor-Lewis esophagectomies for esophageal cancer between May 2011 and June 2021. Data on smoking status and cessation period were prospectively accumulated. Survival data were finally updated on 30 January 2022. Receiver operating characteristic curve analysis for the cut-off value of appropriate cessation period in reducing post-esophagectomy respiratory morbidity as well as analyses for the association of cessation period with short- and long-term outcomes were performed. RESULTS: Post-esophagectomy morbidity significantly diminished overall survival (OS) after esophagectomy (p = 0.0003). A short preoperative smoking cessation period of ≤ 2 months was associated with frequent post-esophagectomy morbidity of Clavien-Dindo classification ≥IIIb (p = 0.0059), pneumonia (p = 0.016), respiratory morbidity (p = 0.0057), and poor OS in clinical stages II and III (p = 0.0015). Moreover, it was an independent factor for poor OS (hazard ratio 1.85, 95% confidence interval 1.068-3.197; p = 0.028), along with body mass index <18.5 and R1 resection. CONCLUSIONS: Sufficient preoperative smoking cessation > 2 months may be effective in improving not only short-term outcomes but also prognosis after esophagectomy for locally advanced esophageal cancer.

Impairment of perioperative activities of daily living is associated with poor prognosis following hepatectomy for hepatocellular carcinoma.

BACKGROUND: The number of cancer patients with impairment of activities of daily living (ADLs) has increased. This study aimed to examine associations of perioperative Barthel index score, a validated measure of ADLs, with survival outcomes following hepatectomy for hepatocellular carcinoma (HCC). METHODS: We analyzed data of 492 consecutive patients who underwent hepatectomy for HCC between 2010 and 2018. Pre- and postoperative ADLs were assessed using the Barthel index (range, 0-100; higher scores indicate greater independence). Preoperative Barthel index score ≤85 or postoperative Barthel index score ≤85 was defined as impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after adjusting for potential confounders. RESULTS: Among the 492 patients, 26 (5.2%) had a preoperative Barthel index score ≤85 and 95 (19%) had a postoperative Barthel index score ≤85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 1.75, 95% confidence interval [CI]: 1.06-2.81, p = 0.028). The association of impairment of perioperative ADLs with recurrence-free survival was not statistically significant. CONCLUSION: Impairment of perioperative ADLs is associated with poor prognosis following hepatectomy for HCC. Maintenance and improvement of perioperative ADLs would be important to provide favorable long-term outcomes in patients with HCC.

Impact of Type of Gastrectomy on Death from Pneumonia in Elderly Patients with Gastric Cancer Over the Long Term.

BACKGROUND: Gastrectomy may induce significant postoperative disabilities and worsen the quality of life in elderly patients. Without a functioning esophagogastric junction (EGJ), swallowing is impaired because of the anatomical and physiological changes after surgery, which increases the risk of postoperative pneumonia. The aim of this study was to identify the impact of the type of surgical procedure on death from pneumonia in elderly patients with gastric cancer (GC) over the long term. METHODS: We analyzed the data of 343 patients with GC who underwent curative gastrectomy in our hospital. We divided the patients into elderly and non-elderly groups. Among them, 109 patients aged ≥ 75 years who underwent curative resection were analyzed, their clinicopathological factors and clinical outcomes were compared, and the impact of the type of surgical procedure on death from pneumonia over the long term was evaluated. The institutional scientific review board of Kumamoto University Hospital was approved for data collection and analysis (No. 1037). RESULTS: There were significantly higher levels of American Society of Anesthesiologists (ASA) and poor nutrition in the elderly group; however, gender, BMI and factors related to pneumonia did not differ significantly between groups. The median duration of follow-up time 1588 days. On the multivariate analysis, age and surgical procedure were selected as independent predictive factors for pneumonia-related survival. CONCLUSION: Preservation of the EGJ as much as possible while maintaining curability is useful for reducing postoperative death from pneumonia over the long term in elderly patients with gastric cancer.

Index of estimated benefit from lymph node dissection for stage I-III transverse colon cancer: an analysis of the JSCCR database.

PURPOSE: Main lymph node metastasis (LNM) dissection of transverse colon (TC) cancer is a difficult surgical procedure. Nonetheless, the main LNM ratio and the benefit of main lymph node (LN) dissection in TC cancer were unclear. This study aimed to identify high-risk patients for LNM and to evaluate the benefit of LN dissection in TC cancer. METHODS: Data for 26,552 colorectal cancer patients between 2007 and 2011 were obtained from the JSCCR database. Of these, 871 stage I-III TC cancer patients underwent surgery with radical LN dissection. These patients were evaluated using the index of estimated benefit from lymph node dissection (IEBLD), where IEBLD = (LNM ratio of each LN station) × (5-year overall survival (OS) rate of the patients with LNM) × 100. RESULTS: None of the patients with depth of invasion pT1-2 had main LNM. The presence of main LNM was associated with depth of invasion pT4, CEA-4H (carcinoembryonic antigen 4 times higher than preoperative cutoff value), or type 3, and 323 patients (37.1%) who had these factors were high-risk patients for main LNM. In these high-risk patients, the LNM ratio, 5-year OS rate of patients with LNM and IEBLD values, respectively, were 43.9%, 70.3%, and 30.5 for the pericolic LN; 20.3%, 66.0%, and 15.1 for the intermediate LN; and 9.6%, 58.5%, and 5.6 for the main LN. CONCLUSION: Main LNM is associated with depth of invasion pT4, CEA-4H, or type 3. The IEBLD for the main LN of high-risk TC cancer patients was over 5.

A retrospective study of preoperative malnutrition based on the Controlling Nutritional Status score as an associated marker for short-term outcomes after open and minimally invasive esophagectomy for esophageal cancer.

PURPOSE: Preoperative malnutrition is a significant risk factor for post-esophagectomy morbidity. The Controlling Nutritional Status (CONUT) is an index used to assess nutritional status, and it has been suggested to predict post-esophagectomy morbidity. However, the difference in the predictive value of CONUT in estimating morbidities between open esophagectomy (OE) and minimally invasive esophagectomy (MIE) has not yet been elucidated. METHODS: This study included patients who underwent a three-incision esophagectomy for esophageal cancer between April 2005 and August 2021. The patients were further divided into two groups according to their preoperative CONUT scores: normal and light malnutrition and moderate and severe malnutrition. Short-term outcomes between these groups were retrospectively compared in the OE and MIE groups. RESULTS: A total of 674 patients who underwent OE (296) and MIE (378) were analyzed. Moreover, 32 patients of the OE group and 16 of the MIE group were classified as having moderate and severe malnutrition, respectively. Moderate and severe malnutrition was significantly associated with a low body mass index, poor performance status, poor American Society of Anesthesiologists physical status, advanced cancer stage, and frequent preoperative treatment. These patients also experienced significantly more frequent morbidities of grade ≥ IIIb according to the Clavien-Dindo classification (CDc), respiratory, and cardiovascular morbidities after OE. Moreover, moderate and severe malnutrition in CONUT was an independent risk factor for morbidity of CDc ≥ IIIb (odds ratio [OR] vs. normal and light malnutrition = 3.38; 95% confidence interval [CI], 1.225-9.332; p = 0.019), respiratory (OR = 3.00; 95% CI, 1.161-7.736; p = 0.023), and cardiovascular morbidities (OR = 3.66; 95% CI, 1.068-12.55; p = 0.039) after OE. Meanwhile, moderate and severe malnutrition in CONUT did not increase the incidence of postoperative morbidities after MIE. CONCLUSION: Preoperative malnutrition in CONUT reflects various disadvantageous clinical factors and could be a predictor of worse short-term outcomes after OE, but it has no value in MIE. The low invasiveness of MIE might reduce the effect of preoperative malnutrition on worse short-term outcomes.

Minimally invasive esophagectomy may contribute to low incidence of postoperative surgical site infection in patients with poor glycemic control.

PURPOSE: High preoperative hemoglobin A1c (HbA1c) levels have been suggested to increase complications after esophagectomy. Minimally invasive esophagectomy (MIE) is less invasive than open esophagectomy (OE) and may reduce postoperative complications. However, it has not been established whether MIE contributes to low morbidity in patients with high preoperative HbA1c levels. Thus, the current study aimed to elucidate the effect of preoperative HbA1c levels on the incidence of complications each after OE and MIE. METHODS: A total of 280 patients who underwent OE and 304 patients who underwent MIE for esophageal cancer between April 2005 and April 2020 were retrospectively analyzed. The OE and MIE groups were further divided into two groups according to their preoperative HbA1c levels (< 6.9%, ≥ 6.9%). RESULTS: Patients with high HbA1c levels had a significantly higher incidence of surgical site infections (SSIs) after OE (P = 0.0048). Multivariate analysis demonstrated that a high HbA1c level was an independent risk factor for frequent SSIs after OE (hazard ratio 2.52; 95% confidence interval, 1.101- 5.739; P = 0.029). On the contrary, a high HbA1c level did not affect the incidence of SSI after MIE (P = 1.00). A high HbA1c level was not associated with the incidence of morbidities other than SSI after OE and MIE. CONCLUSIONS: A high preoperative HbA1c level significantly increased SSI risk after OE but not after MIE. It was suggested that lower invasiveness of MIE could contribute to a low incidence of SSI, even in patients with poor preoperative glycemic control.

Clinicopathological characteristics and prognosis of poorly cohesive cell subtype of gastric cancer.

BACKGROUND: The new World Health Organization (WHO) classification of gastric cancer includes a histological subtype of poorly cohesive carcinoma (PCC), which includes signet-ring cell (SRC) phenotype. We aimed to examine the concordance between preoperative clinical and postoperative histological diagnoses according to the 2010 WHO histological subtypes and to compare the prognoses of these subtypes. METHODS: The study cohort comprised 665 patients who underwent gastrectomy from 2005 to 2019. Histological subtypes were classified into PCC-NOS (non-signet ring cell subtype), SRC, and non-PCC, which were defined by the predominant component in accordance with the 2010 WHO classification of gastric cancer. The concordance of clinical and pathological diagnosis was examined and clinicopathological characteristics and survival outcome of the three subtypes compared. RESULTS: The cancers of 443 patients (66.7%) were classified as non-PCC, of 112 patients (16.8%) as PCC-NOS, and of 110 patients (16.5%) as SRC predominant subtypes. Significant differences in sex, age, tumor location, size, macroscopic type, and pathological TNM category (all P<0.05) were found. The concordance rate of preoperative and postoperative histological subtypes was significantly lower for poorly cohesive than other subtypes (P<0.0001). Preoperative stage tended to be underestimated for PCC-NOS subtype and these patients had poorer overall survival than those with the other two subtypes (P=0.005). Multivariate logistic regression analysis of overall survival showed that WHO histological subtype (PCC-NOS vs. non-PCC/SRC, HR: 1.64, 95% CI: 1.18-2.29, P=0.0034) was a significant independent prognostic factor. CONCLUSION: Our results suggest that poorly cohesive carcinoma subtypes have different biological characteristics and prognoses.

Preoperative transferrin level is a novel indicator of short- and long-term outcomes after esophageal cancer surgery.

BACKGROUND: This study aimed to examine whether preoperative serum transferrin, a rapid-turnover protein, correlates with short- and long-term outcomes after esophagectomy. METHODS: Preoperative transferrin levels, calculated by summing serum iron and unsaturated iron-binding capacity, were evaluated in 224 patients who underwent esophagectomy for stage I-III esophageal cancer without preoperative treatment. Transferrin levels are directly proportional to total iron-binding capacity (TIBC), and we defined TIBC < 250 µg/dL as low transferrin. We evaluated the relationship between preoperative transferrin levels and short- and long-term outcomes after esophagectomy using univariate and multivariate Cox proportional hazards analyses. RESULTS: Of all patients, 25 (11.2%) had low preoperative transferrin levels. Low preoperative transferrin levels were strongly correlated with worse preoperative performance status, advanced pathological T stage, and more open esophagectomy (p = 0.0078, 0.0001, and 0.013, respectively). Patients with low preoperative transferrin levels experienced significantly more frequent postoperative pneumonia in univariate and multivariate analysis [hazard ratio (HR) 3.30, 95% confidence interval (CI) 1.032-10.033, p = 0.0443]. Additionally, these patients were significantly correlated with worse overall survival (OS) in univariate and multivariate analyses (HR 2.75, 95% CI 1.018-7.426, p = 0.0460). Furthermore, we investigated the relationship between OS and postoperative pneumonia to elucidate why low preoperative transferrin, which is an independent risk factor for postoperative pneumonia, leads to poor prognosis. Patients with postoperative pneumonia were strongly associated with a shorter OS (p = 0.0099). CONCLUSION: Preoperative serum transferrin levels may be a novel indicator of postoperative pneumonia and OS after esophagectomy.

Preoperative iron status is a prognosis factor for stage II and III colorectal cancer.

BACKGROUND: Iron deficiency anemia is represented in colorectal cancer (CRC) patients. Iron surplus load to increase non-transferrin bound iron (NTBI), and NTBI promotes cancer progression and influences microbiota. This study investigated whether preoperative serum iron status was associated with prognosis after CRC resection. METHODS: We evaluated preoperative iron and transferrin saturation (TSAT), which was calculated as iron divided by total iron-binding capacity, in 327 patients who underwent surgery for Stage II-III CRC. Fe < 60 µg/dl and TSAT > 40% were defined as low and high iron, respectively. The associations between iron status and overall survival (OS) were evaluated in univariate and multivariate Cox proportional hazards analysis. RESULTS: Of the 327 patients, 179 (54.7%), 124 (37.9%) and 24 (7.3%) had low, normal and high iron, respectively. In univariate analysis, low iron was associated with shorter OS (hazard ratio [HR] 2.821, 95% confidence interval [CI] 1.451-5.485, P = 0.002). High iron was also associated with shorter OS (HR 3.396, 95% CI 1.359-8.489, P = 0.009). In multivariate analysis, high age (P = 0.002), depth of invasion pT4 (P = 0.012), lymph-node metastasis presence (P = 0.035), low albumin (P = 0.011), low iron (HR 2.282, 95% CI 1.163-4.478, P = 0.016) and high iron (HR 3.757, 95% CI 1.486-9.494 P = 0.005) were independently associated with shorter OS. High iron was associated with the amount of intratumoral Fusobacterium nucleatum compared with normal iron. CONCLUSION: Both low and high preoperative iron in Stage II-III CRC patients were associated with unfavorable OS in univariate and multivariate analyses.

Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer.

Glucose transporter 1 (GLUT1) expression is a prognostic marker for esophageal squamous cell carcinoma (ESCC). Recent work on GLUT1 and development of specific inhibitors supports the feasibility of GLUT1 inhibition as a treatment for various cancers. The anti-proliferative effects of GLUT1-specific small interfering RNA (siRNA) and a GLUT1 inhibitor were evaluated in ESCC cell lines. Expression of pro-proliferative and anti-proliferative signaling and effector molecules was examined by western blotting and quantitative RT-PCR. GLUT1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value (SUV) of 18 F-fluoro-deoxyglucose was calculated using the formula: ([pretreatment SUVmax  - posttreatment SUVmax ]/pretreatment SUVmax ) × 100. GLUT1-specific siRNA expression in ESCC cells inhibited their proliferation, increased expression of p27kip, and decreased expression of cyclin-dependent kinase 6, pyruvate kinase muscle isozyme M2, lactate dehydrogenase A and phospho-ERK1/2. Suppression of GLUT1 by siRNA increased low-dose cisplatin-induced inhibition of proliferation of TE-11 ESCC cells, which express high GLUT1 levels. Similarly, BAY-876, a GLUT1 inhibitor, enhanced cisplatin-mediated inhibition of ESCC cell proliferation. GLUT1 expression in pretreatment biopsy samples was associated with the response to chemotherapy as well as the pathological tumor stage and histological response grade after esophagectomy. Finally, GLUT1-negative tumors showed a significantly larger reduction in SUVmax (61.2% ± 4.5%) compared with GLUT1-positive tumors (46.2% ± 4.4%). GLUT1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT1 may be a potential novel therapy for ESCC patients.

Naples Prognostic Score Is a Useful Prognostic Marker in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Systemic inflammation may influence the response to systemic chemotherapy or the prognosis in patients with various cancers. The Naples prognostic score, based on inflammatory and nutritional statuses, is a useful prognostic marker in patients undergoing surgery for colorectal cancer; however, its significance in patients with metastatic colorectal cancer remains unclear. OBJECTIVE: We aimed to evaluate the prognostic significance of the Naples prognostic factor in patients with metastatic colorectal cancer receiving first-line chemotherapy and to compare its prognostic accuracy with the neutrophil:lymphocyte ratio, platelet:lymphocyte ratio, and the systemic immune-inflammatory index. DESIGN: This was a retrospective study of prospectively collected data. SETTINGS: This study was conducted at a university hospital. PATIENTS: A total of 259 patients received first-line systemic chemotherapy for metastatic colorectal cancer. MAIN OUTCOME MEASURES: The Naples prognostic score was calculated by a composite score of albumin and cholesterol concentrations, lymphocyte:monocyte ratio, and neutrophil:lymphocyte ratio. The patients were divided into 3 groups based on increasing Naples scores (groups 0-2), and the associations of the Naples prognostic score with clinicopathologic features and overall survival were evaluated. RESULTS: Higher Naples prognostic score was positively associated with right-sided primary tumors and synchronous metastases and negatively with primary tumor resection. Patients in group 2 (high Naples prognostic score) had significantly shorter overall survival than those in groups 0 and 1 (p = 0.012 and 0.022). Multivariate Cox regression analysis identified the Naples prognostic score as an independent prognostic factor for overall survival (HR = 1.574; p = 0.004). Time-dependent receiver operating characteristic curve analysis showed that Naples prognostic score was more sensitive than other prognostic factors for predicting overall survival. LIMITATIONS: The main limitations are the sample size, single institutional feature, and treatment heterogeneity. CONCLUSIONS: The Naples prognostic score may be a useful prognostic marker in patients with metastatic colorectal cancer receiving systemic chemotherapy. See Video Abstract at http://links.lww.com/DCR/B72. LA PUNTUACIÓN PRONÓSTICA DE NÁPOLES ES UN MARCADOR PRONÓSTICO ÚTIL EN PACIENTES CON CÁNCER COLORRECTAL METASTÁSICO: La inflamación sistémica puede influir en la respuesta a la quimioterapia sistémica o el pronóstico en pacientes con varios tipos de cáncer. La puntuación pronóstica de Nápoles, basada en estados inflamatorios y nutricionales, es un marcador pronóstico útil en pacientes sometidos a cirugía por cáncer colorrectal; sin embargo, su importancia en pacientes con cáncer colorrectal metastásico sigue siendo incierta.El objetivo fue evaluar la importancia pronóstica del factor pronóstico de Nápoles en pacientes con cáncer colorrectal metastásico que reciben quimioterapia de primera línea y comparar su precisión pronóstica con la relación neutrófilos: linfocitos, plaquetas: linfocitos y el índice sistémico inmune-inflamatorio.Este estudio se realizó en un hospital universitario.Este fue un estudio retrospectivo de datos recolectados prospectivamente.Un total de 259 pacientes recibieron quimioterapia sistémica de primera línea para el cáncer colorrectal metastásico.La puntuación pronóstica de Nápoles se calculó mediante una puntuación compuesta de concentraciones de albúmina y colesterol, proporción de linfocitos: monocitos y proporción de neutrófilos: linfocitos. Los pacientes se dividieron en tres grupos basados en el aumento de las puntuaciones de Nápoles (grupos 0-2, respectivamente) y se evaluaron las asociaciones de la puntuación pronóstica de Nápoles con las características clínico-patológicas y la supervivencia general.La puntuación pronóstica de Nápoles es más alta se asoció positivamente con los tumores primarios del lado derecho y metástasis sincrónicas, y negativamente con la resección del tumor primario. Los pacientes del grupo 2 (alto puntaje pronóstico de Nápoles) tuvieron una supervivencia general significativamente menor que los de los grupos 0 y 1 (p = 0.012 y 0.022, respectivamente). El análisis de regresión de Cox multivariado identificó la puntuación pronóstica de Nápoles como un factor pronóstico independiente para la supervivencia global (índice de riesgo = 1.574; p = 0.004). El análisis de la curva característica de funcionamiento del receptor dependiente del tiempo mostró que la puntuación pronóstica de Nápoles era más sensible que otros factores pronósticos para predecir la supervivencia global.Las principales limitaciones son el tamaño de la muestra, la característica institucional única y la heterogeneidad del tratamiento.La puntuación pronóstica de Nápoles puede ser un marcador pronóstico útil en pacientes con cáncer colorrectal metastásico que reciben quimioterapia sistémica. Vea el Abstract del video en http://links.lww.com/DCR/B72.

Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.