Enhanced Clinical Utility of Molecular Budding Signature as a Recurrence Risk Determinant in Stage II and III Colon Cancer Patients.

BACKGROUND: A molecular budding signature (MBS), which consists of seven tumor budding-related genes, was recently presented as a prominent prognostic indicator in colon cancer (CC) using microarray data acquired from frozen specimens. This study aimed to confirm the predictive power of MBS for recurrence risk based on formalin-fixed, paraffin-embedded (FFPE) materials. METHODS: This research utilized the same microarray data from a prior multicenter study using FFPE whole tissue sections, which retrospectively reviewed 232 stage II CC patients without adjuvant chemotherapy and 302 stage III CC patients with adjuvant chemotherapy. All patients underwent upfront curative surgery without neoadjuvant therapy between 2009 and 2012. An MBS score was calculated using the mean of log2 [each signal] of seven genes (MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, and FOXC1) as described before. RESULTS: The MBS-low group exhibited a better relapse-free survival (RFS) than the MBS-high group in stage II (P = 0.0077) and in stage III CC patients (P = 0.0003). Multivariate analyses revealed that the MBS score was an independent prognostic factor in both stage II (P = 0.0257) and stage III patients (P = 0.0022). Especially among T4, N2, or both (high-risk) stage III patients, the MBS-low group demonstrated markedly better RFS compared with the MBS-high group (P = 0.0013). CONCLUSIONS: This study confirmed the predictive power of the MBS for recurrence risk by employing FFPE materials in stage II/III CC patients.

Prognostic impact of desmoplastic reaction in esophageal squamous cell carcinoma patients with neoadjuvant therapy.

AIM: This study aimed to examine the prognostic value of desmoplastic reaction (DR) in esophageal squamous cell carcinoma (ESCC), particularly in patients who received neoadjuvant therapy, such as chemotherapy (NAC) or chemoradiotherapy (NACRT). METHOD: In total, 153 patients with pStage II/III ESCC were included in this study. Ninety-one patients received neoadjuvant therapy (NAC, 70; NACRT, 21). Patients were classified according to three DR categories based on the presence of keloid-like collagen and/or myxoid stroma. RESULTS: In total, 50, 50, and 53 patients were classified as having mature, intermediate, and immature DR, respectively. The weighted kappa coefficient was 0.623 in the patients with preoperative treatments and 0.782, in those without. The 5-year disease-specific survival (DSS) rates in patients with intermediate/immature DR was significantly worse than those with mature DR (40.7% vs. 73.3%, p < 0.001). Similarly, the 5-year DSS rate in patients with intermediate/immature DR was significantly worse than those with mature DR in a study of patients who received neoadjuvant therapy (46.7% vs. 71.2%, p = 0.009). Multivariate analysis revealed that DR (hazard ratio [HR]: 3.15, 95% confidence interval [CI] 1.58-6.27, p = 0.001), along with N factors, was an independent risk factor for DSS. Moreover, multivariate analysis of patients who received neoadjuvant therapy revealed only DR (HR: 2.47, 95% CI 1.02-5.96, p = 0.045) as independent risk factors for DSS. CONCLUSION: The DR classification was a valuable prognostic factor not only in the ESCC patients without neoadjuvant therapy but also in those with neoadjuvant therapy.

Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9.

The tumor microenvironment plays a key role in cancer aggressiveness. Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of our study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immature-type DR (CAFsImmature ) significantly increased proliferation and migration of CRC cell lines and growth of CRC-derived organoids compared to that of CAFs from Mature-type DR (CAFsMature ). Subcutaneous or orthotopic implantation of CRC cells together with CAFsImmature in mice significantly promoted tumor growth and dissemination compared to implantation with CAFsMature . Systematic examination of the expression of "a disintegrin and metalloproteinases" (ADAMs) in CAFs isolated from CRC tissues showed that the secreted isoform of ADAM9 (ADAM9s) was significantly higher in CAFsImmature than in CAFsMature . Knockdown of ADAM9s in CAFsImmature abrogated the promoting effects on CRC cell proliferation and migration. CAFs-derived ADAM9s is implicated in deteriorating survival in CRC patients with Immature-type DR by increasing tumor cell proliferation and dissemination.

Three-dimensional imaging of intramural perineural invasion in colorectal cancer: Three-dimensional reconstruction approach with multiple immunohistochemically stained sections.

Perineural invasion (PNI) at Auerbach's plexus in colorectal cancer (CRC), known as intramural PNI, is associated with adverse prognostic outcomes. This study aimed to characterize the three-dimensional (3D) architecture of CRC with intramural PNI and to evaluate the morphological features of tumor invasion around nerve tissue. Serial tissue sections from two cases of CRC were stained with cytokeratin AE1/AE3 and an anti-S-100 protein antibody. 3D models were reconstructed by scanning the virtual slides. In one case, intramural PNI was observed at the horizontal invasive front. The 3D reconstruction model showed tumor cells that appeared to infiltrate along the nervous meshwork, the structure of which was preserved. In the other case, intramural PNI was observed both at and behind the horizontal invasive front, and the 3D reconstruction model showed that the tumor cells appeared to be involved with nerve cells at the focal part of the horizontal invasive front. However, the nervous meshwork structure was not well identified in cancer-involved areas. This is the first study to characterize the 3D structure of tumor invasion around nerve tissue in CRC, demonstrating the morphological features of intramural PNI in CRC.

Proposal for a tumor budding predictive score derived from endoscopic biopsy samples in colorectal cancer.

BACKGROUND: In colorectal cancer, tumor budding is highlighted as both a prognostic indicator and a predictor of chemosensitivity. However, tumor budding has a serious drawback because of unattainable preoperative assessment, thereby, making it not applicable to decision-making on treatment strategies. Recently, high expressions of seven genes (i.e., MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, and FOXC1) were shown to be associated with high-budding colorectal cancers. This study aimed to propose a budding prediction system using selected RNAs extracted from biopsy specimens. METHODS: The RNA expression levels in 86 surgically resected samples and in 104 samples obtained by colonoscopy before surgery were investigated. RESULTS: The tumor surface expressions of four exclusive genes (i.e., MSLN, SLC4A11, SCEL, and MGAT3) were correlated with the tumor budding grade. Subsequently, the logit P value calculated by multiple logistic regression analysis using the four surface gene expressions was set as the following budding predictive score: Logit (P) = - 0.55 + 0.27*MSLN + 0.16*SLC4A11 + 0.06*MGAT3 + 0.21*SCEL. The effectiveness of the model using colorectal cancer biopsy samples was well corroborated prospectively. CONCLUSION: The budding predictive score that we developed using endoscopic biopsy specimens was clarified to have a high potential for preoperative use.

Mesothelin Expression is Correlated with Chemoresistance in Stage IV Colorectal Cancer.

BACKGROUND: Mesothelin (MSLN) is a cell-surface glycoprotein present on mesothelial cells; its expression in several epithelial cancers generally portends an unfavorable prognosis. We investigated MSLN as a surrogate chemopredictive biomarker and examined the impact of MSLN expression in stage IV colorectal cancer (CRC). METHODS: We recruited 254 patients with CRC who received systemic chemotherapy following primary tumor resection between 2000 and 2019. Resected specimens were immunostained for MSLN and stratified by MSLN expression. The associations of tumor MSLN expression with tumor response in metastatic lesions and survival were evaluated. RESULTS: Of the 247 patients with stage IV CRC, 41 (16.1%) and 213 (83.9%) had high and low MSLN expression, respectively. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, the investigator-assessed objective response rate was 22.0% in the high MSLN expression group and 45.5% in the low MSLN expression group (p = 0.0050). The disease control rates in these groups were 65.9% and 85.9%, respectively (p = 0.00019). In the patients with high MSLN expression, the conversion rate among those with initially unresectable metastases was 0% versus 14% in the patients with low MSLN expression (p = 0.0053). The median overall survival (OS) was 1.5 years (95% confidence interval [CI] 1.1-2.8) in the high MSLN expression group versus 2.6 years (95% CI 2.2-3.0) in the low MSLN expression group. The 3-year OS rates in these groups were 23.5 and 41.5%, respectively (p = 0.0120). CONCLUSIONS: High MSLN expression is correlated with chemoresistance and poor prognoses in stage IV CRC.

Correlation Between Immunoinflammatory Measures and Periostin Expression in Esophageal Squamous Cell Carcinoma: A Single-Center, Retrospective Cohort Study.

BACKGROUND: Immunoinflammatory measures such as the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the C-reactive protein (CRP)-albumin ratio (CAR) are useful prognostic measures in various malignancies. However, no study has investigated the correlation of these measures with microenvironmental inflammation. Periostin (POSTN), a small extracellular matrix protein, strongly associates with cancer microenvironmental inflammation. The current study investigated the correlation of NLR, PLR, and CAR with periostin expression in esophageal squamous cell carcinoma (ESCC). METHODS: The study retrospectively evaluated preoperative NLR, PLR, and CAR hematologically and POSTN immunohistochemically in 171 patients. The correlation of immunoinflammatory measures, POSTN expression, and survival outcomes was measured. RESULTS: The study showed a significant correlation of POSTN-positive expression with poor overall survival (OS) (P < 0.0001) and recurrence-free survival (RFS) (P = 0.03). The POSTN-positive group had higher PLR (189.6 ± 8 vs. 159.3 ± 12; P = 0.04) and CAR (0.36 ± 0.06 vs. 0.14 ± 0.09; P < 0.05) than the POSTN-negative group, whereas NLR did not differ between the two groups (3.27 ± 0.19 vs. 2.65 ± 0.28; P = 0.07). The uni- and multivariate analyses showed that POSTN-positive expression (hazard ratio [HR], 1.595; 95% confidence interval [CI], 0.770-3.031; P = 0.03), CAR (HR, 1.663; 95% CI, 1.016-2.764; P = 0.03), gender (HR, 2.303; 95% CI, 1.067-6.019; P = 0.03), and tumor depth (HR, 1.957; 95% CI, 1.122-3.526; P = 0.01) were independent prognostic factors. CONCLUSIONS: Because POSTN-positive expression strongly correlates with immunoinflammatory measures, especially PLR and CAR, it is an independent prognostic factor in ESCC.

Histological categorisation of the desmoplastic reaction is a predictor of patient prognosis in oesophageal squamous cell carcinoma.

AIMS: Histological categorisation of the desmoplastic reaction (DR) is an independent prognostic factor in colorectal cancer. However, it is unknown whether DR categorisation is predictive of oesophageal squamous cell carcinoma (OSCC) outcomes. This study aimed to evaluate the prognostic value of DR categorisation in OSCC patients. METHODS AND RESULTS: Data were collected from 118 patients with OSCC who underwent a curative oesophagectomy with T2 or deeper wall invasion. The DR in each tumour was classified as mature, intermediate or immature based on the presence or absence of keloid-like collagen and myxoid stroma. We identified 49 mature DR tumours, 41 intermediate DR tumours and 28 immature DR tumours. The 5-year overall survival (OS) rate was highest in the mature DR group (42.8%), followed by the intermediate DR group (25.0%) and the immature DR group (19.9%) (P = 0.022, log-rank test; P = 0.006, log-rank trend test). The 5-year disease-specific survival (DSS) rate was also highest in the mature DR group (48.5%), followed by the intermediate DR group (30.8%) and the immature DR group (26.8%) (P = 0.031, log-rank test; P = 0.010, log-rank trend test, respectively). Multivariate analysis revealed that an immature DR was an independent poor prognostic factor of OS and DSS (P = 0.002 and P = 0.004). CONCLUSIONS: DR categorisation of OSCC stroma following oesophagectomy is a useful diagnostic tool and an independent prognostic marker.

Evaluation of a 55-gene classifier as a prognostic biomarker for adjuvant chemotherapy in stage III colon cancer patients.

BACKGROUND: Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. METHODS: We retrospectively identified patients aged 20-79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. RESULTS: Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465-3.308; P = 0.67) and 0.791 (95% CI, 0.329-1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145-1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. CONCLUSIONS: Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879 ).

Prognostic Impact of Budding Grade in Patients With Residual Liver Recurrence of Colorectal Cancer After Initial Hepatectomy.

BACKGROUND: Many patients undergoing hepatectomy for colorectal liver metastases (CRLM) experience recurrence. However, no criteria for screening candidates to undergo repeat hepatectomy (RH) for CRLM have been established. Budding, one form by which colorectal carcinoma malignancies are expressed, is a new pathologic index. This study aimed to analyze prognostic factors, including budding, and to provide criteria for screening candidates to undergo RH for recurrent CRLM. METHODS: Data of 186 consecutive patients who underwent hepatectomy for CRLM between April 2008 and December 2015 were collected. Survival was calculated using the Kaplan-Meier method. Uni- and multivariate analyses were performed to determine factors significantly affecting mortality. RESULTS: Of 186 patients, 131 experienced recurrence after hepatectomy, with 83 of the 131 patients showing recurrence in the liver, and 52 of these 83 patients undergoing primary surgery at the authors' institution and having information on budding grade. In the univariate analysis, preoperative chemotherapy, budding grade, extrahepatic metastases, and number of liver metastases at the time of recurrence were associated with overall survival (OS) for the 52 patients. In the multivariate analysis, budding grade and number of liver metastases at the time of recurrence were associated with OS. CONCLUSION: The study examined simple prognostic factors that could help to screen patients better for RH. Repeat hepatectomy improved the prognosis for patients with recurrent CRLM. The independent prognostic factors for OS were number of liver metastases at recurrence as a conventional factor and budding grade as a new pathologic factor. With budding used as an index, patients who could benefit from hepatectomy can be screened more precisely.

Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer.

BACKGROUND: Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance. METHODS: Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene. RESULTS: We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3, FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013). CONCLUSIONS: We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.

A Validation Study for Recurrence Risk Stratification of Stage II Colon Cancer Using the 55-Gene Classifier.

INTRODUCTION: DNA microarrays, such as the consensus molecular subtype (CMS) classification using >600 genes, are used to predict cancer patient prognosis. We recently constructed a simple 55-gene classifier (55GC) system to risk stratify colon cancer (CC). OBJECTIVE: Here, we validate the 55GC specifically for stage II CC and compare it with CMS categories. METHODS: Tissue sections from 232 stage II CC patients who underwent curative surgery without adjuvant chemotherapy between 2009 and 2012 were subjected to DNA microarray analysis. RESULTS: Based on the 55GC, patients were classified into microsatellite instability-like (27%), chromosomal instability-like (41%), and stromal (32%) subtypes with 5-year relapse-free survival (RFS) rates of 88.5, 83.3, and 71.2%, respectively (stromal vs. others: p = 0.0049). Multivariate analysis by Cox's proportional hazard model revealed that the stromal subtype, pT4, and the number of lymph nodes examined (<12) were independent poor prognostic factors. The overall concordance rate between 55GC and CMS was 72%, and 5-year RFS rates of patients with CMS1, CMS2, CMS3, and CMS4 cancers were 100, 85.5, 92.3, and 73.0%, respectively (p = 0.0113). CONCLUSIONS: We conclude that the 55GC is a useful and reproducible grading system for stage II CC recurrence risk stratification.

Expression and Function of a Disintegrin and Metalloproteinases in Cancer-Associated Fibroblasts of Colorectal Cancer.

BACKGROUND: Cancer tissues consist of cancer cells and stroma, the latter of which dictates cancer tissue microenvironment. We recently reported that the desmoplastic reaction (DR) pattern at the invasive front in colorectal cancer (CRC) is a promising prognostic indicator. However, the molecular mechanisms of DR formation and contribution to patients' prognosis remain unclear. SUMMARY: The tumor tissue microenvironment composed of extracellular matrix (ECM), soluble factors (growth factors/cytokine/cytokine), and stromal cells controls tumor growth and spread. Among stromal cells, cancer-associated fibroblasts (CAFs) play a key role in development of the cancer tissue microenvironment, and they are responsible for DR formation. CAFs express a disintegrin and metalloproteinases (ADAMs), which modulate cancer tissue microenvironmental factors. We isolated CAFs and normal fibroblasts from colon tissues of patients with CRC and characterized them. CAFs showed the increased expression of several ADAM species including ADAM9, ADAM10, ADAM12, and ADAM17, and the expression was further increased on the ECM-coated plates. Our in vitro and in vivo studies using CAFs and CRC cells suggest that ADAM expression is associated with the morphological DR category, and ADAMs may affect cancer malignancy through tumor proliferation in CRC. Key Message: This review summarizes the present knowledge on ADAMs in cancer and describes our recent findings regarding the molecular biological background of DR mainly by focusing on ADAMs.

Association Between the Frequency of Glove Change and the Risk of Blood and Body Fluid Exposure in Gastrointestinal Surgery.

BACKGROUND: Surgical gloves are used to prevent the transmission of microorganisms from the surgeon's hands to the patient and vice versa. Little is known on the optimal frequency of glove changing. Therefore, we aimed to examine the optimal frequency of glove change during surgery by assessing the glove perforation rate in gastrointestinal surgery. METHODS: In this observational prospective cohort study, we investigated the incidence of perforation of 5,267 gloves during gastrointestinal surgeries. RESULTS: The overall glove perforation rate was 10.1%. There was no significant difference between single gloving (10.2%) and double gloving (10.0%; p = 0.8491). However, the perforation rate of the inner glove (5.7%) was found to be significantly lower than that of the outer glove (11.6%) (p < 0.0001). A significant difference in perforation rate was observed after wearing inner gloves for 240 min (< 240 min, 4.4%; ≤ 240 min, 7.2%; p = 0.0314), and outer gloves for 60 min (< 60 min, 7.1%; ≤ 60 min, 12.6%; p < 0.0001). We found cumulative perforation rate to rapidly increase until the wear time was 90 min. CONCLUSION: The inner gloves and outer gloves have a higher perforation rate as the wear time increased. To reduce the risk of intraoperative blood and fluid exposure and prevent healthcare-associated infection, gloves should be changed for approximately every 60-90 min for outer gloves and approximately every 240 min for inner gloves.

Differential clinical impacts of tumour budding evaluated by the use of immunohistochemical and haematoxylin and eosin staining in stage II colorectal cancer.

AIMS: The aim of this study was to clarify the quantitative and qualitative differences in tumour budding identification between haematoxylin and eosin (H&E) staining and immunohistochemical (IHC) staining for cytokeratin, and to estimate the respective clinical impacts in stage II colorectal cancer. METHODS AND RESULTS: We retrospectively examined 314 surgically resected cases of stage II colorectal cancer, and assessed tumour budding on serial section slides with H&E staining and IHC staining for cytokeratin. Tumour budding counts based on cytokeratin-stained slides were strongly correlated with those based on H&E-stained slides, and had higher detection and reproducibility. On the basis of receiver operating characteristic analyses, the optimal cut-off values of budding counts for relapse-free survival (RFS) were 7 and 16 in a ×200 microscopic field with H&E and IHC staining, respectively. With these cut-off values, tumour budding based on H&E staining had a significant correlation with RFS (80.3% and 93.2% of 5-year RFS in the high-budding group and the low-budding group, respectively), and similar results were observed for IHC staining (79.9% and 91.7%, respectively). The Akaike Information Criterion value for RFS with H&E staining was favourable as compared with that with IHC staining. CONCLUSIONS: Tumour budding counts based on cytokeratin-stained slides showed higher detection and better reproducibility, but did not have as satisfactory clinical impacts as those based on H&E staining.

Differential Survival Benefits of 5-Fluorouracil-Based Adjuvant Chemotherapy for Patients With Microsatellite-Stable Stage III Colorectal Cancer According to the Tumor Budding Status: A Retrospective Analysis.

BACKGROUND: Recent research has established tumor budding as a prognostic factor and a possible histomorphologic reflection of epithelial-mesenchymal transition in colorectal cancer, highlighting the ability of cancer cells exhibiting epithelial-mesenchymal transition to resist chemotherapy. OBJECTIVE: This study aimed to investigate the clinical benefits of adjuvant chemotherapy according to the tumor budding status in microsatellite-stable stage III colorectal cancer. DESIGN: This was a retrospective study of 2 cohorts. SETTINGS: The study was conducted at the National Defense Medical College in Japan. PATIENTS: We reviewed 2 data sets of patients with microsatellite-stable stage III colorectal cancer with curatively intended surgery (R0) from 1999 to 2005 (first cohort; n = 203) and 2006 to 2012 (second cohort; n = 346). In both cohorts, 128 and 203 patients received 5-fluorouracil-based adjuvant chemotherapy and 75 and 143 patients did not. MAIN OUTCOME MEASURES: We assessed the benefits of adjuvant chemotherapy according to the grades of tumor budding based on the cancer-specific survival. RESULTS: In low-budding tumors, the chemotherapy group exhibited better cancer-specific survival than the surgery-alone group (first cohort, 93.1% vs 65.5%, p = 0.001; second cohort, 94.0% vs 76.0%, p < 0.0001). Conversely, the prognostic difference between the chemotherapy and surgery-alone groups was statistically insignificant in high-budding tumors (first cohort, 59.7% vs 52.4%, p = 0.57; second cohort, 83.1% vs 75.6%, p = 0.19). The multivariate analysis corroborated the benefits of adjuvant chemotherapy in low-budding tumors (first cohort, p = 0.002, HR = 0.28; second cohort, p < 0.0001, HR = 0.23) but not in high-budding tumors. LIMITATIONS: Postoperative adjuvant chemotherapy and treatments for recurrence were not homogeneous, and the patient backgrounds differed between the chemotherapy and surgery alone groups. CONCLUSIONS: The high-budding group demonstrated resistance to 5-fluorouracil-based chemotherapy, whereas the low-budding group exhibited significant survival benefits from adjuvant chemotherapy in stage III colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B14. BENEFICIOS DE SUPERVIVENCIA DIFERENCIAL DE LA QUIMIOTERAPIA ADYUVANTE BASADA EN 5-FLUOROURACILO PARA PACIENTES CON CÁNCER COLORRECTAL EN ESTADIO III ESTABLE CON MICROSATÉLITE SEGÚN EL ESTADO DE BROTACIÓN DEL TUMOR: UN ANÁLISIS RETROSPECTIVO:: Investigaciones recientes han establecido la aparición de tumores como un factor pronóstico y una posible reflexión histomorfológica de la transición epitelial-mesenquimatosa en el cáncer colorrectal, destacando la capacidad de las células cancerosas que presentan una transición epitelio-mesenquimática para resistir la quimioterapia.El objetivo de este estudio es investigar los beneficios clínicos de la quimioterapia adyuvante según el estado de brotación del tumor en el cáncer colorrectal en estadio III estable con microsatélite.Este fue un estudio retrospectivo de dos cohortes.El estudio se realizó en la Escuela de Medicina de la Defensa Nacional de Japón.Revisamos dos conjuntos de datos de pacientes con cáncer colorrectal en estadio III estable con microsatélite con cirugía de intención curativa (R0) de 1999 a 2005 (primera cohorte; n = 203) y 2006 a 2012 (segunda cohorte; n = 346). En ambas cohortes, 128 y 203 pacientes recibieron quimioterapia adyuvante basada en 5-fluorouracilo y 75 y 143 pacientes no, respectivamente.Evaluamos los beneficios de la quimioterapia adyuvante de acuerdo con los grados de brotación del tumor en función de la supervivencia específica del cáncer.n los tumores con brotes bajos, el grupo de quimioterapia mostró una mejor supervivencia específica al cáncer que el grupo con cirugía sola (primera cohorte, 93.1% vs. 65.5%, p = 0.001; segunda cohorte, 94.0% vs. 76.0%, p < 0.0001). A la inversa, la diferencia pronóstica entre los grupos de quimioterapia y cirugía sola fue estadísticamente insignificante en los tumores de brotes elevados (primera cohorte, 59.7% vs. 52.4%, p = 0.57; segunda cohorte, 83.1% vs. 75.6%, p = 0.19). El análisis multivariado corroboró los beneficios de la quimioterapia adyuvante en los tumores de brotes bajos (primera cohorte, p = 0,002, índice de riesgo: 0,28; segundo cohorte, p <0,0001, índice de riesgo: 0,23) pero no en los tumores de alto brote.a quimioterapia adyuvante postoperatoria y los tratamientos para la recurrencia no fueron homogéneos, y los antecedentes de los pacientes difirieron entre los grupos de quimioterapia y cirugía sola.El grupo de alto brote demostró resistencia a la quimioterapia basada en 5-fluorouracilo, mientras que el grupo de bajo brote mostró beneficios significativos de supervivencia de la quimioterapia adyuvante en el cáncer colorrectal en estadio III. Vea el Resumen del Video en http://links.lww.com/DCR/B14.

Cancer-induced spiculation on computed tomography: a significant preoperative prognostic factor for colorectal cancer.

PURPOSE: Cancer-induced spiculation (CIS) on computed tomography, which is reticular or linear opacification of the pericolorectal fat tissues around the cancer site, is generally regarded as cancer infiltration into T3 or T4, but its clinicopathological significance is unknown. This study examines the correlation between CIS and clinicopathological findings to establish its prognostic value. METHODS: The subjects of this retrospective study were 335 patients with colorectal cancer (CRC), who underwent curative surgery between January, 2010 and December, 2011, at the National Defense Medical College Hospital in Saitama Prefecture, Japan. RESULTS: The level of interobserver agreement in the evaluation of CIS was substantial (83%; kappa value, 0.65). The presence of CIS was specific for T3/T4 disease (positive predictive value, 88.3%), and was significantly associated with tumor size and venous invasion. The 5-year relapse-free survival rate was significantly lower in patients with CIS than in those without CIS (68.6% and 84.0%, respectively, p = 0.001). Subgroup analysis revealed remarkable prognostic differences in patients with stage III and T3 disease. Multivariate analysis revealed that CIS was a significant independent prognostic factor. CONCLUSIONS: CIS was a significant preoperative prognostic factor and could be useful in the selection of preoperative therapy for patients with CRC.

A New N Staging System for Colorectal Cancer in the Era of Extended Lymphadenectomy.

BACKGROUND: Complete mesocolic excision is becoming popular in colon cancer surgery in Western countries, and in the tumor-node-metastasis (TNM) classification of rectal cancer, a part of the lateral pelvic lymph nodes is classified as regional. However, the appropriateness of TNM staging according to the assessment of nodal status exclusively by extended lymphadenectomy remains unclear. PATIENTS AND METHODS: Using a nationwide multicenter database in Japan, we retrospectively analyzed 6866 patients with stage III colorectal cancer (CRC) treated with extended (D3) dissection. First, the best cutoff values for the number of metastatic nodes were explored. Second, the utility of the metastatic status of the main lymph nodes (i.e., at the origin of the feeding artery) and the lateral pelvic lymph nodes ("jN3" category in the Japanese staging system) as N staging criteria was evaluated. The modified N staging system that had the best risk stratification power was determined according to the Akaike information criterion (AIC). RESULTS: Excellent performance was noted when the number of metastatic nodes was categorized by cutoff values of "3/4" and "6/7." Categorization of nodal metastasis was proven the most clinically efficacious when classified as modified-N1 (N1 and jN3-negative), modified-N2a (N2a and jN3-negative), and modified-N2b (N2b and/or jN3-positive; AIC, 22,810.8), rather than the classification based on the TNM (AIC, 22,849.2) or Japanese staging system (AIC, 22,811.1). CONCLUSIONS: We structured a modified N staging system according to the number and extent of lymph node metastases. The modified system may be used in stage III cases for precise risk stratification.

Prognostic Value of Preoperative Systemic Immunoinflammatory Measures in Patients with Esophageal Cancer.

BACKGROUND: It is reported that several systemic immunoinflammatory measures, including systemic immune-inflammatory index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and C-reactive protein (CRP)-to-albumin ratio (CAR), are associated with survival in patients with various types of cancer. OBJECTIVE: The aim of the present study was to clear which systemic immunoinflammatory measures had the greatest prognostic values. In addition, we examined which component had the greatest prognostic power in patients with esophageal cancer. METHODS: Preoperative systemic immunoinflammatory measures were evaluated in 143 patients undergoing esophageal resection for esophageal cancer from 2009 to 2014. Univariate and multivariate analyses were performed to determine the prognostic significance of these markers. Receiver operating characteristic (ROC) curves were plotted, and the area under the ROC curves (AUROCs) were compared to verify the accuracy of each measure in predicting overall survival (OS). RESULTS: In univariate analysis, preoperative SII, NLR, and CAR were the predictors of OS in patients who underwent esophagectomy for esophageal cancer (p < 0.05, respectively), whereas in multivariate analysis, CAR and pathological tumor depth were the significant predictors of OS (hazard ratio [HR] 1.994, p = 0.03 vs. HR 1.967, p = 0.02, respectively). According to AUROC, the CRP (0.66) and albumin levels (0.66) were more important systemic immunoinflammatory measures than neutrophil (0.58), lymphocyte (0.63), and platelet (0.56) levels. CONCLUSION: Among systemic immunoinflammatory measures, CAR was the most significant predictor of OS in patients with esophageal cancer. CRP and albumin levels were more important components of systemic immunoinflammatory measures.