How Does Omitting Additional Surgery After Local Excision Affect the Prognostic Outcome of Patients With High-risk T1 Colorectal Cancer?

OBJECTIVE: To investigate how omitting additional surgery after local excision (LE) affects patient outcomes in high-risk T1 colorectal cancer (CRC). BACKGROUND: It is debatable whether additional surgery should be performed for all patients with high-risk T1 CRC regardless of the tolerability of invasive procedures. METHODS: Patients who had received LE for T1 CRC at the Japanese Society for Cancer of the Colon and Rectum institutions between 2009 and 2016 were analyzed. Those who had received additional surgical resection and those who did not were matched one-on-one by the propensity score-matching method. A total of 401 propensity score-matched pairs were extracted from 1975 patients at 27 Japanese Society for Cancer of the Colon and Rectum institutions and were compared. RESULTS: Regional lymph node metastasis was observed in 31 (7.7%) patients in the LE + surgery group. Comparatively, the incidence of oncologic adverse events was low in the LE-alone group, such as the 5-year cumulative risk of local recurrence (4.1%) or overall recurrence (5.5%). In addition, the difference in the 5-year cancer-specific survival between the LE + surgery and LE-alone groups was only 1.8% (99.7% and 97.9%, respectively), whereas the 5-year overall survival was significantly lower in the LE-alone group than in the LE + surgery group [88.5% vs 94.5%, respectively ( P = 0.002)]. CONCLUSIONS: Those who had decided to omit additional surgery at the dedicated center for CRC treatment presented a small number of oncologic events and a satisfactory cancer-specific survival, which may suggest an important role of risk assessment regarding nononcologic adverse events to achieve a best practice for each individual with high-risk T1 tumors.

Long-Term Outcomes of Additional Surgery After Endoscopic Resection Versus Primary Surgery for T1 Colorectal Cancer.

INTRODUCTION: There is considerable concern about whether endoscopic resection (ER) before additional surgery (AS) for T1 colorectal cancer (CRC) has oncologically potential adverse effects. Therefore, the aim of this study was to compare the long-term outcomes, including overall survival (OS), of patients treated with AS after ER vs primary surgery (PS) for T1 CRC using a propensity score-matched analysis from a large observational study. METHODS: This study investigated 6,105 patients with T1 CRC treated with either ER or surgical resection between 2009 and 2016 at 27 high-volume Japanese institutions, with those undergoing surgery alone included in the PS group and those undergoing AS after ER included in the AS group. Propensity score matching was used for long-term outcomes of mortality and recurrence analysis. RESULTS: After propensity score matching, 1,219 of 2,438 patients were identified in each group. The 5-year OS rates in the AS and PS groups were 97.1% and 96.0%, respectively (hazard ratio: 0.72, 95% confidence interval: 0.49-1.08), indicating the noninferiority of the AS group. Moreover, 32 patients (2.6%) in the AS group and 24 (2.0%) in the PS group had recurrences, with no significant difference between the 2 groups (odds ratio: 1.34, 95% confidence interval: 0.76-2.40, P = 0.344). DISCUSSION: ER before AS for T1 CRC had no adverse effect on patients' long-term outcomes, including the 5-year OS rate. ER is a viable first-line treatment option for endoscopically resectable T1 CRC.

Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes.

INTRODUCTION: To verify the value of the pathological criteria for additional treatment in locally resected pT1 colorectal carcinoma (CRC) which have been used in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines since 2009. METHODS: We enrolled 4,667 patients with pT1 CRC treated at 27 institutions between July 2009 and December 2016 (1,257 patients with local resection alone [group A], 1,512 patients with additional surgery after local resection [group B], and 1,898 patients with surgery alone [group C]). All 5 factors of the JSCCR guidelines (submucosal resection margin, tumor histologic grade, submucosal invasion depth, lymphovascular invasion, and tumor budding) for lymph node metastasis (LNM) had been diagnosed prospectively. RESULTS: Any of the risk factors were present in 3,751 patients. The LNM incidence was 10.4% (95% confidence interval 9.4-11.5) in group B/C patients with risk factors, whereas it was 1.8% (95% confidence interval 0.4-5.3) in those without risk factors ( P < 0.01). In group A, the incidence of recurrence was 3.6% in patients with risk factors, but it was only 0.4% in patients without risk factors ( P < 0.01). The disease-free survival rate of group A patients classified as risk positive was significantly worse than those of groups B and C patients. However, the 5-year disease-free survival rate in group A patients with no risk was 99.6%. DISCUSSION: Our large-scale real-world multicenter study demonstrated the validity of the JSCCR criteria for pT1 CRC after local resection, especially regarding favorable outcomes in patients with low risk of LNM.

Development and Validation Study of the Prognostic Impact of Deep Learning-Determined Myxoid Stroma After Neoadjuvant Chemotherapy in Patients with Esophageal Squamous Cell Carcinoma.

PURPOSE: This study was designed to investigate the prognostic significance of artificial intelligence (AI)-based quantification of myxoid stroma in patients undergoing esophageal squamous cell carcinoma (ESCC) surgery after neoadjuvant chemotherapy (NAC) and to verify its significance in an independent validation cohort from another hospital. METHODS: We evaluated two datasets of patients with pathological stage II or III ESCC who underwent surgery after NAC. Cohort 1 consisted of 85 patients who underwent R0 surgery for the primary tumor after NAC. Cohort 2, the validation cohort, consisted of 80 patients who received same treatments in another hospital. AI-based myxoid stroma was evaluated in resected specimens, and its area was categorized by using the receiver operating characteristic curve for overall survival (OS) of cohort 1. RESULTS: The F1 scores, which are the degree of agreement between the automatically detected myxoid stroma and manual annotations, were 0.83 and 0.79 for cohorts 1 and 2. The myxoid stroma-high group had a significantly poorer prognosis than the myxoid stroma-low group in terms of OS, disease-specific survival (DSS), and recurrence-free survival (RFS) in cohort 1. Comparable results were observed in cohort 2, where OS, DSS, and RFS were significantly affected by myxoid stroma. Multivariate analysis for RFS revealed that AI-determined myxoid stroma-high was one of the independent prognostic factors in cohort 1 (hazard ratio [HR] 1.97, p = 0.037) and cohort 2 (HR 4.45, p < 0.001). CONCLUSIONS: AI-determined myxoid stroma may be a novel and useful prognostic factor for patients with pathological stage II or III ESCC after NAC.

Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study.

BACKGROUND AND AIMS: Since 2009, the Japanese Society for Cancer of the Colon and Rectum guidelines have recommended that tumor budding and submucosal invasion depth, in addition to lymphovascular invasion and tumor grade, be included as risk factors for lymph node metastasis (LNM) in patients with T1 colorectal cancer (CRC). In this study, a novel nomogram was developed and validated by usirge-scale, real-world data, including the Japanese Society for Cancer of the Colon and Rectum risk factors, to accurately evaluate the risk of LNM in T1 CRC. METHODS: Data from 4673 patients with T1 CRC treated at 27 high-volume institutions between 2009 and 2016 were analyzed for LNM risk. To prepare a nonrandom split sample, the total cohort was divided into development and validation cohorts. Pathologic findings were extracted from the medical records of each participating institution. The discrimination ability was measured by using the concordance index, and the variability in each prediction was evaluated by using calibration curves. RESULTS: Six independent risk factors for LNM, including submucosal invasion depth and tumor budding, were identified in the development cohort and entered into a nomogram. The concordance index was .784 for the clinical calculator in the development cohort and .790 in the validation cohort. The calibration curve approached the 45-degree diagonal in the validation cohort. CONCLUSIONS: This is the first nomogram to include submucosal invasion depth and tumor budding for use in routine pathologic diagnosis based on data from a nationwide multi-institutional study. This nomogram, developed with real-world data, should improve decision-making for an appropriate treatment strategy for T1 CRC.

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.

Deep-learning-based classification of desmoplastic reaction on H&E predicts poor prognosis in oesophageal squamous cell carcinoma.

AIMS: Desmoplastic reaction (DR) categorisation has been shown to be a promising prognostic factor in oesophageal squamous cell carcinoma (ESCC). The usual DR evaluation is performed using semiquantitative scores, which can be subjective. This study aimed to investigate whether a deep-learning classifier could be used for DR classification. We further assessed the prognostic significance of the deep-learning classifier and compared it to that of manual DR reporting and other pathological factors currently used in the clinic. METHODS AND RESULTS: From 222 surgically resected ESCC cases, 31 randomly selected haematoxylin-eosin-digitised whole slides of patients with immature DR were used to train and develop a deep-learning classifier. The classifier was trained for 89 370 iterations. The accuracy of the deep-learning classifier was assessed to 30 unseen cases, and the results revealed a Dice coefficient score of 0.81. For survival analysis, the classifier was then applied to the entire cohort of patients, which was split into a training (n = 156) and a test (n = 66) cohort. The automated DR classification had a higher prognostic significance for disease-specific survival than the manually classified DR in both the training and test cohorts. In addition, the automated DR classification outperformed the prognostic accuracy of the gold-standard factors of tumour depth and lymph node metastasis. CONCLUSIONS: This study demonstrated that DR can be objectively and quantitatively assessed in ESCC using a deep-learning classifier and that automatically classed DR has a higher prognostic significance than manual DR and other features currently used in the clinic.

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.

Histopathological atlas of desmoplastic reaction characterization in colorectal cancer.

Emergent scientific evidence indicates the central role of cancer-associated fibroblasts in determining whether the microenvironment of cancer works as friend or foe of the host; however, there is no unified histological evaluation framework of fibrotic stroma in colorectal cancers. Myxoid stroma and keloid-like collagen are site-specific histopathological features generated by cancer-associated fibroblasts, which appear exclusively in the tumor front during desmoplastic reaction. On the basis of these two stromal components, desmoplastic reaction is categorized into three patterns-immature, intermediate and mature-using hematoxylin and eosin staining. In January 2020, a prospective randomized clinical trial, JCOG1805, to elucidate the value of adjuvant chemotherapy in stage II colorectal cancer patients with pathological risk factors of recurrence was launched in Japan, in which intermediate/immature desmoplastic reaction is one of the four risk factors selected as inclusion criteria. This paper covers the diagnostic criteria for the desmoplastic reaction classification being used in the JCOG1805 study.

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.

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.