Clinical significance of metastatic tumor deposit foci in rectal cancer in the lateral pelvic lymph node area.

BACKGROUND: Although previous studies have demonstrated that tumor deposits (TDs) are associated with worse prognosis in colon cancer, their clinical significance in rectal cancer has not been fully elucidated, especially in the lateral pelvic lymph node (LPLN) area. This study aimed to clarify the clinical significance of TDs, focusing on the number of metastatic foci, including lymph node metastases (LNMs) and TDs, in the LPLN area. METHODS: This retrospective study involved 226 consecutive patients with cStage II/III low rectal cancer who underwent LPLN dissection. Metastatic foci, including LNM and TD, in the LPLN area were defined as lateral pelvic metastases (LP-M) and were evaluated according to LP-M status: presence (absence vs. presence), histopathological classification (LNM vs. TD), and number (one to three vs. four or more). We evaluated the relapse-free survival of each model and compared them using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: Forty-nine of 226 patients (22%) had LP-M, and 15 patients (7%) had TDs. The median number of LP-M per patient was one (range, 1-9). The best risk stratification power was observed for number (AIC, 758; c-index, 0.668) compared with presence (AIC, 759; c-index, 0.665) and histopathological classification (AIC, 761; c-index, 0.664). The number of LP-M was an independent prognostic factor for both relapse-free and overall survival, and was significantly associated with cumulative local recurrence. CONCLUSION: The number of metastatic foci, including LNMs and TDs, in the LPLN area is useful for risk stratification of patients with low rectal cancer.

Salivary leukocyte esterase activity by SillHa is a risk indicator of periodontal disease.

BACKGROUND: There is increasing evidence that diagnostic salivary tests measuring inflammatory biomarkers are being developed to assess inflammatory status for early detection, prevention, and progression of periodontal disease. Therefore, the aim of the present study was to investigate and identify the salivary biomarker that can predict the inflammatory status of periodontal disease. METHODS: A total of 36 patients (28 women and 8 men) with an average age of 57 years were investigated. Unstimulated saliva was collected from the recruited subjects and analyzed using SillHa, a saliva-testing device that measures bacteria count, saliva buffer capacity, acidity, leukocyte esterase, protein, and ammonia. Periodontal parameters were then obtained by clinical examination and initial periodontal therapy was performed. Data obtained with SillHa were compared with clinical periodontal parameters at baseline, re-examination (three months from baseline), and final examination (six months from re-examination). RESULTS: Leukocyte esterase activity in saliva measured by SillHa; BOP and PCR measured by clinical examination showed a significant difference between baseline and final examination and between re-examination and final examination. Patients in the lower median group (group 1) had a significant difference in leukocyte esterase activity between baseline and final examination and re-examination and final examination. In addition, patients in Group 1 had significantly lower BOP between baseline and final examination. While patients in the higher median group (group 2) showed a modest decrease in leukocyte esterase activity, which was significant only between baseline and final examination, no significant changes were observed concerning BOP. Furthermore, the associated systemic disease was observed in 30% and 81.2% of group 1 and 2 patients, respectively. CONCLUSION: The results suggest that leukocyte esterase activity in saliva measured by SillHa could serve as a reliable diagnostic marker for monitoring inflammatory status in periodontal disease.

A Comparative Clinical Study of Lateral Lumbar Interbody Fusion between Patients with Multiply Operated Back and Patients with First-Time Surgery.

Background and Objectives: Patients with multiply operated back (MOB) may suffer from persistent lower-back pain associated with back muscle damage and epidural fibrosis following repeated back surgery (Failed Back Spinal Syndrome). Lateral lumbar interbody fusion (LLIF) is considered to be favorable for MOB patients. However, little scientific research has been carried out for this issue due to variety of the pathogenesis. The purpose of this study was to compare the clinical results of MOB patients and first-time surgery patients who underwent LLIF for lumbar spinal stenosis with degenerative scoliosis and/or degenerative spondylolisthesis (spinal instability). Materials and Methods: LLIF was performed for lumbar spinal stenosis with spinal instability in 55 consecutive cases of single hospital (30 males, 25 females, average age: 69). Clinical outcomes were compared between the MOB patient group (MOB group) and the first surgical patient group (F group). We evaluated the Japanese Orthopaedic Association (JOA) scores and JOA Back Pain Evaluation Questionnaire (JOABPEQ) before and 2 years after surgery. MOB patients were defined as those who have had one or more lumbar surgery on the same intervertebral or adjacent vertebrae in the past. Results: There were 20 cases (12 males, 8 females, average age: 71) in MOB group, and 35 cases (19 males, 16 females, average age: 68) in the F group. There was no significant difference between the two groups in terms of age, sex, number of intervertebral fixations, modic change in fused intervertebral end plate, score of brief scale for evaluation of psychiatric problem, lumbar lordosis, and sagittal vertical axis before and after surgery. The preoperative JOA scores averaged 12.5 points in the MOB group and averaged 11.6 points in the F group. The postoperative JOA scores averaged 23.9 points in the MOB group and averaged 24.7 points in the F group. The preoperative JOABPEQ averaged 36.3 points in the MOB group and averaged 35.4 points in the F group. The postoperative average JOA score was 75.4 in the MOB group and 70.2 in the F group. Conclusions: Based on the results, there was no significant difference in clinical outcomes of the two groups, and there was no new residual lower-back pain. Thus, we considered that LLIF one option for patients with MOB.

[Cancer of the Ascending Colon and Left Breast in an Older Adult Complicated by Thoracic Aortic Aneurysm].

An 87-year-old woman with a gradually enlarging mass in her left breast, diagnosed as having left-sided breast cancer with skin invasion by a local practitioner, was referred to our hospital. Computed tomography revealed ascending colon cancer with abdominal wall invasion and a thoracic aortic aneurysm(Stanford type B), in addition to breast cancer with skin invasion. A thoracic endovascular aortic repair and bypass surgery between the subclavian arteries were both performed for the thoracic aortic aneurysm. After 6 days, a right hemicolectomy and D2 lymphadenectomy were performed for the ascending colon cancer. A postoperative pathological diagnosis of pT3N0M0, pStage Ⅱa, was made. A total left mastectomy with a full-thickness skin graft for left breast cancer was performed after 2 months following the ascending colon cancer surgery. The postoperative pathological diagnosis was pT3N0M0, pStage ⅡB. No evidence of local recurrence or distant metastasis of the ascending colon cancer has been observed at 20 months postoperatively, or of the breast cancer after 18 months following surgery.

[A Case of Appendiceal Carcinoma with BRAF V600E Mutation and Microsatellite Instability-High].

A 75-year-old woman presented to our hospital with abdominal pain and melena. Colonoscopy revealed an ulcer at the appendiceal orifice. Histopathological examination of biopsy specimens revealed adenocarcinoma. Computed tomography showed an appendiceal mass of 11.8×6.7 cm in size involving the cecum and terminal ileum without any distant metastatic findings. Ileocecal resection with regional lymph node dissection to the root of the ileocolonic artery was performed. Histopathological examination of the specimen revealed appendiceal adenocarcinoma. Molecular subtype of the tumor was BRAF V600E mutation and microsatellite instability-high(MSI-H). The pathological stage was pT4bpN1bcM0, pStage ⅢC. She received 8 courses of CapeOX as adjuvant chemotherapy and no recurrence was noted 12 months following the surgery. The establishment of standard treatment strategies including surgery, chemotherapy, and immunotherapy for carcinoma of the appendix with BRAF V600E mutation and/or MSI-H is needed.

How Worries about Interpersonal Relationships, Academic Performance, Family Support, and Classmate Social Capital Influence Suicidal Ideation among Adolescents in Japan.

Suicide is an important public health issue for adolescents. To investigate the risk and protective factors for adolescent suicide, a cross-sectional questionnaire-based survey was conducted at a junior high school (n = 379) in Japan in 2018. After obtaining survey data, we conducted univariate and logistic regression analyses to test for associations between suicidal ideation and several factors, including worries (i.e., about school life, interpersonal relationships at school, family life, interpersonal relationships at home, and academic performance), perceived support from school staff and family members, and social capital. In this context, the existence of trustful relationships between classmates was used as indicators of social capital. The results showed that the prevalence of suicidal ideation was 10.5%. The risk of suicidal ideation was increased by worries about 1) interpersonal relationships at school, 2) interpersonal relationships at home, and 3) academic performance, but was decreased by social support from family members and trusting relationships. Further, the rate of suicidal ideation was higher among students who expressed all these three worries when compared to those who expressed two or fewer worries. In addition, looking at students who expressed all these three worries simultaneously, the rate of suicidal ideation was higher among those with lower levels of support from family members and fewer trustful relationships. Our results suggest that the prevention of adolescent suicide should include strategies for reducing worries about interpersonal relationships at school/home and academic performance while finding ways to enhance family support and classmate social capital.

A case series describing the risk of periodontal disease in Marfan syndrome patients harboring a possible aortic aneurysm or dissection.

BACKGROUND: Marfan syndrome (MFS) is a systemic disorder of connective tissues caused by insufficient elastic fiber formation that leads to structural weakness and results in various tissue disorders, including cardiovascular and periodontal disease. Notably however, the risk of periodontal disease in MFS patients affected by an aortic aneurysm or dissection has not yet been clarified. METHODS: We investigated the periodontal condition in the following three groups: MFS patients diagnosed with an aortic aneurysm or dissection with a planned aortic surgery (MFS surgery), MFS patients who had already undergone aortic surgery (MFS post-surgery) and healthy control patients (Healthy). The periodontal condition of all of these patients was evaluated at their first visit, reassessed again at two-month after the first visit, and evaluated again at a six-month follow-up after the reassessment. RESULTS: A total of 14 participants, 3 MFS surgery patients, 4 MFS post-surgery patients and 7 healthy control volunteers were examined. Saliva examinations revealed no significant differences between any of the groups at the first visit, reassessment, or follow-up. Interestingly, the MFS surgery cases showed a higher BOP and PISA at the first visit and follow-up compared with the other groups. In contrast, the MFS surgery patients showed an improvement in their LVDd and EF values, both markers of cardiac function, at the reassessment and follow-up compared with the first visit. CONCLUSIONS: MFS associated with an aortic aneurysm or dissection leads to a higher risk of periodontal disease, indicating the need for more frequent oral hygiene maintenance in these patients. In addition, MFS patients who undergo frequent professional cleaning of their teeth show a lower onset of cardiovascular disease, suggesting that professional oral hygiene in these cases contributes to a healthier condition.

Minimally Invasive Spinal Treatment (MIST)-A New Concept in the Treatment of Spinal Diseases: A Narrative Review.

In the past two decades, minimally invasive spine surgery (MISS) techniques have been developed for spinal surgery. Historically, minimizing invasiveness in decompression surgery was initially reported as a MISS technique. In recent years, MISS techniques have also been applied for spinal stabilization techniques, which were defined as minimally invasive spine stabilization (MISt), including percutaneous pedicle screws (PPS) fixation, lateral lumbar interbody fusion, balloon kyphoplasty, percutaneous vertebroplasty, cortical bone trajectory, and cervical total disc replacement. These MISS techniques typically provide many advantages such as preservation of paraspinal musculature, less blood loss, a shorter operative time, less postoperative pain, and a lower infection rate as well as being more cost-effective compared to traditional open techniques. However, even MISS techniques are associated with several limitations including technical difficulty, training opportunities, surgical cost, equipment cost, and radiation exposure. These downsides of surgical treatments make conservative treatments more feasible option. In the future, medicine must become "minimally invasive" in the broadest sense-for all patients, conventional surgeries, medical personnel, hospital management, nursing care, and the medical economy. As a new framework for the treatment of spinal diseases, the concept of minimally invasive spinal treatment (MIST) has been proposed.

[A Case of Long-Term Survival with Multidisciplinary Treatment after Surgery for Duodenal Cancer with Left Supraclavicular Lymph Node Metastasis].

The patient was a 71-year-old man with a diagnosis of duodenal carcinoma. Abdominal computed tomography(CT) showed no distant metastasis, and he underwent subtotal stomach-preserving pancreaticoduodenectomy. Postoperative adjuvant chemotherapy was not administered. A left supraclavicular lymph node recurrence was detected on CT 15 months after surgery. Capecitabine and oxaliplatin(CAPOX)therapy was administered and the metastatic lesion shrank. Positron emission tomography(PET)-CT showed no lesions at other sites and left cervical lymph node dissection was performed 5 months after the recurrence. Postoperative adjuvant therapy with S-1 was administered for 6 months. However, 2 years and 10 months after the first recurrence, CT showed recurrence in the left supraclavicular lymph node. CAPOX therapy was resumed, but due to an allergic reaction to oxaliplatin, the patient was treated with capecitabine alone. The recurrent lesion was gradually increased in size, and FOLFIRI therapy was introduced. One year and 5 months after secondary recurrence, PET-CT showed that the second recurrent lesion had grown but was confined to the left supraclavicular lymph node, so radiation therapy(60 Gy)to the left neck was performed. The disease was stable for about 10 months and chemotherapy could be discontinued. The lesion increased in size thereafter, and the patient died 7 years after initial surgery.

[A Case of Granulocyte Colony-Stimulating Factor-Associated Aortitis during Neoadjuvant Chemotherapy for Esophageal Cancer].

A 71-year-old man with middle thoracic esophageal cancer was treated with neoadjuvant chemotherapy using docetaxel plus 5-FU plus cisplatin therapy and was also administered pegfilgrastim. Blood tests showed elevated white blood cell counts and C-reactive protein levels before the start of the third course. Contrast-enhanced computed tomography revealed wall thickening of the aortic arch. We diagnosed this as aortitis due to pegfilgrastim. Inflammation was improved with conservative treatment. We then performed video-assisted thoracoscopic esophagectomy. Drug-induced vasculitis should be included in the differential diagnosis of patients with elevated inflammation markers of unknown cause following the administration of granulocyte colony-stimulating factor preparations.

[Laparoscopic Abdominoperineal Resection for Anal Canal Cancer with Pagetoid Spread].

A woman in her 60s had been aware of perianal erosions for 1 month. Skin biopsy showed Paget's cells in the stratified squamous epithelium, and immunohistochemistry showed negative staining for CK7 and positive staining for CK20. Colonoscopy revealed well-differentiated adenocarcinoma in the anal canal. Computed tomography showed neither regional lymph node metastasis nor distant metastasis. Hence, she was diagnosed with anal canal carcinoma with pagetoid spread. We determined the extent of resection of the skin lesion preoperatively by mapping biopsy, and performed laparoscopic abdominoperineal resection. The pathological findings revealed adenocarcinoma(tub1, tub2), and the skin resection margin was negative. Immunohistochemistry for Paget's cells in the stratified squamous epithelium showed negative staining for GCDFP-15 and CK7, and positive staining for CK20. Twenty-four months after surgery, we detected right inguinal lymph node metastasis and performed right inguinal lymphadenectomy. As of 4 months after the lymphadenectomy, no local recurrence or distant metastasis has been detected during follow-up examinations.

Clinical Significance of Mesenteric Lymph Node Involvement in the Pattern of Liver Metastasis in Patients with Ovarian Cancer.

BACKGROUND: Mesenteric lymph node (MLN) involvement is often observed in ovarian cancer (OC) with rectosigmoid invasion. This study aimed to investigate the clinical significance of MLN involvement in the pattern of liver metastasis in patients with OC. METHODS: We included 85 stage II-IV OC patients who underwent primary or interval debulking surgery. Twenty-seven patients underwent rectosigmoid resection, whose status of MLN involvement was judged from hematoxylin and eosin (H&E) staining of resected specimens. The prognostic significance of clinicopathological characteristics, including MLN involvement, was evaluated using univariate and multivariate analyses. RESULTS: MLN involvement was detected in 14/85 patients with stage II-IV OC. Residual tumor status, cytology of ascites, and MLN involvement were independent prognostic factors for progression-free survival (PFS; p = 0.033, p = 0.014, and p = 0.008, respectively). When patients were classified into three groups (no MLN, one MLN, two or more MLNs), the number of MLNs involved corresponded to three distinct groups in PFS (p = 0.001). The 3-year cumulative incidence of liver metastasis of patients with MLN involvement was significantly higher than that of patients without MLN involvement (61.1% vs. 8.9%, p < 0.001). MLN involvement was significantly associated with liver metastasis of hematogenous origin (p < 0.001) compared with peritoneal disseminated origin. CONCLUSION: MLN involvement is an important prognostic factor in OC, predicting poor prognosis and liver metastasis of hematogenous origin.

[A Case of Surgical Resection of Anaplastic Carcinoma of the Pancreas(Pleomorphic Cell Type)with Poor Response to Neoadjuvant Chemotherapy].

A 62-year-old man was incidentally found to have a pancreatic tumor by CT. He was diagnosed with pancreatic cancer by EUS-FNAB. Gemcitabine(GEM)plus nab-paclitaxel(PTX)was started as neoadjuvant chemotherapy(NAC)for resectable pancreatic cancer. However, after the end of the second course, the tumor grew rapidly and invaded the stomach, so NAC was discontinued, and surgery was performed. The pathological diagnosis was anaplastic ductal carcinoma of the pleomorphic cell type, and the histological response was Grade 1a. Multiple liver metastases appeared during adjuvant chemotherapy with S-1, so GEM plus nab-PTX and modified FOLFIRINOX were administered, but the therapeutic response was poor, the patient died 9 months after surgery. Anaplastic carcinoma has a poor response to chemotherapy and may be included with cancers showing treatment resistance to NAC, as seen in our case. It is necessary to pay attention to anaplastic carcinoma during the course of NAC for pancreatic cancer.

[Laparoscopic Abdominoperineal Resection after Preoperative Chemoradiotherapy for Adenocarcinoma Associated with Anal Fistula].

A 72-year-old man had a chief complaint of anal pain and difficulty in defecation. He was diagnosed with adenocarcinoma by biopsy from a tumor of the anal canal. A computed tomography scan revealed neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa anal canal cancer. Preoperative capecitabine- based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. Digital rectal examination and imaging evaluation 8 weeks after preoperative CRT revealed that the tumor had shrunk. Fifteen weeks after preoperative CRT, laparoscopic abdominoperineal resection was performed. The pathological findings showed mucinous adenocarcinoma associated with anal fistula. At present, 12 months after the operation, no local recurrence and distant metastasis has been detected under follow-up evaluations.

Verification of the Japanese staging system for rectal cancer, focusing on differences with the TNM classification.

PURPOSE: The 9th Japanese Classification of Colorectal Cancer (9th JSCCR) has two main differences from the TNM classification (8th AJCC): first, main or lateral lymph node metastasis is classified as jN3; second, tumor nodules (ND) are treated as lymph node metastasis. In this study, we verified the 9th JSCCR for rectal cancer, focusing on the differences with the 8th AJCC. METHODS: This retrospective analysis involved 212 patients with stage I-III rectal cancer. ND was evaluated using whole-mount sections. We evaluated the relapse-free survival of each staging system, and compared the prognostic significance of the different staging systems using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: Main or lateral lymph node metastasis was detected in nine of 212 (4%) patients. ND was detected in 79 of 212 (37%) patients. The best risk stratification power was observed in the 9th JSCCR (AIC, 759; c-index, 0.708) compared with the 7th JSCCR (AIC, 771; c-index, 0.681), 8th JSCCR (AIC, 768; c-index, 0.696), and the 8th AJCC (AIC, 766; c-index, 0.691). CONCLUSIONS: The 9th JSCCR, which includes the concepts of jN3 and ND, is useful for the risk stratification of rectal cancer, and the contributes to precise decision-making for follow-up management and adjuvant therapy.

The clinical significance of distal spread differs according to the primary tumor location in rectal cancer.

PURPOSE: Treatment strategies of rectal cancer differ between tumors located above (RS/Ra) and below (Rb) the peritoneal reflection. Based on the extent of distal spread (DS), the Japanese Society for Cancer of Colon and Rectum proposed an optimal distal margin in RS/Ra and Rb tumors. In this study, we investigated the clinical significance of DS between RS/Ra and Rb tumors. METHODS: We analyzed 287 stage I-III rectal cancer patients who underwent curative intent resection without preoperative therapy. DS and other pathological factors were evaluated using whole-mount sections. To investigate the clinical significance of DS in RS/Ra and Rb tumors, clinicopathological variables, including DS, were analyzed for the survival outcome according to the tumor group. RESULTS: DS was detected in 20 out of 185 (11%) patients with RS/Ra tumors and 8 out of 102 (8%) patients with Rb tumors. DS was not significantly associated with the overall survival (OS) or relapse-free survival (RFS) in RS/Ra tumors, but was an independent prognostic factor for the OS and RFS in Rb tumors (P = 0.002 and 0.007, respectively). CONCLUSIONS: The clinical significance of DS differs between RS/Ra and Rb tumors. DS is associated with a worse survival in Rb tumors, but not in RS/Ra tumors.

[A Case of a"Watch and Wait Therapy"Approach after Preoperative Chemoradiotherapy for Rectal Cancer Accompanied by Severe Emphysema].

A 72-year-old man was referred to our hospital for treatment for rectal cancer. Digital rectal examination and colonoscopy revealed a 4 cm tumor located at the anterior rectal wall 5 cm away from the anal verge, and pathological examination confirmed that the tumor was adenocarcinoma. A computed tomography scan detected neither regional lymph node metastasis nor distant metastasis. Hence, he was diagnosed with cT3N0M0, cStage Ⅱa rectal cancer. The preoperative general examination revealed bradyarrhythmia and severe emphysema, and he was considered to be high risk for general anesthesia. After placement of a pacemaker, preoperative capecitabine-based chemoradiotherapy(CRT)(50.4 Gy in 28 fractions of 1.8 Gy each)was implemented. The digital rectal examination and imaging evaluation 4 weeks after preoperative CRT revealed that the tumor disappeared, and pathological examination showed no malignant findings. Considering the risks of general anesthesia, the"watch and wait therapy"approach was adopted with sufficient informed consent. At present, 15 months after preoperative CRT, no evidence of regrowth or distant metastasis has been detected under rigorous follow- up evaluations.

[Long-Term Survival after Surgery with Postoperative Chemotherapy for Perihilar Cholangiocarcinoma with Residual Invasive Carcinoma at Ductal Resection Margins-A Case Report].

A 64-year-old man with liver dysfunction was given a diagnosis of perihilar cholangiocarcinoma(Bismuth type Ⅳ). The tumor was predominantly right-sided and invaded to the bifurcation of the right and left portal veins. After confirming sufficient liver functional reserve and future liver remnant, the patient underwent extended right hepatectomy, extrahepatic bile duct resection, and portal vein resection and reconstruction. Intraoperative examination of frozen sections revealed the presence of residual invasive carcinoma on both the hepatic and duodenal sides of the ductal resection margins. However, we did not perform pancreaticoduodenectomy or additional resection of the margin-positive proximal bile duct considering the curability and invasiveness of these procedures. He received postoperative chemotherapy with biweekly gemcitabine plus cisplatin for 1 year, followed by gemcitabine monotherapy for 1 year, and S-1 monotherapy has been performed since then. He remains alive and well with no evidence of disease 63 months after surgery.

[A Case of High-Frequency Microsatellite Instability in Colorectal Cancer with MSH2 Mutation Detected Using Gene Panel Testing with a Next-Generation Sequencer].

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.

SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer.

AIMS: SMAD4 acts as a tumour suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC) patients. Although next-generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC. METHODS AND RESULTS: We retrospectively investigated 201 patients with stage I-IV CRC, by using a 415-gene panel. To analyse the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive-front pathological markers: tumour budding, poorly differentiated cluster, and Crohn-like lymphoid reaction. Fifty-six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive-front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn-like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I-III disease, SMAD4 alteration was significantly associated with poor prognosis for relapse-free and overall survival (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival. CONCLUSION: SMAD4 alteration is associated with invasive-front pathological markers and poor prognosis in stage I-III CRC patients.