Salvage surgery for pouch-related complication after ileal pouch-anal anastomosis: a report of two cases.

BACKGROUND: Pouch-related complications (PRCs), such as pelvic abscesses and perianal complex fistulas, can occur after ileal pouch-anal anastomosis (IPAA) in ulcerative colitis (UC). They are often difficult to treat and require salvage surgery. We report two cases of PRC associated with fistulas. CASE PRESENTATION: First case: A 38-year-old man was diagnosed with UC at age 26 years. Four months after the diagnosis of UC, the patient underwent hand-assisted laparoscopic restorative proctocolectomy, IPAA, and ileostomy for acute fulminant UC. Two years after the closure of the ileostomy, the patient developed a perianal abscess and underwent ileostomy reconstruction. He was referred to our department at 35 years of age, because his symptoms did not improve despite repeated seton drainage of a complicated perineal fistula. We diagnosed PRC with a pelvic abscess and complicated pouch fistula and performed salvage surgery. This diagnosis was revised to Crohn's disease. SECOND CASE: A 50-year-old man was diagnosed with UC at age 18 years and was administered high doses of steroids; however, his symptoms did not improve. He underwent restorative proctocolectomy, IPAA, and ileostomy at another hospital. The ileostomy was closed, and his condition stabilized thereafter. At 35 years of age, perianal pain developed, and he was diagnosed with a complicated pouch-perineal fistula. A fistula was observed near the staple line of the ileal end closure on the head side of the pouch. Reconstruction of the ileostomy and seton drainage were performed; however, his symptoms did not improve, and he was referred to our hospital. We diagnosed PRC with a pelvic abscess and a complicated pouch fistula and performed salvage surgery. The resected specimen showed strictures in two locations: at the oral site of the afferent limb (at the pouch) and at the IPAA. Both patients returned to society and are currently outpatients. CONCLUSIONS: We encountered two cases of PRC after IPAA that did not improve with seton drainage or ileostomy. Pouch resection was performed after considering the patient's quality of life and reintegration into society.

Investigation of Expanded Human Adipose-derived Stem Cell Dosage and Timing for Improved Defecation Function.

BACKGROUND/AIM: Although certain treatment options exist for intestinal incontinence, none are curative. Adipose-derived stem cells (ADSCs) have emerged as promising therapeutic agents, but most preclinical studies of their effectiveness for anal function have used autologous or allogeneic ADSCs. In this study, the effectiveness, timing of administration, and required dosage of human ADSCs were investigated for clinical application. MATERIALS AND METHODS: A 10-mm balloon catheter was used to induce anal sphincter injury in immunodeficient mice in the following experimental groups (n=4 per group): ADSC (injected ADSCs after injury), PBS (injected phosphate-buffered saline after injury), and control (uninjured). The effects of different timing (immediately after injection and 30 days following injury) and number of human ADSCs administered was compared among groups based on defecation status and pathological evaluation. RESULTS: In terms of defecation status, groups receiving ≥1×104 human ADSCs after injection showed improvement. Pathological images showed that compared to the PBS group, the thinnest part of the sphincter was thicker for animals that received ≥1×104 human ADSCs, and fibrosis of the sphincter was notable in those treated with 1×103 human ADSCs or PBS. Furthermore, defecation status was improved by administration of human ADSCs, not only immediately after injury, but also at 30 days following injury. CONCLUSION: Human ADSC administration in a mouse model of anal sphincter injury was effective. Injection of ≥1×104 human ADSCs was the amount necessary to improve defecation status, an effect detected in both the acute and chronic phases.

Portal vein wedge resection and patch venoplasty with autologous vein grafts for hepatobiliary-pancreatic cancer.

BACKGROUND: Advanced hepatobiliary-pancreatic cancer often invades critical blood vessels, including the portal vein (PV) and hepatic artery. Resection with tumor-free resection margins is crucial to achieving a favorable prognosis in these patients. Herein, we present our cases and surgical techniques for PV wedge resection with patch venoplasty using autologous vein grafts during surgery for pancreatic ductal adenocarcinoma (PDAC) and perihilar cholangiocarcinoma (PhCC). CASE PRESENTATION: Case 1: 73-year-old female patient with PDAC; underwent subtotal stomach-preserving pancreatoduodenectomy, with superior mesenteric vein wedge resection and venoplasty with the right gonadal vein. Case 2: 67-year-old male patient with PDAC; underwent distal pancreatectomy and celiac axis resection, with PV wedge resection and venoplasty with the middle colic vein. Case 3: 51-year-old female patient with type IV PhCC; underwent left hepatectomy with caudate lobectomy and bile duct resection, with hilar PV wedge resection and venoplasty with the inferior mesenteric vein (IMV). Case 4: 69-year-old male patient with type IIIA PhCC; underwent right hepatopancreatoduodenectomy, with hilar PV resection and patch venoplasty with the IMV. All patients survived for over 12 months after the surgery, without local recurrence. CONCLUSIONS: PV wedge resection and patch venoplasty is a useful technique for obtaining tumor-free margins in surgeries for hepatobiliary-pancreatic cancer.

Histological differentiation between sporadic and colitis-associated intestinal cancer in a nationwide study: A propensity-score-matched analysis.

BACKGROUND AND AIM: Colitis-associated intestinal cancer (CAC) can develop in patients with inflammatory bowel disease; however, the malignant grade of CAC may differ from that of sporadic colorectal cancer (CRC). Therefore, we compared histological findings distinct from cancer stage between CAC and sporadic CRC to evaluate the features of CAC. METHODS: We reviewed the clinical and histological data collected from a nationwide database in Japan between 1983 and 2020. Patient characteristics were compared to distinguish ulcerative colitis (UC), Crohn's disease (CD), and sporadic CRC. Comparisons were performed by using all collected data and propensity score-matched data. RESULTS: A total of 1077 patients with UC-CAC, 297 with CD-CAC, and 136 927 with sporadic CRC were included. Although the prevalence of well or moderately differentiated adenocarcinoma (Tub1 and Tub2) decreased according to tumor progression for all diseases (P < 0.01), the prevalence of other histological findings, including signet ring cell carcinoma, mucinous carcinoma, poorly differentiated adenocarcinoma, or squamous cell carcinoma, was significantly higher in CAC than in sporadic CRC. Based on propensity score-matched data for 982 patients with UC and 268 with CD, the prevalence of histological findings other than Tub1 and Tub2 was also significantly higher in those with CAC. At pT4, mucinous carcinoma occurred at a significantly higher rate in patients with CD (45/86 [52.3%]) than in those with sporadic CRC (13/88 [14.8%]) (P < 0.01). CONCLUSION: CAC, including early-stage CAC, has a higher malignant grade than sporadic CRC, and this difference increases in significance with tumor progression.

Resection of anorectal fistula cancer associated with Crohn's disease after preoperative chemoradiotherapy: a case report.

BACKGROUND: Anorectal fistula cancer is often diagnosed in an advanced state, and radical resection is difficult when invasion of the pelvic wall is observed. In addition, there is currently no clear evidence for perioperative treatment of locally advanced cases. We report a case of anorectal fistula cancer with widespread infiltration diagnosed during the course of Crohn's disease, which was curatively resected after preoperative chemoradiotherapy. CASE PRESENTATION: A 49-year-old man who had been diagnosed with Crohn's disease (ileocolonic type) at the age of 25 and was found to have an anorectal fistula and perianal abscess at the age of 44 was referred to our department with complaints of abdominal pain and diarrhea. Computed tomography (CT) showed anal stenosis due to a pelvic mass. Pathological analysis of a biopsy taken under general anesthesia indicated mucinous carcinoma. Magnetic resonance imaging (MRI) revealed infiltration into the prostate, seminal vesicles, levator ani muscle, and left internal obturator muscle, and the patient was diagnosed with cT4N0M0 cStage IIIB anorectal fistula cancer (UICC TNM classification 8th edition). After performing a laparoscopic sigmoid colostomy, chemoradiation therapy (capecitabine + oxaliplatin, 50.4 Gy/28fr) was initiated. The patient then underwent laparoscopic total pelvic exenteration, colonic conduit diversion, extensive perineal resection, and reconstruction using bilateral gluteus maximus flaps and a right rectus abdominis musculocutaneous flap. The pathological diagnosis was mucinous adenocarcinoma, pT4, and all margins were negative. No recurrence was evident 6 months after the operation without adjuvant chemotherapy. CONCLUSION: We described a case of curative resection after preoperative chemoradiotherapy for anorectal fistula cancer with extensive invasion that was diagnosed during the course of Crohn's disease.An accumulation of cases is needed to determine the usefulness of preoperative chemoradiation therapy for local control of anorectal fistula cancer associated with Crohn's disease.

Metastases and treatment-resistant lineages in patient-derived cancer cells of colorectal cancer.

Circulating tumor cells (CTCs) play an important role in metastasis and recurrence. However, which cells comprise the complex tumor lineages in recurrence and are key in metastasis are unknown in colorectal cancer (CRC). CRC with high expression of POU5F1 has a poor prognosis with a high incidence of liver metastatic recurrence. We aim to reveal the key cells promoting metastasis and identify treatment-resistant lineages with established EGFP-expressing organoids in two-dimensional culture (2DOs) under the POU5F1 promotor. POU5F1-expressing cells are highly present in relapsed clinical patients' blood as CTCs. Sorted POU5F1-expressing cells from 2DOs have cancer stem cell abilities and abundantly form liver metastases in vivo. Single-cell RNA sequencing of 2DOs identifies heterogeneous populations derived from POU5F1-expressing cells and the Wnt signaling pathway is enriched in POU5F1-expressing cells. Characteristic high expression of CTLA4 is observed in POU5F1-expressing cells and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Demethylation in some CpG islands at the transcriptional start sites of POU5F1 and CTLA4 is observed. The Wnt/ß-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.

Crohn's disease-related anal fistula cancer diagnosed by examination under anesthesia: a case report.

BACKGROUND: As the number of patients with inflammatory bowel disease (IBD) increases, the incidence of IBD-related colorectal cancer (CRC) is also on the rise. Crohn's disease (CD)-related CRC has been reported to have a poorer prognosis than sporadic CRC, and the early detection of CD-related CRC is difficult. Japanese patients with CD are reported to have a higher frequency of anorectal cancer than the Western population; however, methods for early diagnosis have not yet been established because of perianal pain during the examination. CASE PRESENTATION: We report a case of CD-related anal fistula cancer that was detected early by surveillance examination under anesthesia (EUA). The patient was a 37-year-old man, diagnosed with CD at the age of 15 years and started medical treatment. However, due to poor disease control, the intestinal tract remained highly inflamed and the patient continued to have over 10 bowel movements per day. He was referred to our hospital for surgical treatment after a colonoscopy (CS), which revealed multiple active ulcers and stenoses. Since three perianal seton drainage tubes had been placed around his anus since the age of 33 years, we decided to perform an EUA to rule out cancer coexistence in the anorectal region. After a random biopsy of the rectum by CS under general anesthesia, we resected and curetted multiple perianal fistulas as much as possible and reinserted the seton drainage tubes. Pathological examination of the fistula tract revealed adenocarcinoma in one tract, indicating the coexistence of anal fistula cancer. Based on the diagnosis of multiple intestinal stenoses and anal fistula cancer due to CD, we performed hand-assisted laparoscopic total colectomy, rectal amputation, extensive perineal resection, and reconstruction using a left rectus abdominis flap. CONCLUSION: In a long-term CD patient with anorectal lesions, we performed an EUA to diagnose the coexistence of anal fistula cancer at an early stage, and surgical resection was achieved. EUA is effective for the early detection and treatment of CD-related CRC and may contribute to an improved prognosis.

Endoscopic Lesions of Postoperative Anastomotic Area in Patients With Crohn's Disease in the Biologic Era: A Japanese Multi-Centre Nationwide Cohort Study.

BACKGROUND AND AIMS: Many patients have endoscopic evidence of recurrent Crohn's disease [CD] at 1 year after intestinal resection. These lesions predict future clinical recurrence. We endoscopically evaluated postoperative anastomotic lesions in CD patients from a large cohort of postoperative CD patients. METHODS: We retrospectively enrolled CD patients who underwent surgical resection between 2008 and 2013 at 19 inflammatory bowel disease [IBD]-specialist institutions. The initial analyses included patients who underwent ileocolonoscopy ~1 year after intestinal resection. Follow-up analyses assessed any changes in the endoscopic findings over time. We evaluated the postoperative endoscopic findings, which were classified into four categories [no lesion, mild, intermediate, severe] at the sites of the anastomotic line and peri-anastomosis. RESULTS: In total, 267 CD patients underwent postoperative ileocolonoscopy. Postoperative anastomotic lesions were widely detected in index ileocolonoscopy [61.0%] and were more frequently detected in follow-up ileocolonoscopy [74.9%]. Endoscopic severity also increased. Patients with intermediate or severe peri-anastomotic or anastomotic line lesions at the index ileocolonoscopy required significantly more interventions, including endoscopic dilatation or surgery, than patients with mild lesions or no lesions. CONCLUSIONS: Frequent anastomotic lesions were observed at the postoperative index ileocolonoscopy. These gradually increased for subsequent ileocolonoscopy, even in the biologic era. Regarding lesions on the anastomotic line, intermediate lesions on the anastomotic line [e.g. irregular or deep ulcers] might be considered recurrent disease, and mild lesions [e.g. linear superficial ulcers] might be considered non-recurrent disease. Prospective studies are needed to resolve this issue, including treatment enhancement.

Clinical outcomes of neoadjuvant chemotherapy for resectable colorectal liver metastasis with intermediate risk of postoperative recurrence: A multi-institutional retrospective study.

Aims: Risk-scoring systems for colorectal liver metastasis (CRLM) after hepatectomy allow prognoses to be predicted preoperatively. We investigated the clinical outcomes of neoadjuvant chemotherapy for resectable CRLM according to patient risk status, aiming to determine the subgroup of patients who could benefit from neoadjuvant chemotherapy. Methods: In this multi-institutional retrospective analysis, the preoperative risk score was calculated from six previously reported factors: synchronous metastases, primary lymph node positivity, tumor number, largest tumor diameter, extrahepatic metastasis, and the preoperative carbohydrate antigen 19-9 level. Patients were divided into three groups according to their risk scores: low risk (score = 0), intermediate risk (score 1-10), and high risk (score ≥11). Overall and recurrence-free survival curves were calculated using the Kaplan-Meier method. After propensity-score matching in the intermediate-risk group, we compared clinicopathological features and outcomes. Results: There were 318 cases, from 20 institutions. The preoperative risk score could be calculated in 277 cases. There were 34, 192, and 51 patients in the low-, intermediate-, and high-risk groups, respectively. Intermediate-risk group patients who received neoadjuvant chemotherapy had significantly better recurrence-free survival than that of patients without neoadjuvant chemotherapy (P = .0453). After propensity-score matching in the intermediate-risk group, the recurrence-free survival rate was better in patients who received neoadjuvant chemotherapy (P = .0261). But the overall survival rate was not improved after the matching. Conclusion: Neoadjuvant chemotherapy for resectable CRLM might prolong the recurrence-free survival period for intermediate-risk patients with preoperative risk scores in the range of 1-10, but the overall survival was not improved by neoadjuvant chemotherapy.

Annual report on National Clinical Database 2020 for gastroenterological surgery in Japan.

Aim: The National Clinical Database (NCD) of Japan is a nationwide data entry system for surgery, and it marked its 10th anniversary in 2020. The aim was to present the 2020 annual report of gastroenterological surgery of the NCD. Methods: The data of the surgical procedures stipulated by the training curriculum for board-certified surgeons of the Japanese Society of Gastroenterological Surgery in the NCD from 2011 to 2020 were summarized. Results: In total, 5 622 845 cases, including 593 088 cases in 2020, were extracted from the NCD. The total number of gastroenterological surgeries increased gradually in these 10 years, except for the year 2020 due to the COVID-19 pandemic. The annual number of surgeries of each organ, except the pancreas and liver, decreased by 0.4%-13.1% in 2020 compared to 2019. The surgical patients were consistently aging, with more than 20% of all gastroenterological surgeries in 2020 involving patients aged 80 years or older. The participation of board-certified surgeons increased for each organ (75.9%-95.7% in 2020). The rates of endoscopic surgery also increased constantly. Although the incidences of postoperative complications of each organ increased by 0.7%-7.9% in these 10 years, postoperative mortality rates decreased by 0.2%-1.5%. Conclusions: We present here the short-term outcomes of each gastroenterological operative procedure in 2020. This review of the 10-years of NCD data of gastroenterological surgery revealed a consistent increase of the number of surgeries (except for in 2020), especially endoscopic procedures, and aging of the Japanese population. The good safety of Japanese gastroenterological surgeries was also indicated.

Identification of a novel type of focal adhesion remodelling via FAK/FRNK replacement, and its contribution to cancer progression.

Numerous studies have investigated the various cellular responses against genotoxic stress, including those mediated by focal adhesions. We here identified a novel type of focal adhesion remodelling that occurs under genotoxic stress conditions, which involves the replacement of active focal adhesion kinase (FAK) with FAK-related non-kinase (FRNK). FRNK stabilized focal adhesions, leading to strong cell-matrix adhesion, and FRNK-depleted cells were easily detached from extracellular matrix upon genotoxic stress. This remodelling occurred in a wide variety of cells. In vivo, the stomachs of Frnk-knockout mice were severely damaged by genotoxic stress, highlighting the protective role of FRNK against genotoxic stress. FRNK was also found to play a vital role in cancer progression, because FRNK depletion significantly inhibited cancer dissemination and progression in a mouse cancer model. Furthermore, in human cancers, FRNK was predominantly expressed in metastatic tissues and not in primary tissues. We hence conclude that this novel type of focal adhesion remodelling reinforces cell adhesion and acts against genotoxic stress, which results in the protection of normal tissues, but in turn facilitates cancer progression.

Tumor-suppressive role of the musculoaponeurotic fibrosarcoma gene in colorectal cancer.

Somatic cell reprogramming using the microRNAs miR-200c, miR-302s, and miR-369s leads to increased expression of cyclin-dependent kinase inhibitors in human colorectal cancer (CRC) cells and suppressed tumor growth. Here, we investigated whether these microRNAs inhibit colorectal tumorigenesis in CPC;Apc mice, which are prone to colon and rectal polyps. Repeated administration of microRNAs inhibited polyp formation. Microarray analysis indicated that c-MAF, which reportedly shows oncogene-like behavior in multiple myeloma and T cell lymphoma, decreased in tumor samples but increased in microRNA-treated normal mucosa. Immunohistochemistry identified downregulation of c-MAF as an early tumorigenesis event in CRC, with low c-MAF expression associated with poor prognosis. Of note, c-MAF expression and p53 protein levels were inversely correlated in CRC samples. c-MAF knockout led to enhanced tumor formation in azoxymethane/dextran sodium sulfate-treated mice, with activation of cancer-promoting genes. c-MAF may play a tumor-suppressive role in CRC development.

Super Carbonate Apatite-miR-497a-5p Complex Is a Promising Therapeutic Option against Inflammatory Bowel Disease.

The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-ß/Smad signal pathway is inactivated in patients with Crohn's disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify certain miRNAs that activate TGF-ß/Smad signal pathway and aimed to prove in vivo therapeutic efficacy in mouse model. Through Smad binding element (SBE) reporter assays, we focused on miR-497a-5p. This miRNA is common between mouse and human species and enhanced the activity of TGF-ß/Smad signal pathway, decreased Smad 7 and/or increased phosphorylated Smad 3 expression in non-tumor cell line HEK293, colorectal cancer cell line HCT116 and mouse macrophage J774a.1 cells. MiR-497a-5p also suppressed the production of inflammatory cytokines TNF-α, IL-12p40, a subunit of IL-23, and IL-6 when J774a.1 cells were stimulated by lipopolysaccharides (LPS). In a long-term therapeutic model for mouse dextran sodium sulfate (DSS)-induced colitis, systemic delivery of miR-497a-5p load on super carbonate apatite (sCA) nanoparticle as a vehicle restored epithelial structure of the colonic mucosa and suppressed bowel inflammation compared with negative control miRNA treatment. Our data suggest that sCA-miR-497a-5p may potentially have a therapeutic ability against IBD although further investigation is essential.

Cancer-specific tissue-resident memory T-cells express ZNF683 in colorectal cancer.

BACKGROUND: Tissue-resident memory T (Trm) cells are associated with cytotoxicity not only in viral infection and autoimmune disease pathologies but also in many cancers. Tumour-infiltrating CD103+ Trm cells predominantly comprise CD8 T cells that express cytotoxic activation and immune checkpoint molecules called exhausted markers. This study aimed to investigate the role of Trm in colorectal cancer (CRC) and characterise the cancer-specific Trm. METHODS: Immunochemical staining with anti-CD8 and anti-CD103 antibodies for resected CRC tissues was used to identify the tumour-infiltrating Trm cells. The Kaplan-Meier estimator was used to evaluate the prognostic significance. Cells immune to CRC were targeted for single-cell RNA-seq analysis to characterise cancer-specific Trm cells in CRC. RESULTS: The number of CD103+/CD8+ tumour-infiltrating lymphocytes (TILs) was a favourable prognostic and predictive factor of the overall survival and recurrence-free survival in patients with CRC. Single-cell RNA-seq analysis of 17,257 CRC-infiltrating immune cells revealed a more increased zinc finger protein 683 (ZNF683) expression in cancer Trm cells than in noncancer Trm cells and in high-infiltrating Trm cells than low-infiltrating Trm in cancer, with an upregulated T-cell receptor (TCR)- and interferon-γ (IFN-γ) signalling-related gene expression in ZNF683+ Trm cells. CONCLUSIONS: The number of CD103+/CD8+ TILs is a prognostic predictive factor in CRC. In addition, we identified the ZNF683 expression as one of the candidate markers of cancer-specific Trm cells. IFN-γ and TCR signalling and ZNF683 expression are involved in Trm cell activation in tumours and are promising targets for cancer immunity regulation.

Crohn's Disease-Associated Anorectal Cancer Has a Poor Prognosis With High Local Recurrence: A Subanalysis of the Nationwide Japanese Study.

INTRODUCTION: Colorectal cancer (CRC) is one of the major life-threatening complications in patients with Crohn's disease (CD). Previous studies of CD-associated CRC (CD-CRC) have involved only small numbers of patients, and no large series have been reported from Asia. The aim of this study was to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC. METHODS: A large nationwide database was used to identify patients with CD-CRC (n = 233) and sporadic CRC (n = 129,783) over a 40-year period, from 1980 to 2020. Five-year overall survival (OS), recurrence-free survival (RFS), and clinicopathological characteristics were investigated. The prognosis of CD-CRC was further evaluated in groups divided by colon cancer and anorectal cancer (RC). Multivariable Cox regression analysis was used to adjust for confounding by unbalanced covariables. RESULTS: Compared with sporadic cases, patients with CD-CRC were younger; more often had RC, multiple lesions, and mucinous adenocarcinoma; and had lower R0 resection rates. Five-year OS was worse for CD-CRC than for sporadic CRC (53.99% vs 71.17%, P < 0.001). Multivariable Cox regression analysis revealed that CD was associated with significantly poorer survival (hazard ratio 2.36, 95% confidence interval: 1.54-3.62, P < 0.0001). Evaluation by tumor location showed significantly worse 5-year OS and RFS of CD-RC compared with sporadic RC. Recurrence was identified in 39.57% of CD-RC cases and was mostly local. DISCUSSION: Poor prognosis of CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.

[A Case Report-A Successful Case of Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer with an Aberrant Right Hepatic Artery].

In cases of pancreatic cancer with anatomical variations of the hepatic artery, it is important to evaluate the hemodynamics of each case for surgical indication. We report the case of a 68-year-old man with locally advanced pancreatic cancer and an aberrant right hepatic artery who underwent distal pancreatectomy with celiac axis resection(DP-CAR). He was admitted to our institute due to abdominal discomfort. A CT scan showed pancreatic cancer invading the common hepatic artery. He underwent chemoradiotherapy with a diagnosis of locally advanced pancreatic cancer. After the tumor downstaging, we performed DP-CAR, which included a gastroduodenal artery and a proper hepatic artery resection. Even though delayed gastric emptying was observed after the operation, he was discharged on postoperative day 36.

Phase II dose titration study of regorafenib in progressive unresectable metastatic colorectal cancer.

Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9-3.7) and median overall survival of 10.0 months (95% CI 6.9-15.2). Common grade 3-4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015).

[FOLFIRI plus RAM Therapy in Later Line of Unresectable Colorectal Cancer].

FOLFIRI plus ramucirumab(RAM)therapy has been reported to be effective and safe in the RAISE trial as second-line treatment for unresectable colorectal cancer. It is hypothesized that RAM may be effective in patients with PD treated with FOLFIRI plus bevacizumab(Bev)due to different mechanism of action from that of Bev, which is also an angiogenesis inhibitor. From January 2017 to December 2021, we conducted a retrospective study of 6 patients who had PD with 5-FU, oxaliplatin, irinotecan, or Bev as first or second-line treatment at our institution and who received FOLFIRI plus RAM in later line treatment. The 6 cases consisted of 3 patients in the third-line treatment, 1 patient in the fourth-line treatment, and 2 patients in the sixth-line treatment. The anti-tumor effect was PD in all cases in the third-line and fourth-line treatment, but the 2 patients of sixth-line treatment were controlled diseases.

Tumor-infiltrating T cells as a risk factor for lymph node metastasis in patients with submucosal colorectal cancer.

Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8+ tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion. Using immunohistochemical staining, we identified CD8 + T cells in surgically resected specimens from 98 patients with SM-CRC. We showed that low CD8+ tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8+ tumor-infiltrating T cell and the number of CD103+ tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells.