A Mature Tertiary Lymphoid Structure with a Ki-67-Positive Proliferating Germinal Center Is Associated with a Good Prognosis and High Intratumoral Immune Cell Infiltration in Advanced Colorectal Cancer.

Tertiary lymphoid structures (TLSs) are complex lymphocyte clusters that arise in non-lymphoid tissues due to inflammation or cancer. A mature TLS with proliferating germinal centers is associated with a favorable prognosis in various cancers. However, the effect of TLS maturity on advanced colorectal cancer (CRC) remains unexplored. We analyzed the significance of TLS maturity and tumor Ki-67 expression in surgically resected tumors from 78 patients with pathological T4 CRC. Mature TLS was defined as the organized infiltration of T and B cells with Ki-67-positive proliferating germinal centers. We analyzed the relationship between TLS maturity and intratumoral immune cell infiltration. Mature TLS with germinal center Ki-67 expression was associated with microsatellite instability and improved survival; however, high tumor Ki-67 expression was associated with poor survival in the same cohort. Multivariate analysis identified the absence of mature TLS as an independent predictor of poor post-recurrence overall survival. Intratumoral infiltration of T lymphocytes and macrophages was significantly elevated in tumors with mature TLS compared to those lacking it. High Ki-67 levels and absent mature TLS were identified as poor prognostic factors in advanced CRC. Mature TLS could serve as a promising marker for patients at high-risk of CRC.

Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.

Risks and Outcomes of Early Dose Reduction in Adjuvant CAPOX Therapy for Colorectal Cancer.

BACKGROUND/AIM: Adjuvant capecitabine and oxaliplatin (CAPOX) therapy is standard strategy for colorectal cancer with risk of recurrence. Early dose reduction (EDR) of CAPOX therapy is commonly used in real-world practice. However, there is limited evidence regarding the effectiveness of CAPOX for patients who had EDR. Therefore, this study aimed to clarify the risks of EDR and its effect on long-term outcomes and body composition factors. PATIENTS AND METHODS: Patients who received CAPOX therapy after radical surgery for colorectal cancer between June 2013 and December 2021 were included. EDR was defined as dose reduction within four courses of CAPOX therapy. Body composition factors were measured for 1 year following surgery to determine the EDR effects. RESULTS: Eighty-four patients were included; 35 (42%) of them had EDR. The multivariate analysis revealed that underweight [odds ratio (OR)=4.95, 95% confidence interval (CI)=1.13-21.7, p=0.03] was a risk factor for EDR. Relapse-free survival (RFS) was significantly better in the non-EDR group (p=0.01). The 5-year RFS rates for the non-EDR and EDR groups were 88.7% and 65.4%, respectively. The multivariate analysis revealed that age >65 years [hazard ratio (HR)=3.97; 95% CI=1.16-13.62, p=0.03] and EDR (HR=7.62; 95% CI=1.71-33.91, p=0.005) were associated with poorer RFS. The 1-year body composition analysis revealed decreases in all factors in the EDR group. CONCLUSION: Preoperative underweight status was associated with EDR, which resulted in decreased RFS and body composition factors when compared with the non-EDR group. Therefore, avoiding EDR and early nutritional intervention after EDR may improve outcomes.

Preoperative factors associated with lateral lymph node metastasis in lower rectal cancer and the evaluation of the middle rectal artery.

PURPOSE: This study aimed to identify cases in which lateral lymph node (LLN) dissection (LLND) can be excluded by clarifying preoperative factors, including an evaluation of the middle rectal artery (MRA), associated with LLN metastasis. METHODS: Fifty-five consecutive patients who underwent preoperative positron emission tomography-computed tomography (PET/CT) and total mesorectal excision with LLND for rectal cancer were included. We retrospectively investigated the preoperative clinical factors associated with pathological LLN (pLLN) metastasis. We analyzed the regions of pLLN metastasis using MRA. RESULTS: pLLN metastasis occurred in 13 (23.6%) patients. According to a multivariate analysis, clinical LLN (cLLN) metastasis based on short-axis size and LLN status based on PET/CT were independent preoperative factors of pLLN metastasis. The negative predictive value (NPV) was high (97.1%) in patients evaluated as negative based on PET/CT and cLLN short-axis size. MRA was detected in 24 patients (43.6%) using contrast-enhanced CT, and there was a significant relationship between pLLN metastasis and the presence of MRA. pLLN metastasis in the internal iliac region but not in the obturator region was significantly correlated with the presence of MRA. CONCLUSION: Combined cLLN metastasis based on short-axis size and PET/CT showed a higher NPV, suggesting this to be a useful method for identifying cases in which LLND can be excluded.

Damage to the Descending Colon after Endoscopic Balloon Dilatation following a Minor Traffic Accident in a Patient with Crohn's Disease: A Case Report.

Introduction: Crohn's disease (CD) is complicated by intestinal strictures and fistula formation; however, intestinal perforation is relatively rare. Case Presentation: Following a traffic accident in the evening, a 39-year-old woman experienced abdominal pain that worsened the following morning and was taken to the emergency department. She had a 17-year history of CD and eight endoscopic balloon dilations for descending colonic strictures. She presented with a high fever of 40.0°C, along with tenderness and rebound pain throughout her abdomen, with the most substantial point being in the lower left abdomen. Computed tomography showed thickening of the descending colon wall, increased fat concentration around the wall, and a slight presence of air in the mesentery near the intestinal wall. We diagnosed the patient with generalized peritonitis due to traumatic penetration of the mesentery of the descending colon and performed emergency surgery. Intraoperative observation of the abdominal cavity with a laparoscope revealed purulent ascites but no apparent perforation or edematous mesentery, with white moss and redness in the descending colon. This prompted the decision to perform peritoneal lavage drainage and a transverse colonic double colostomy. The postoperative course was favorable, and the patient was discharged from the hospital on the postoperative day 14. Four months after discharge, colostomy closure was performed. Conclusion: Relatively minor trauma in patients with CD can result in colon injury. An injured bowel is usually accompanied by active lesions due to CD; however, caution is required, as endoscopic balloon dilatation without accompaniment may be a background factor.

Squamous cell carcinoma of the anus successfully treated with multidisciplinary therapy for metachronous metastatic and local recurrences after DCF chemotherapy: a case report.

BACKGROUND: Docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy is reportedly an effective treatment strategy for squamous cell carcinoma of the anus (SCCA). However, studies regarding its use in Japanese patients remain scarce. CASE PRESENTATION: Here, we present the case of an 82-year-old woman with SCCA, cStage IIIB. Chemoradiotherapy was initiated after colostomy of the anorectal mass; however, para-aortic lymph node recurrence was observed 3 months after treatment completion. Five courses of DCF chemotherapy were subsequently administered, resulting in a complete response (CR). Two years and 1 month later, the aortic lymph node was enlarged again, and the patient achieved CR again after radiotherapy. Nine months later, local recurrence was detected in the anal canal, and laparoscopic perineal rectal amputation was performed. The patient remains progression-free 5 years and 10 months after the initial treatment and 1 year and 7 months after the final treatment. CONCLUSIONS: Our findings suggest that complementary treatment after DCF chemotherapy may be efficacious in Japanese patients with SCCA and help achieve CR. Despite occasional local recurrences, this approach may help achieve long-term progression-free survival.

Two-Team Transanal Total Mesorectal Excision and En Bloc Resection of the Lateral Pelvic Lymph Nodes, Main Iliac Vessels, and Pelvic Plexus for Locally Advanced Rectal Cancer With Lateral Lymph Node Metastasis.

BACKGROUND: Here, we describe the precise surgical technique for a novel procedure involving 2-team transanal total mesorectal excision with en bloc lateral pelvic lymph node (LPLN) dissection combined with resection of the involved main internal iliac vessels and pelvic plexus. METHODS: From September 2020 to May 2023, 4 patients underwent the procedure at our hospital. RESULTS: The operation time and blood loss were 272 to 412 minutes and 10 to 124 mL, respectively. No patients required conversion to open surgery or exhibited Clavien-Dindo grade III or worse postoperative complications, although 2 developed grade II urinary dysfunction. All surgical margins were negative. CONCLUSIONS: Our novel 2-team method can facilitate safe and satisfactory surgery, even for highly advanced rectal cancer. The transanal approach offers excellent visibility and operability, even during LPLN and adjacent structure dissection. Furthermore, initial dissection of the distal branches of the iliac vessels prevents excessive lymphatic tissue congestion, facilitating easier, and clearer dissection.

Adjuvant Chemotherapy With UFT/LV Versus UFT/LV Plus PSK in Stage II/III Colorectal Cancer.

BACKGROUND/AIM: Uracil-tegafur+leucovorin (UFT/LV), an oral adjuvant therapy for stage II/III colorectal cancer, is non-inferior to standard weekly fluorouracil and folinate. Although polysaccharide K (PSK) has been evaluated as a postoperative adjuvant colorectal cancer drug, its efficacy remains unclear. This randomized phase II trial compared UFT/LV+PSK with UFT/LV as adjuvant chemotherapy. PATIENTS AND METHODS: Between April 2011 and August 2016, 186 patients who underwent radical resection randomly received 6 months of UFT/LV (Group A: 300 mg/m2/day UFT and 75 mg/day LV, every 35 days for five cycles), 6 months of UFT/LV+PSK (Group B: standard UFT/LV regimen and daily administration of 3 g/day of PSK), or 12 months of UFT/LV+PSK (Group C). The primary endpoint was the 3-year disease-free survival. RESULTS: Groups A, B, and C consisted of 37, 75, and 74 patients, of which treatment was completed by 33 (89.2%), 63 (84.9%), and 53 (70.4%) patients, respectively (p=0.0279). Adverse event incidence for all grades were 59.5%, 52.1%, and 59.2%, and for grade ≥3 were 13.5%, 9.6%, and 9.9%, respectively. The 3-year disease-free survival rates were 72.5%, 82.2%, and 74.2%, respectively, with no significant differences. The preoperative lymphocyte ratio did not significantly differ between groups. CONCLUSION: UFT/LV+PSK is comparable to UFT/LV therapy in terms of prognostic efficacy and reduced adverse effects. Thus, UFT/LV+PSK is a useful adjuvant chemotherapy option for patients with high-risk stage II/III colorectal cancer.

Retrograde drainage for duodenal stump leakage using ileal decompression tube guided by double-balloon endoscopy: a novel case report.

BACKGROUND: Duodenal stump leakage is a serious post-gastrectomy complication, and there have been no reports on endoscopic drainage. CASE PRESENTATION: We report a case of duodenal stump leakage after laparoscopic gastrectomy with Roux-en-Y reconstruction in a 68-year-old man. First-line conservative management was ineffective. Reoperation was performed because of severe abdominal pain and increased ascites. After reoperation, duodenal stump leakage recurred with bleeding from the anterior superior pancreaticoduodenal artery. Coil embolization and pigtail catheter insertion were performed. Furthermore, we retrogradely inserted an ileal tube for tube decompression near the duodenal stump using double-balloon endoscopy for effective drainage. After tube insertion, duodenal stump leakage decreased; on the 47th primary postoperative day, the patient was discharged. The primary postoperative course was uneventful after 1 year and 9 months of follow-up. CONCLUSIONS: This is the first successful case of duodenal stump leakage treated with retrograde decompression tube insertion near the duodenal stump using double-balloon endoscopy.

Prognostic value of a modified­immune scoring system in patients with pathological T4 colorectal cancer.

Tumor-infiltrating immune cells, such as lymphocytes and macrophages, have been associated with tumor aggressiveness, prognosis and treatment response in colorectal cancer (CRC). An immune scoring system, Immunoscore (IS), based on tumor-infiltrating T cells in stage I-III CRC, was used to predict prognosis. An alternative immune scoring signature of immune activation (SIA) reflects the balance between anti- and pro-tumoral immune components. The present study aimed to evaluate the prognostic value of modified IS (mIS) and modified SIA (mSIA) in locally advanced pathological T4 (pT4) CRC, including stage IV CRC. Immunohistochemical staining for immune cell markers, such as CD3 (pan-T cell marker), CD8 (anti-tumoral cytotoxic T cell marker) and CD163 (tumor-supportive macrophage marker), in specimens from patients with radically resected pT4 CRC at stages II-IV was performed. mIS levels in the T4 CRC cohort were not associated with prognosis. However, low mSIA levels were associated with low survival. Furthermore, low mSIA was an independent predictor of recurrence in patients with radically resected pT4 CRC. In patients with CRC who did not receive postoperative adjuvant chemotherapy, low mSIA was a major poor prognostic factor; however, this was not observed in patients receiving adjuvant chemotherapy. Evaluation of the tumor-infiltrating immune cell population could serve as a valuable marker of recurrence and poor prognosis in patients with locally advanced CRC. mSIA assessment after radical CRC resection may be promising for identifying high-risk patients with pT4 CRC who require aggressive adjuvant chemotherapy.