CDX2 Is a Prognostic Biomarker for Unresectable Metastatic Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) with reduced expression of the homeobox transcription factor CDX2, a master gene essential for the development and maintenance of the intestinal tract, is known as a poor prognosis subtype of CRC. The recurrence rate is high in patients with CDX2low CRC. However, the prognostic significance of CDX2 in advanced CRC is unclear. This study aimed to elucidate the prognostic significance of CDX2 in unresectable metastatic CRC (mCRC). PATIENTS AND METHODS: Twenty-nine patients with unresectable mCRC who underwent primary site resection at the Kobe University Hospital during a 6-year period from January 2008 to January 2015 were included. The tissues from those patients were immunohistochemically stained with anti-CDX2 antibody (clone: CDX2-88). The patients were divided into CDX2high CRC group and CDX2low CRC group and their prognoses were analyzed. RESULTS: There were no clear differences in background between the two groups. A low CDX2 expression was associated with reduced overall survival (37.67 months vs. 25.32 months, p=0.03) and tended to associate with reduced progression-free survival (17.4 months vs. 12.9 months, p=0.37). Two patients received chemotherapy after resection of the primary lesion and obtained pathological complete response. CONCLUSION: CDX2 expression might be a possible prognostic biomarker for unresectable mCRC.

[Long-Term Survival with Distal Pancreatectomy and Postoperative Chemotherapy in a Patient of Pancreatic Invasive Ductal Adenocarcinoma of the Tail with Peritoneal Dissemination].

A 68-year-old man was referred to our hospital for detailed examination of the pancreatic tail tumor. The tumor was diagnosed as the pancreatic invasive ductal adenocarcinoma and the distal pancreatectomy was scheduled. During surgery, a 2 mm white nodule was observed on the posterior wall of the stomach. Intraoperative frozen section showed no obvious malignant findings, suggesting leiomyoma or gastrointestinal stromal tumor. Distal pancreatectomy with D2 lymphadenectomy was completed as planned. However, this nodule was later confirmed by permanent pathological specimen to be peritoneal dissemination of pancreatic cancer and final diagnosis was invasive ductal carcinoma of pancreatic tail, pT3, pN1a, M1 (PER), pStage Ⅳ. He received chemotherapy for 17 months. Although liver metastasis was appeared 26 months after surgery, the disease is still being controlled with chemotherapy at 33 months.

Reduced Number and Immune Dysfunction of CD4+ T Cells in Obesity Accelerate Colorectal Cancer Progression.

Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.

Simple Cancer Stem Cell Markers Predict Neoadjuvant Chemotherapy Resistance of Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute to resistance against neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC). We conducted a retrospective observational study for the relationship between the expression levels of CSC markers in biopsy specimens prior to 5-fluorouracil plus cisplatin (FP)-NAC and the pathological responses. PATIENTS AND METHODS: We included 171 patients with ESCC who underwent the FP-NAC followed by radical resection. Biopsy specimens prior to the FP-NAC were obtained and immunochemically stained for CD44, CD133, and CD24. RESULTS: The biopsy specimens of the non-responders had the CD44high/CD24low expression at high levels, which was found as an independent predictor of not only FP-NAC resistance but also poor overall survival by multivariate analyses. CONCLUSION: CD44high/CD24low expression in the biopsy specimens prior to FP-NAC may be a predictor of FP-NAC resistance and poor prognosis of ESCC patients.

Short-term and long-term outcomes after laparoscopic surgery for elderly patients with colorectal cancer aged over 80 years: a propensity score matching analysis.

PURPOSE: There has been an increase in the percentage of elderly patients with colorectal cancer (CRC). However, few studies have reported the short- and long-term outcomes of laparoscopic surgery for elderly patients with CRC aged over 80 years. METHODS: This study included 529 patients who underwent laparoscopic resection for clinical stage 0-III CRC at Kobe University Hospital between January 2010 and December 2018. Propensity score matching (PSM) was used to create balanced cohorts of the elderly (aged ≥ 80, n = 113) and the non-elderly (aged < 80, n = 113). Their clinical outcomes were compared after PSM. RESULTS: After matching, carcinoembryonic antigen (CEA) level was higher in the non-elderly group, and adjuvant chemotherapy was less frequently employed in the elderly group. D3 dissection was performed more frequently and the number of the harvested lymph nodes tended to be larger in the non-elderly group. There was no significant difference in the rates of postoperative complications, reoperation within 30 days, and 30-day mortality between the groups. The 5-year relapse-free survival rate was not statistically different between the two groups (77.3% for the non-elderly vs. 62.7% for the elderly, p = 0.13). The multivariate analyses for the whole cohort showed that the factors of sex, tumor location, operation time, and conversion to open surgery, but not the age, were significant predictors of postoperative complications. CONCLUSION: Laparoscopic surgery for colorectal cancer patients aged over 80 years is technically and oncologically safe.

CD244+ polymorphonuclear myeloid­derived suppressor cells reflect the status of peritoneal dissemination in a colon cancer mouse model.

Despite the recent development of chemotherapeutic agents, the prognosis of colorectal cancer (CRC) patients with peritoneal dissemination (PD) remains poor. The tumor immune microenvironment (TIME) has drawn attention as a key contributing factor of tumor progression. Of TIME components, myeloid­derived suppressor cells (MDSCs) are considered to play a responsible role in the immunosuppressive characteristics of the TIME. MDSCs are classified into two major subsets: Monocytic MDSCs (M­MDSCs) and polymorphonuclear MDSCs (PMN­MDSCs). Therefore, we hypothesize that MDSCs would play important roles in the PD­relevant TIME and PD progression. To address this hypothesis, we established PD mouse models. As the PD nodules consisted scarcely of immune cells, we focused on the peritoneal cavity, but not PD nodule, to evaluate the PD­relevant TIME. As a result, intraperitoneal PMN­MDSCs were found to be substantially increased in association with PD progression. Based on these results, we phenotypically and functionally verified the usefulness of CD244 for identifying PMN­MDSCs. In addition, the concentrations of interleukin (IL)­6 and granulocyte­colony stimulating factor (G­CSF) were significantly increased in the peritoneal cavity, both of which were produced by the tumors and thought to contribute to the increases in the PMN­MDSCs. In vivo depletion of the PMN­MDSCs by anti­Ly6G monoclonal antibody (mAb) significantly inhibited the PD progression and reverted CD4+ and CD8+ T cells in the peritoneal cavity and the peripheral blood. Collectively, these results suggest that the targeted therapy for PMN­MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T­cell­based immunotherapy for CRC­derived PD.

Feasibility and Safety of Lateral Pelvic Lymph Node Dissection After Neoadjuvant Chemoradiotherapy for Elderly Patients With Locally Advanced Rectal Cancer.

BACKGROUND/AIM: The safety of neoadjuvant chemoradiotherapy (NACRT) combined with total mesorectal excision (TME) and selective lateral pelvic lymph node dissection (LLND) is unclear in elderly patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Forty-two patients with LARC underwent TME and selective LLND following NACRT at Kobe University Hospital. The clinical outcomes were retrospectively compared between the elderly (aged ≥70 years, n=13) and non-elderly patients (aged <70, n=29). RESULTS: Twelve of the thirteen elderly patients could complete NACRT. Although the overall rate of postoperative complications did not differ between the groups, abdominal wound infection and deep vein thrombosis developed more frequently in the elderly group. The length of the postoperative hospital stay was similar. Three-year overall survival and 3-year relapse-free survival rates were similar between the groups. CONCLUSION: Selective LLND after NACRT is safe for elderly patients with LARC.

Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity.

(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.