Metformin combined with local irradiation provokes abscopal effects in a murine rectal cancer model.

Although preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. LuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously (sc) in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumors were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flow cytometry and immunohistochemistry. Local RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases were unchanged in metformin or RT alone, but significantly reduced in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-γ production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.

Programmed cell death ligand 1 expression on monocytes is inversely correlated with tumour response to preoperative chemoradiotherapy for locally advanced rectal cancer.

AIM: The clinical efficacy of chemoradiotherapy (CRT) is largely dependent on host immune status. The aim of this study was to identify possible markers expressed on circulating mononuclear cells to predict tumour response in patients with locally advanced rectal cancer (LARC). METHODS: Peripheral blood samples were obtained from 47 patients diagnosed with LARC before and after CRT. The numbers of lymphocytes and monocyte subsets were analysed using flow cytometry. Based on clinical and pathological findings, patients were classified as high or low responders. RESULTS: Lymphocyte counts were markedly decreased after CRT. Total numbers of lymphocytes (p = 0.030) and CD4(+) T cells (p = 0.041) in post-CRT samples were significantly lower in low responders than in high responders. In contrast, monocyte counts were not reduced and the number of CD14dim (+) CD16(+) nonclassical (patrolling) monocytes were somewhat increased after CRT (p = 0.050). Moreover, the ratios of programmed cell death ligand 1 (PD-L1) (+) cells on patrolling monocytes before and after CRT were significantly higher in low responders than in high responders (p = 0.0046, p = 0.0006). The same trend was observed for classical and intermediate monocytes. The expression of PD-L1 on patrolling monocytes before CRT correlated inversely with the number of T cells and natural killer (NK) cells after CRT. PD-L1(+) ratio in patrolling monocytes was an independent predictor for response to CRT. CONCLUSION: Programmed cell death ligand 1 (PD-L1) expression on patrolling monocytes suppresses cell-mediated immunity in patients receiving CRT which could be related to tumour response, and may be a useful biomarker for decision-making in the management of patients with LARC.

CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model.

BACKGROUND: Anti-tumor effects of radiation therapy (RT) largely depend on host immune function. Adenosine with its strong immunosuppressive properties is an important immune checkpoint molecule. METHOD: We examined how intra-tumoral adenosine levels modify anti-tumor effects of RT in a murine model using an anti-CD73 antibody which blocks the rate-limiting enzyme to produce extracellular adenosine. We also evaluated CD73 expression in irradiated human rectal cancer tissue. RESULTS: LuM-1, a highly metastatic murine colon cancer, expresses CD73 with significantly enhanced expression after RT. Subcutaneous (sc) transfer of LuM-1 in Balb/c mice developed macroscopic sc tumors and microscopic pulmonary metastases within 2 weeks. Adenosine levels in the sc tumor were increased after RT. Selective RT (4Gyx3) suppressed the growth of the irradiated sc tumor, but did not affect the growth of lung metastases which were shielded from RT. Intraperitoneal administration of anti-CD73 antibody (200 µg × 6) alone did not produce antitumor effects. However, when combined with RT in the same protocol, anti-CD73 antibody further delayed the growth of sc tumors and suppressed the development of lung metastases presumably through abscopal effects. Splenocytes derived from RT+ CD73 antibody treated mice showed enhanced IFN-γ production and cytotoxicity against LuM-1 compared to controls. Immunohistochemical studies of irradiated human rectal cancer showed that high expression of CD73 in remnant tumor cells and/or stroma is significantly associated with worse outcome. CONCLUSION: These results suggest that adenosine plays an important role in the anti-tumor effects mediated by RT and that CD73/adenosine axis blockade may enhance the anti-tumor effect of RT, and improve the outcomes of patients with locally advanced rectal cancer.

Crohn's disease presenting as a ceco-urachal fistula.

We report the case of a patient with Crohn's disease who initially presented with a ceco-urachal fistula. The patient was a 31-year-old female who underwent an appendectomy 6 years before presenting to our institution. She had a one-year history of diarrhea, and had recently developed polyuria and a sensation of residual urine. She was admitted with fever and lower abdominal pain. Endoscopy and computed tomography revealed a ceco-urachal fistula, which was consistent with Crohn's disease. An urachal resection was performed, which included partial cystectomy and ileocecal resection. A ceco-urachal fistula is a rare initial symptom of Crohn's disease. During the surgical management of such cases, it is necessary to resect the urachus, the affected portion of the bladder, the fistula, and the affected part of the digestive tract in order to avoid recurrence.

Synchronous metastatic squamous cell carcinoma to the colon and cervical lymph nodes from a carcinoma of unknown primary site: A case report.

Metastatic squamous cell carcinoma (SCC) from an unknown primary site to the colon has not been reported previously. A 75-year-old woman presented with a mass in the left submandibular region. Biopsy revealed a Class V lesion, but the histologic type was undetermined. Surgical resection of the left submandibular gland with cervical lymph node dissection was performed. However, SCC was seen in the lymph nodes only, with no tumor in the submandibular gland. Three months after surgery, computed tomography revealed that the preoperatively diagnosed lesion in the transverse colon had grown considerably. A laparoscopic right hemicolectomy was performed. Histological examination showed features of SCC, similar to the findings in the cervical lymph nodes. We report a rare case of synchronous metastatic SCC to the colon and cervical lymph nodes from a carcinoma of unknown primary site.

Pretreatment of gastric outlet obstruction with pancrelipase: Report of a case.

INTRODUCTION: Gastric outlet obstruction is characterized by the retention of gastric contents. Removal of gastric contents is an important part of the treatment strategy. The use of a nasogastric tube alone can result in inadequate removal of gastric contents. We treated a patient with advanced gastric cancer and gastric outlet obstruction with pancrelipase to aid in the removal of gastric contents. PRESENTATION OF CASE: The patient is an 81-year-old man with a Type 3 gastric cancer nearly circumferentially involving the antrum, resulting in gastric outlet obstruction. A nasogastric tube was placed for four days, but drainage of gastric contents was inadequate. Pancrelipase was then given orally for four days, and gastric contents were evacuated. The patient underwent distal gastrectomy with Roux-en-Y reconstruction and was discharged from the hospital on postoperative day 14. DISCUSSION: This report suggests that pancrelipase may be beneficial in the treatment of patients with gastric outlet obstruction. CONCLUSION: Pancrelipase allowed gastric contents to be evacuated in a short period of time in a patient with gastric outlet obstruction.

[Y-graft replacement with left renal artery reconstruction for acute aortic dissection type B].

A 56-year-old male was admitted to our hospital for acute type B aortic dissection. He received conservative therapy but follow-up computed tomography (CT) revealed a low-enhanced left kidney and severe stenosis of the left common iliac artery due to the expansion of the false lumen. Serum blood urea nitrogen (BUN) and creatinine increased and renovascular hypertension worsened with severe intermittent claudication of the left leg. We performed Y-graft replacement with reconstruction of the left renal artery. Postoperative CT showed a well-enhanced left kidney and no stenosis of the left common iliac artery. Intermittent claudication and renal dysfunction improved and his hypertension became controllable. He was discharged on the 17th postoperative day.