鯉沼 広治

INTRODUCTION AND IMPORTANCE: Brain and thyroid metastasis from rectal cancer are uncommon, and the prognosis is poor. We report a patient with rectal cancer who developed metachronous lung, brain and thyroid metastases. Each metastatic lesion was curatively resected resulting in prolonged survival. CASE PRESENTATION: A 60-year-old male underwent rectal cancer resection, and the pathological diagnosis was tubular adenocarcinoma, pT2,pN1a,M0, pStageⅢa. Ten years after rectal resection, a solitary tumor in the left lung was detected. The tumor was resected thoracoscopically and the pathological diagnosis was metastatic tumor. Three years after the pulmonary resection, a solitary brain tumor was detected. The tumor was removed surgically, and the pathology was metastatic tumor. Two years after brain resection, a thyroid mass was detected. A partial thyroidectomy was performed and the pathology with immunohistochemical staining confirmed the thyroid lesion as a metastasis from the previous rectal cancer. Four years after thyroid resection (19 years after the initial rectal resection), he died from multiple lung and bone metastases. CLINICAL DISCUSSION: Colorectal metastases to the brain and thyroid gland are uncommon and are usually found with other distant metastases. Overall survival has been reported to be extremely poor. In this patient, lung, brain, and thyroid metastases were solitary and metachronous, and each lesion was curatively resected. Surgical treatment might contribute to prolonged survival. CONCLUSION: The treatment strategy of each patient should be individualized and depends on the timing of metastasis development. Selected patients with complete resection of metachronous metastases may have prolonged survival.

BACKGROUND: Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of colonic polyps, and extracolonic manifestations are likely to occur. Pancreatic tumors are rare extracolonic manifestations in patients with FAP, among which solid-pseudopapillary neoplasm (SPN) are extremely rare. We report here a patient with an SPN of the pancreas found during the follow-up of FAP. CASE PRESENTATION: A 20-year-old woman was diagnosed with FAP 3 years previously by colonoscopy which revealed less than 100 colonic polyps within the entire colon. She complained of left upper abdominal pain and a 10-cm solid and cystic pancreatic tumor was found by computed tomography scan. Solid and cystic components within the tumor were seen on abdominal magnetic resonance imaging. Simultaneous laparoscopic resection of the distal pancreas and subtotal colectomy was performed. Histopathological findings confirmed the pancreatic tumor as an SPN without malignancy. Abnormal staining of beta-catenin was observed by immunohistochemical study. Multiple polyps in the colorectum were not malignant. Molecular biological analysis from peripheral blood samples revealed a decrease in the copy number of the promoter 1A and 1B region of the APC gene, which resulted in decreased expression of the APC gene. CONCLUSIONS: A rare association of SPN with FAP is reported. The genetic background with relation to beta-catenin abnormalities is interesting to consider tumor development. So far, there are few reports of SPN in a patient with FAP. Both lesions were treated simultaneously by laparoscopic resection.

Fecalomas most commonly occur in constipated patients and are rarely reported after colectomy. A 55-year-old Japanese female presented with a fecaloma after colectomy, which was impacted at a functional end-to-end anastomosis (FEEA) site. Four and a half years ago, she underwent sigmoidectomy for colon cancer. A follow-up computed tomography (CT) scan revealed an 11 cm incidental fecaloma. The patient was advised to undergo surgery, but she desired nonoperative management because of minimal symptoms, and was referred to our institution. On the day of admission (day 1), mechanical fragmentation of the fecaloma was attempted during the first colonoscopy. Although a large block of stool was evacuated after a second colonoscopic fragmentation on day 8, the third colonoscopy on day 21 and CT scan on day 22 showed no significant change in the fecaloma. Frequent colonoscopic fragmentation was performed, with a fourth, fifth, and sixth colonoscopy on days 24, 29, and 31, respectively. After the size reduction was confirmed at the sixth colonoscopy, the patient was discharged home on day 34. The fecaloma completely resolved after the seventh colonoscopic fragmentation on day 44. Sixteen months after treatment, there is no evidence of recurrent fecaloma. According to the literature, risk factors for fecaloma after colectomy include female gender, left-side colonic anastomosis, and FEEA. FEEA might not be recommended for anastomoses in the left colon, particularly in female patients, to avoid this complication. Colonoscopic fragmentation is recommended for fecalomas at an anastomotic site after colectomy in patients without an absolute indication for surgery.

Aim: PD-1/PD-L1 blockade therapy is now widely used for the treatment of advanced malignancies. Although PD-L1 is known to be expressed by various host cells as well as tumor cells, the role of PD-L1 on non-malignant cells and its clinical significance is unknown. We evaluated cell type-specific expression of PD-L1 in colorectal cancer (CRC) specimens using multicolor flow cytometry. Methods: Single cell suspensions were made from 21 surgically resected CRC specimens, and immunostained with various mAbs conjugated with different fluorescent dyes. Tumor cells, stromal cells, and immune cells were identified as CD326(+), CD90(+) and CD45(+) phenotype, respectively. CD11b(+) myeloid cells, CD19(+) B cells and CD4(+) or CD8(+) T cells were also stained in different samples, and their frequencies in the total cell population and the ratio of PD-L1(+) cells to each phenotype were determined. Results: PD-L1 was expressed by all the cell types. The ratio of PD-L1(+) cells to CD326(+) tumor cells was 19.1% ± 14.0%, lower than those for CD90(+) stromal cells (39.6% ± 16.0%) and CD11b(+) myeloid cells (31.9% ± 14.3%). The ratio of PD-L1(+) cells in tumor cells correlated strongly with the ratio in stromal cells, while only weakly with that in myeloid cells. Tumor cells were divided into two populations by CD326 expression levels, and the PD-L1 positive ratios were inversely correlated with the rate of CD326 highly expressing cells as well as mean fluorescein intensity of CD326 in tumor cells, while positively correlated with the frequencies of stromal cells or myeloid cells in CRC. Conclusion: PD-L1 is differentially expressed on various cell types in CRC. PD-L1 on tumor cells may be upregulated together with CD326 downregulation in the process of epithelial mesenchymal transition. Quantification of cell type-specific expression of PD-L1 using multicolor flow cytometry may provide useful information for the immunotherapy of solid tumors.

Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I-III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N-stage was significantly lower in metformin-treated patients (P < .05) with prolonged disease-free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin-treated patients (P < .001). In those tumors, there were more CD68(+) tumor-associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2-phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM.

BACKGROUND: Goblet cell carcinoid (GCC) is a neuroendocrine tumor usually found in the appendix. GCCs exhibit characteristic findings with mixed endocrine-exocrine features such as staining positive for neuroendocrine markers and producing mucin. The primary GCC of the rectum is exceedingly rare. CASE PRESENTATION: A 77-year-old Japanese male presented with hematochezia. Anal tenderness and a hard mass in the anal canal were found on the digital rectal examination, and colonoscopy was performed. Colonoscopy showed an irregularly shaped mass in the anal canal. Biopsy showed mixed features including adenocarcinoma in situ, well-differentiated adenocarcinoma, and mucinous carcinoma with invasive proliferation. No metastatic lesions were found on the computed tomography scan. Pelvic magnetic resonance imaging scan showed extramural growth of a tumor on the ventral side of the rectum without invasion to the prostate. Laparoscopic abdominoperineal resection was performed. The final diagnosis was well-differentiated adenocarcinoma in the mucosa and goblet cell carcinoid from the submucosa to the adventitia of the rectum. The patient was discharged from the hospital on postoperative day 16. Six months after resection, a computed tomography scan revealed multiple metastatic lesions in the liver. Several chemotherapy regimens were given, and the patient has stable disease 27 months after surgery. CONCLUSION: We present a patient with rectal GCC with metachronous liver metastases. Since GCC grows intramurally and is biologically aggressive compared to typical carcinoid lesions, the disease is usually diagnosed at an advanced stage. The development of optimal adjuvant chemotherapy is needed for those patients.

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.

INTRODUCTION: Metastases to the thyroid gland in patients with colorectal cancer are uncommon. We report a patient with rectal cancer who developed a metastasis to the thyroid gland. PRESENTATION OF CASE: The patient was a 45-year-old female five years status post rectal cancer resection. A thyroid lesion was detected on PET-CT scan with synchronous lung metastases. After pulmonary resection, a partial thyroidectomy was performed and pathological examination with immunohistochemical staining confirmed that the lesion was a metastasis from previous rectal cancer. She is free from recurrence two years after thyroid surgery. DISCUSSION: Colorectal metastases to the thyroid gland are usually seen with widespread disease, often with lung and liver metastases. The overall outcomes of previously reported patients with thyroid metastases were extremely poor, with most patients dying within months of diagnosis. Careful attention should be given to other sites of metastatic disease including the thyroid gland during postoperative follow-up. PET scan may be helpful to establish the diagnosis. CONCLUSION: Treatment decisions must be individualized, and depend on the presence of systemic disease. Selected patients may benefit from resection of metastases, and PET scan may be useful to identify patients who will benefit from resection.

INTRODUCTION: Internal hernias are rare after laparoscopic colorectal resections. We report a patient with an internal hernia through a defect in the transverse mesocolon following laparoscopic resection. PRESENTATION OF CASE: A 52-year-old male underwent laparoscopic colectomy for transverse colon cancer and had an unremarkable postoperative course. Thirty days postoperatively, he presented to the emergency room with sudden onset abdominal pain and vomiting. Enhanced abdominal computed tomography scan showed strangulated small intestine in the left upper abdomen. An internal hernia through the mesenteric defect created during the recent colon resection was suspected, and emergency laparotomy was performed. One hundred thirty cm of small intestine was found herniated through a mesenteric defect. After repositioning the ischemic-appearing intestine, a 5 cm defect in the transverse mesocolon was found which had not been closed during the previous laparoscopic operation. No intestinal resection was needed, and the mesenteric defect closed with non-absorbable sutures. The post-operative course was unremarkable except for paralytic ileus, which resolved without further intervention. DISCUSSION: The incidence of internal hernia through a mesenteric defect after laparoscopic colorectal resection is quite low. Therefore, routine closure of the mesenteric defect after laparoscopic colorectal resection is not required. However, a left sided defect in the transverse mesocolon might be at higher risk of causing an internal hernia on anatomic grounds. CONCLUSION: We believe that mesenteric defects should be closed after laparoscopic resection of the left side of transverse colon, regardless of their size.