Falciform ligament hernia with specific abdominal symptom.

Falciform ligament hernia is a very rare internal hernia and is difficult to diagnose before surgery. We report a case of falciform ligament hernia with a specific symptom and image findings, which led to an accurate diagnosis and subsequent laparoscopic surgery. A 15-year-old adolescent boy with no previous medical history showed epigastric pain and was referred to our hospital. The abdominal pain was strong in the supine position and was alleviated in the knee-chest position. Contrast-enhanced computed tomography showed that the round ligament was recognized as a cord-like structure, and the mesentery of the small intestine was located at the cranioventral side of the ligament. He was diagnosed as having falciform ligament hernia, and emergency laparoscopic surgery was performed. The small intestine passed through the falciform ligament; however, it showed no sign of ischemia, and bowel resection was not required. The malposed intestine was repositioned, and the falciform ligament was cut to prevent hernia recurrence. The specific abdominal symptom and computed tomography image finding were useful to make the correct diagnosis in this case.

[Lung Metastasis from Alpha-Fetoprotein Resulting in Esophagogastric Junction Cancer-A Case Report].

A 51-year-old male underwent total gastrectomy for esophagogastric junction cancer(T3N0M0, Stage ⅡA). He was diagnosed with an alpha-fetoprotein(AFP) producing tumor and hepatoid adenocarcinoma. One month after radical surgery, computed tomography(CT) showed lung metastasis, and the patient's serum AFP level was high. He underwent chemotherapy( S-1 and wPTX/RAM)and eventually died 4 months after surgery.

[Two Cases of Alpha-Fetoprotein Producing Gastric Cancer].

Case 1: A 51-year-old man underwent total gastrectomy for esophagogastric junction cancer. Pathological diagnosis was alpha-fetoprotein(AFP)producing cancer. One month after the surgery, lung metastasis was found on CT. Despite systemic chemotherapy, he died 4 months after the surgery. Case 2: A 79-year-old man underwent open distal gastrectomy for gastric cancer. Pathological diagnosis was AFP producing cancer. Six months after the surgery, multiple lymph node metastases were found on CT. He received chemotherapy and radiation therapy. He is currently alive 9 years 8 months after the surgery.

Concurrent Expression of CD47 and CD44 in Colorectal Cancer Promotes Malignancy.

CD47 activates signal regulatory protein alpha expressed on macrophages and suppresses its phagocytic ability; therefore, CD47 is drawing attention as an immune checkpoint in the innate immune system. Expression of CD47 in cancer is thought to allow cancer cells to escape antitumor immunity of the innate immune system. In this study, expression of CD47 was examined by immunostaining in colorectal cancer (CRC) and compared with the expression of CD44, which is a marker for cancer stem cells. In 95 cases of stage II-IV CRC, CD47 and CD44 showed overexpression in 82 and 80 cases, respectively. Both expression levels correlated with distant metastasis. Moreover, the expression of CD47 and CD44 in each case showed a significant correlation. In stage III cases, disease-free survival of cases showing high expression of CD47 and CD44 was worse than that of the cases with low expression. Furthermore, 3 of the stage IV cases were administered nivolumab, a checkpoint inhibitor of the acquired immune system, and 2 patients showed recurrence thereafter. All recurrent tumors highly expressed CD47 and CD44 and showed the epithelial-mesenchymal transition (EMT) phenotype. Our results suggest that CD47 promotes the malignancy of CRC in association with EMT and enhances the stemness of cancer cells. Moreover, our study suggests that CD47 and CD44 are involved in imparting resistance to programmed cell death (PD)-1/PD-ligand 1 inhibitors.

Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial.

BACKGROUND: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. METHODS: We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. FINDINGS: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). INTERPRETATION: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. FUNDING: Epidemiological and Clinical Research Information Network.

Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer.

We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (A)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed A-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in HT29 cells. Reduction of hepatic ATG production by cholesterol-conjugated antisense S-oligodeoxynucleotide suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and A-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated angiotensin activation enhances liver metastasis of CRC and may therefore provide a possible target for antimetastatic therapy in CRC.

HMGB1 attenuates anti-metastatic defense of the lymph nodes in colorectal cancer.

BACKGROUND: Cancer-secreted high mobility group 1 (HMGB1) induces apoptosis of macrophages and suppresses the host anti-cancer immune system. OBJECTIVE: We here examined the effect of HMGB1 on macrophages in the lymph nodes of colorectal cancer (CRC) patients. METHODS: Regional lymph nodes of 50 Dukes C CRCs were compared with 50 Dukes B CRCs. RESULTS: Dukes C tumors exhibited higher HMGB1 labeling indices and higher HMGB1 concentrations in primary tumors than Dukes B CRCs. Macrophages in the regional lymph nodes were decreased in non-metastasized nodes as well as metastasized nodes in Dukes C cases, whereas macrophage numbers in Dukes B nodes were higher than in Dukes C nodes. Nodal HMGB1 concentration was higher in Dukes C nodes than in Dukes B nodes, being inversely correlated with macrophage numbers. Nodal HMGB1 concentration was correlated with HMGB1 concentration and lymph vessel density in the primary tumors. CONCLUSION: These data suggest that HMGB1 secreted from primary tumors spread to the regional lymph nodes decreases the number of macrophages to attenuate the anti-metastatic defense of the lymph nodes in patients with CRCs.

HMGB1 attenuates anti-metastatic defence of the liver in colorectal cancer.

High mobility group box (HMGB) 1 induces apoptosis of monocyte-lineage cells. We examined the effect of HMGB1 on Kupffer cells (KCs). In 50 Dukes C and 12 liver-metastasised Dukes D colorectal cancers (CRCs), higher HMGB1 concentration in the primary tumours and metastatic foci, and fewer KCs were found in Dukes D cases than in Dukes C cases. The portal blood HMGB1 concentration was higher in Dukes D cases than in Dukes C cases. HMGB1 induced growth inhibition and apoptosis in mouse KCs in a dose-dependent manner, which was associated with the phosphorylation of c-Jun N-terminal kinase (JNK). JNK inhibition and knockdown of HMGB1 receptor abrogated growth inhibition and apoptosis. In a nude mouse liver metastasis model, the caecal administration of HMGB1 decreased the number of KCs and increased the embedment of Colo320 CRC cells in a dose-dependent manner. HMGB1 transfection increased the liver metastasis of Colo320 cells, and the metastasis was inhibited by anti-HMGB1 antibody administration. These results suggest that HMGB1 secreted from primary tumours decreases the number of KCs and attenuates the anti-metastatic defence of the liver in patients with CRCs.

Suppression of dendritic cells by HMGB1 is associated with lymph node metastasis of human colon cancer.

High mobility groupbox-1 (HMGB1) is a multifunctional cytokine secreted by cancer cells, which accelerates cell growth, invasion and angiogenesis in cancer, and induces apoptosis in macrophages. Thioglycolate-stimulated mouse peritoneal macrophages were induced to differentiate into dendritic cells by co-treatment with IL-4 and GM-CSF. The number of mouse peritoneal macrophage-derived dendritic cells (PMDDCs) showed a dose-dependent decrease in hrHMGB1 treatment. HMGB1-treated PMDDCs showed obvious apoptosis and increased the level of phosphorylated JNK. Intraperitoneal administration of HMGB1 decreased CD205-positive splenic dendritic cells in C57BL mice. To confirm the HMGB1-induced inhibitory effect on dendritic cells, 16 cases of human colon cancer invaded into the subserosal layer were examined. The 8 nodal metastasis-positive cases showed higher nodal HMGB1 concentrations (74 +/- 23 vs. 41 +/- 15 microg/ml, p = 0.0116) in lymph node tissues and lower CD205-positive nodal dendritic cell numbers (86 +/- 22 vs. 137 +/- 43/mm(2), p = 0.0224) than those in the 8 metastasis-negative cases. Primary tumor tissues of metastasis-positive cases showed higher tumor HMGB1 levels (116 +/- 33 vs. 37 +/- 18 microg/ml, p = 0.0007) and lower CD205-positive intratumoral dendritic cell numbers (21 +/- 13 vs. 62 +/- 23 /mm(2), p = 0.0068) than those in metastasis-negative cases. These findings suggest that HMGB1 produced by colon cancer cells suppressed nodal dendritic cells to disturb host anti-cancer immunity.

Methionine-enkephalin secreted by human colorectal cancer cells suppresses T lymphocytes.

The role of methionine-enkephalin (MENK) as an immunomodulator in colorectal carcinomas (CRC) was examined. MENK was produced in CT26, IEC6A, Colo320, and HT29 CRC cell lines but not in IEC6 intestinal cells. MENK secretion was associated with tumorigenicity and metastasis of CRC cells in syngeneic rodent models. The MENK concentration in subcutaneous tumors of CT26 and IEC6A CRC cells exhibited an inverse correlation with the number of tumor-infiltrating T lymphocytes. MENK inhibited the growth of MOLT-4 T-lymphoblastic cells in a dose-dependent manner. Furthermore, it increased the phosphorylation level of c-Jun N-terminal kinase and induced apoptosis in MOLT-4 cells. MENK-induced apoptosis was abrogated by a c-Jun N-terminal kinase inhibitor. Immunohistochemical analysis revealed moderate to strong expression of MENK in 33 (54%) of 61 CRC. MENK expression was associated with Dukes' staging, nodal metastasis, and liver metastasis. The MENK concentration in tumor tissues was higher in Dukes' C cases than in Dukes' B cases. MENK expression was associated with tumor-infiltrating T lymphocytes, especially those belonging to the CD4(+) subset. These findings suggest that MENK secreted by CRC cells caused escape of the host from the effects of immunity.

[A case of occult breast carcinoma with irradiation therapy and axillary lymph node dissection].

A 78-year-old woman was seen at the hospital for a swollen left axillary node. There was an elastic hard mass measuring 0.7 cm in diameter in the left axilla, but no breast mass was palpable in the bilateral breasts. Mammography did not reveal any tumor and calcification, and there was no abnormalities on breast ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). Aspiration biopsy cytology of the left axillary node revealed adenocarcinoma. Systemic examination failed to reveal primary lesion. Thus, to make the diagnosis, we enucleated the axillary nodule. Immunohistochemical staining for the excisional specimen revealed an estrogen receptor, progesterone receptor and gross cystic disease fluid protein-15 (GCDFP-15) was strongly positive, so we diagnosed it as an occult breast carcinoma. After obtaining her informed consent, the patient underwent left axillary lymph node dissection and irradiation therapy of the left breast. The patient has been disease-free under adjuvant chemoendocrine therapy. We treated the occult breast carcinoma with radiation therapy of the breast and axillary lymph node dissection, and provided a review of the literature.