The role of graft and host accommodation in a hamster-to-rat cardiac transplantation model

BACKGROUND: We evaluated the importance and mechanism of graft and host accommodation in hamster-to-rat cardiac xenotransplantation models. METHODS: To evaluate graft accommodation, accommodated hamster grafts (Group 2) were transplanted to na?ve host rats treated with FK506, and compared with na?ve hamster grafts (Group 1). To evaluate host accommodation, three groups were evaluated: naive hamster hearts were transplanted to na?ve hosts treated with FK506 (Group 3: 0.5 mg/kg, Group 4: 1.0 mg/kg) and splenectomy, and compared with accommodating hosts (Group 5) with FK506 0.5 mg/kg and splenectomy. We examined graft survival, histopathology, antihamster antibodies and B-1 cells in blood. RESULTS: Graft survival in Group 2 (3.4+/-0.9 days) was not significantly different from that in Group 1 (2.8+/-0.4 days). Graft survival in Groups 4 and 5 (>30 days) was significantly prolonged compared with that in Group 3 (6.0+/-0.7 days). Histopathology of Groups 1-3 showed humoral rejection, whereas Groups 4 and 5 showed normal histology and expression of protective genes. In Groups 1-3, antihamster immunoglobulin (Ig) M and B-1 cells increased significantly compared to Groups 4 and 5, where IgM and B-1 cells remained low or were reduced. CONCLUSIONS: Host accommodation was more important than graft accommodation. Accommodating grafts expressing protective genes were rejected with an elevation of both IgM and B-1 cells. In accommodated hosts, both IgM and B-1 cells decreased, suggesting that B-1 cells may be responsible for the production of antihamster antibodies. These results suggest that sufficient suppression of B-1 cells, resulting in decreased titers of antihamster antibodies, may play an important role in host accommodation.     

Diagnostic Sensitivity of Contrast Swallow for Leakage after Gastric Resection

INTRODUCTION: We examined the clinical manifestations and computed tomography findings of patients with leakage after gastrectomy for cancer and determined the sensitivity of the contrast swallow for the leakage diagnosis. METHODS: The medical records of 331 consecutive patients undergoing gastrectomy between January 1992 and December 2003 were reviewed. Routine contrast swallow was performed in all patients before oral intake. Once leakage was suspected, an emergency contrast swallow was performed and its diagnostic sensitivity determined. RESULTS: In total, leakage was diagnosed 9 of 17 times by the contrast swallow, for a diagnostic sensitivity of 53%. The clinical signs or another imaging modality often corrected the misdiagnosis. CONCLUSIONS: The diagnostic sensitivity of contrast swallow for leakage after gastrectomy was low. Therefore, if we employ the contrast swallow technique, we should keep in mind its low sensitivity.     

Pretreatment with eplerenone reduces stroke volume in mouse middle cerebral artery occlusion model

Eplerenone, a mineralocorticoid receptor antagonist, is reported to be effective to prevent end-stage cardiovascular damage induced by aldosterone. However, the effect of eplerenone on brain damage is not fully understood. Here, we investigated whether pretreatment with eplerenone attenuates stroke size in mice subjected to middle cerebral artery occlusion. Middle cerebral artery occlusion with a microfilament technique induced focal ischemia, to approximately 25% of the total area in a coronal section of the brain. Treatment with eplerenone at a dose of 1.67 mg/g chow significantly reduced the ischemic area, ischemic volume, and neurological deficit, without a blood pressure-lowering effect. Laser-Doppler flowmetry analysis showed a decrease in surface cerebral blood flow in the peripheral region after 1 h of middle cerebral artery occlusion. This decrease was smaller in mice treated with eplerenone. Superoxide production evaluated by staining with dihydroethidium was attenuated in the ischemic area of the brain in eplerenone-treated mice. Taken together, our findings suggest that eplerenone has a protective effect on ischemic brain damage, at least partly due to improvement of cerebral blood flow in the penumbra and reduction of oxidative stress.     

An analysis of factors causing poor surgical outcome in patients with cervical myelopathy due to ossification of the posterior longitudinal ligament: anterior decompression with spinal fusion versus laminoplasty

OBJECTIVE: We compared the surgical outcome of anterior decompression with spinal fusion (ASF) with the surgical outcome of laminoplasty for patients with cervical myelopathy due to ossification of the posterior longitudinal ligament. METHODS: The study group comprised 19 ASF patients (A-group) and 40 laminoplasty patients (P-group) treated from 1993 to 2002 with 1 year or longer follow-up. The Japanese Orthopedic Association scoring system was used to evaluate cervical myelopathy, and the recovery rate calculated 1 year after surgery. RESULTS: The mean recovery rate was 68.4% in the A-group and 52.5% in the P-group (P<0.05). Fifteen patients had a recovery rate less than 40%: 2 in the A-group and 13 in the P-group. One P-group patient and none of the A-group patients developed postoperative aggravation of their neurologic status. The P-group was divided into 2 subgroups: a good outcome group comprising patients whose recovery rate was 40% or higher (n=27) and a poor outcome group comprising patients whose recovery rate was less than 40% (n=13). The mean age at surgery was 59.9 years in the good outcome group and 68.0 years in the poor outcome group (P<0.05). The mean range of intervertebral mobility at maximum cord compression level before surgery was 6.9 degrees in the good outcome group and 10 degrees in the poor outcome group (P<0.05). CONCLUSIONS: These results demonstrated that the surgical outcome of ASF was superior to the surgical outcome of laminoplasty. Elderly patients treated with laminoplasty showed an especially poor surgical outcome. We suggest that hypermobility of vertebrae at the cord compression level is a risk factor for poor surgical outcome after laminoplasty. Based on these results, we recommend that ASF should be the first choice of treatment for patients with significant ossification of the posterior longitudinal ligament and a hypermobile cervical spine. When laminoplasty is used for such cases, the addition of posterior instrumented fusion would be desirable for stabilizing the spine and decreasing damage to the spinal cord.     

Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas

Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.     

Quantitative hypermethylation of NMDAR2B in human gastric cancer

NMDA receptor Type 2B (NMDAR2B) is a candidate TSG first identified in esophageal squamous cell carcinoma (ESCC). To evaluate NMDAR2B methylation in gastric cancer progression, we performed quantitative methylation-specific PCR (MSP), RT-PCR and immnunohistochemistry (IHC) in primary gastric tissues and colony formation assays in gastric cancer cell lines. We found that the expression of NMDAR2B was reactivated by the demethylating agent, 5-aza-2'-deoxycytidine, with or without trichostatin A in gastric cancer cell lines. Moreover, inactivation of NMDAR2B was found to be closely correlated with promoter methylation status in gastric cell lines and primary gastric tumors. IHC data also showed that NMDAR2B was specifically expressed in gastric epithelial cells and its expression was diminished or absent in gastric cancer epithelium. Quantitative analysis of NMDAR2B promoter methylation showed 61% (17/28) hypermethylation in primary gastric tumors versus 5% (1/20) in normal gastric tissues from nongastric cancer patients. Forced over-expression of NMDAR2B in gastric cancer cell lines significantly inhibited cell colony formation. Taken together, the above results suggest that NMDAR2B methylation is a common and important biologically relevant event in gastric cancer progression.     

Multicenter phase II study of irinotecan plus bolus fluorouracil/l-leucovorin for metastasic colorectal cancer

Treatment of metastatic colorectal cancer remains inadequate. PATIENTS AND METHODS: In a multicentre Phase II study, irinotecan (100 mg/m2), 5-fluorouracil (5-FU) (500 mg/m2), and l-leucovorin (l-LV) (250 mg/m2) were administered on days 1, 8, and 15 of a five-week cycle. Forty-five patients were enrolled. RESULTS: The objective response rate was 26.7%. The median survival time was 21.8 months and the one-year survival rate was 73.3%. The median number of cycles was 4.0, with a median relative dose intensity of 83.3% for both irinotecan and 5-FU. Grade 3 or 4 haematological toxicities were anaemia in four patients, leukopaenia in six patients, and neutropaenia in 15 patients, while non-haematological toxicities were diarrhoea in three patients, and nausea, vomiting, anorexia and increased transaminases in two patients each. No treatment-related deaths occurred. CONCLUSION: Irinotecan plus 5-FU/l-LV can be used to treat metastatic colorectal cancer on an outpatient basis.     

Sentinel lymph node biopsy for 102 patients with primary cutaneous melanoma at a single Japanese institute

Sentinel lymph node biopsy (SLNB) is a widely accepted standard procedure for patients with clinically localized melanoma. Melanoma prevalence and Clark's subtype differ between Asians and Caucasians. Here, we evaluated our experience on SLNB for cutaneous melanoma in a Japanese population. SLNB was performed for patients with melanoma between July 2000 and June 2014. We retrospectively analyzed 102 patients regarding association of clinicopathological features with sentinel lymph node (SLN) status, melanoma‐specific survival (MSS) and disease‐free survival (DFS). A positive SLN was significantly associated with primary Breslow thickness. Compared with 43 patients with negative SLN, 59 patients with positive SLN had significantly shorter MSS (5‐year survival rate, 94.3% vs 63.2%; P = 0.0002) and DFS (5‐year survival rate, 92.7% vs 63.4%; P = 0.0004). According to our subgroup analyses, nine patients with positive non‐SLN had significantly shorter MSS compared with 32 patients with negative non‐SLN (5‐year survival rate, 32.4% vs 68.5%; P = 0.0273). The survival of 51 Japanese patients with acral lentiginous melanoma (ALM) was not inferior to the survival of patients with other Clark's subtype. Breslow thickness is an important factor for both MSS and DFS, and the status of SLN is the most predictive prognostic factor in Japanese patients with clinically localized melanomas, as in case of Caucasians. Features of ALM may be different between Asians and Caucasians.