Junji Kishimoto

Reliability and validity of the japanese-language version of the Impact of event scale-revised (IES-R-J): Four studies of different traumatic events

The authors developed the Japanese-language version of the Impact of Event Scale-Revised (IES-R-J) and investigated its reliability and validity in four different groups: workers with lifetime mixed traumatic events, survivors of an arsenic poisoning case, survivors of the Hanshin-Awaji earthquake, and survivors of the Tokyo Metro sarin attack. Evidence includes retest reliability and internal consistency of the IES-R-J. Posttraumatic stress disorder (PTSD) and partial PTSD cases indicated significantly higher scores than non-PTSD cases. The IES-R-J can be a useful self-rating diagnostic instrument particularly for survivors with PTSD symptoms as a clinical concern (PTSD + partial PTSD) by using a 24/25 cutoff in total score. In analysis of scale structure, the majority of intrusion and hyperarousal items were subsumed under the same cluster, whereas avoidance items made up a separate cluster. Female patients indicated higher scores than male patients. A negative weak correlation between age and the score was found only among female earthquake survivors. The IES-R-J can be used as a validated instrument in future international comparative research.

Elective Colon and Rectal Surgery Differ in Risk Factors for Wound Infection: Results of Prospective Surveillance

Objective:The objective of this study was to clarify the incidence and risk factors for developing incisional surgical site infection (SSI) in both elective colon and rectal surgery. Summary Background Data:SSI is a frequent complication after elective colorectal resection. The National Nosocomial Infection Surveillance system surveys all colorectal surgeries together, without differentiating the type of colorectal surgery performed. However, rectal surgery may have a higher risk for SSI, and identifying risk factors that are more specific to each procedure would be more predictive. Methods:We conducted prospective SSI surveillance of all elective colorectal resections performed by a single surgeon in a single institution from November 2000 to July 2004. The data for colon and rectal surgeries were collected separately. The outcome of interest was incisional SSI. Univariate and multivariate analyses were performed to determine the predictive significance of variables in each type of surgery. Results:A total of 556 colorectal resections, consisting of 339 colon and 217 rectal surgeries, were admitted to the program. The incisional SSI rates in colon and rectal surgeries were 9.4% and 18.0%, respectively (P = 0.0033). Risk factors for developing incisional SSI in colon surgery were ostomy closure (OR = 7.3) and lack of oral antibiotics (OR = 3.3), while in rectal surgery, risk factors were preoperative steroids (OR = 3.7), preoperative radiation (OR = 2.8), and ostomy creation (OR = 4.9). Conclusions:Colon and rectal surgeries differ with regard to incidence and risk factors for developing incisional SSI. SSI surveillance for such surgeries should be performed separately, as this should lead to more efficient identification of risk factors and a reduction in SSI.

Prognosis and risk factors of metastasis in colorectal carcinoids: results of a nationwide registry over 15 years

Background: Colorectal carcinoids are often described as low-grade malignant. However, no study has compared the survival between patients with colorectal carcinoids and those with carcinomas, in a large series. In addition, no global consensus has been established on the crucial determinants of metastasis in colorectal carcinoids. Aim: To determine the predictive factors for metastasis in colorectal carcinoids and clarify their prognosis compared with adenocarcinomas. Methods: Data of all patients diagnosed as having colorectal carcinoids were extracted from a large nationwide database of colorectal tumours, the Multi-Institutional Registry of Large-Bowel Cancer in Japan, for the period from 1984 to 1998. Risk factors for lymph node (LN) metastases and distant metastases were analysed among those who were undergoing surgery, by univariate and multivariate analysis. Cancer-specific survival was also compared between patients with colorectal carcinoids and those with adenocarcinomas registered in the same period. Results: Among the 90 057 cases of colorectal tumours that were diagnosed, a total of 345 cases of carcinoids were identified, including 247 colorectal carcinoids of those undergoing surgery. Risk factors for LN metastasis were tumour size ⩾11 mm and lymphatic invasion, whereas those for distant metastasis were tumour size ⩾21 mm and venous invasion. Colorectal carcinoids without these risk factors exhibited no LN metastasis or distant metastasis. Cancer-specific survival of patients with colorectal carcinoids without metastasis was better than that of those with adenocarcinomas. However, the survival was similar between carcinoids and adenocarcinomas if the tumours had LN metastasis or distant metastasis. Conclusions: The presence of metastasis in colorectal carcinoids could lead to survival that is as poor as in adenocarcinomas. Tumours ⩽10 mm and without lymphatic invasion could be curatively treated by local resection, but others would need radical LN dissection.

Ulcerative colitis‐associated colorectal cancer shows a poorer survival than sporadic colorectal cancer: A nationwide Japanese study

Background: The clinicopathological features of ulcerative colitis‐associated colorectal cancer (UC‐CRC) have not yet been fully clarified, especially in Asian populations. This study aimed to clarify the prognosis and clinicopathological features of UC‐CRC in comparison with sporadic CRC in the Japanese population. Methods: Histologically diagnosed UC‐CRC patients between 1978 to 1998 were extracted from the Multi‐Institutional Registry of Large‐Bowel Cancer in Japan, a large nationwide CRC database, and the clinicopathological features and postoperative survival rates of UC‐CRC patients and sporadic CRC patients were compared. Results: Among the 108,536 CRC patients registered between 1978 and 1998, a total of 169 UC‐CRC patients were identified, including 121 patients who had been treated surgically. The proportion of UC‐CRC patients increased in the period between 1995 and 1998 compared to that between 1978 and 1994. Comparisons with the sporadic CRC patients showed that the UC‐CRC patients were younger, had a higher proportion of multiple cancer lesions, had higher proportions of superficial type lesions and invasive type lesions morphologically, and had higher proportions of mucinous or signet ring cell carcinomas. In stage III, UC‐CRC patients had a poorer survival rate than the sporadic CRC patients (43.3% versus 57.4%, P = 0.0320). Conclusions: UC‐CRC increased over the investigated time periods and showed a poorer survival than sporadic CRC in the advanced stage, while no difference was observed in the early stage. By detecting UC‐CRC at an early stage we can expect a similar postoperative outcomes to that of sporadic CRC. These results stress the importance of surveillance for the early detection of UC‐CRC. Inflamm Bowel Dis 2011

Sessile serrated adenoma with early neoplastic progression: A clinicopathologic and molecular study

Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, &bgr;-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of &bgr;-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear &bgr;-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and &bgr;-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma.

Synergistic effects of FGF-2 with insulin or IGF-I on the proliferation of human auricular chondrocytes.

Chondrocyte preparation with the safety and efficiency is the first step in cartilage regenerative medicine. To prepare a chondrocyte proliferation medium that does not contain fetal bovine serum (FBS) and that provides more than a 1000-fold increase in cell numbers within approximately 1 month, we attempted to use the medium containing 5% human serum (HS), but it exerted no more than twofold increase in 2 weeks. To compensate for the limited proliferation ability in HS, we investigated the combinational effects of 12 factors [i.e., fibroblast growth factor(FGF)-2, insulin-like growth factor(IGF)-I, insulin, bone morphogenetic protein-2, parathyroid hormone, growth hormone, dexamethasone, 1α25-dihydroxy vitamin D3, L-3,3′,5′-triodothyronine, interleukine-1 receptor antagonist, 17β-estradiol, and testosterone] on the proliferation of human auricular chondrocytes by analysis of variance in fractional factorial design. As a result, FGF-2, dexamethasone, insulin, and IGF-I possessed promotional effects on proliferation, while the combination of FGF-2 with insulin or IGF-I synergistically enhanced the proliferation. Actually, the chondrocytes increased 7.5-fold in number in 2 weeks in a medium containing 5% HS with 10 ng/ml FGF-2, while the cell number synergistically gained a 10–12-fold increase with 5 μg/ml insulin or 100 ng/ml IGF-I in the same period. The proliferation effects were more enhanced at a concentration of 100 ng/ml for FGF-2, and especially for the combination of 100 ng/ml FGF-2 and 5 μg/ml insulin (approximately 16-fold within 2 weeks). In the long-term culture with repeated passaging, this combination provided more than 10,000-fold within 8 weeks (i.e., passage 4). Thus, we concluded that such a combination of FGF-2 with insulin or IGF-I may be useful for promotion of auricular chondrocyte proliferation in a clinical application for cartilage regeneration.

Nanoparticle-Mediated Delivery of Pitavastatin Into Lungs Ameliorates the Development and Induces Regression of Monocrotaline-Induced Pulmonary Artery Hypertension

Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH.

RADIOSURGERY TO REDUCE THE RISK OF FIRST HEMORRHAGE FROM BRAIN ARTERIOVENOUS MALFORMATIONS

OBJECTIVEIt remains unclear whether or not and to what extent stereotactic radiosurgery can reduce the risk of first intracranial hemorrhage from brain arteriovenous malformations. METHODSWe performed a retrospective observational investigation of 500 patients with arteriovenous malformations who were treated with gamma knife radiosurgery. The risk of first hemorrhage was analyzed using the Cox proportional-hazards model with age at radiosurgery and angiographic obliteration included as time-dependent covariates. Three periods were defined: from birth to radiosurgery (before radiosurgery); from radiosurgery to angiographic obliteration (latency period); and from angiographic obliteration to end of the follow-up period (after obliteration). RESULTSHemorrhage was documented before radiosurgery in 318 patients (median observation period, 30.0 yr), during the latency period in 11 patients (median observation period, 2.2 yr), and after obliteration in two patients (median observation period, 5.5 yr). Compared with the period before radiosurgery, the risk of hemorrhage decreased by 86% after obliteration (hazard ratio, 0.14; 95% confidence interval, 0.03–0.55; P = 0.005), whereas the reduction observed during the latency period was not statistically significant (hazard ratio, 0.56; 95% confidence interval, 0.31–1.04; P = 0.07). Irrespective of obliteration, the risk of hemorrhage decreased by 62% after radiosurgery (hazard ratio, 0.38; 95% confidence interval, 0.22–0.67; P = 0.001). Similar results were observed when the 33 patients who had undergone previous therapy were excluded from the analysis. CONCLUSIONStereotactic radiosurgery significantly reduces the risk of first hemorrhage from brain arteriovenous malformations. The extent of the decrease might be greater if angiography indicates the evidence of obliteration.

The efficacy of prostaglandin E1 derivative in patients with lumbar spinal stenosis.

Study Design. Randomized controlled trial. Objective. To examine the effect of limaprost, an oral prostaglandin (PG) E1 derivative, on health-related quality of life (HRQOL) in patients with symptomatic lumbar spinal stenosis (LSS), compared to etodolac, a NSAID. Summary of Background Data. Limaprost, an oral PGE1 derivative, was developed in Japan to treat numerous ischemic symptoms of thromboangiitis obliterans (TAO) and LSS. Previous studies have demonstrated the effectiveness of limaprost in the symptoms in patients with LSS. However, the evidence for effect on patient-reported outcomes, such as patient’s HRQOL or satisfaction, is limited. Methods. This study was conducted at 4 study sites in Japan. Briefly, inclusion criteria were: age between 50 and 85 years; presence of both neurogenic intermittent claudication (NIC) and cauda equina symptoms (at least presence of bilateral numbness in the lower limbs); and MRI-confirmed central stenosis with acquired degenerative LSS. Limaprost (15 &mgr;g/d) or etodolac (400 mg/d) was administered for 8 weeks. The primary outcome was Short Form (SF)-36, and the secondary outcomes were the verbal rating scale of low back pain and leg numbness, walking distance, subjective improvement, and satisfaction. Results. A total of 79 participants were randomized (limaprost:etodolac = 39:40). Thirteen participants withdrew from the study (limaprost:etodolac = 5:8) and 66 completed the study (limaprost:etodolac = 34:32). Comparisons showed that limaprost resulted in significantly greater improvements in the SF-36 subscales of physical functioning, role physical, bodily pain, vitality, and mental health. Limaprost was also significantly better than etodolac for leg numbness, NIC distance, and subjective improvement and satisfaction. In the subgroup analysis stratified by symptom severity, limaprost seemed more effective for milder symptoms. No serious adverse effects were reported in either treatment group. Conclusion. In this study, limaprost was found to be efficacious on most outcome measures, such as HRQOL, symptoms and subjective satisfaction, in LSS patents with cauda equina symptoms.

Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.