Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma.

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.

Internal anomalies in thalidomide embryopathy: results of imaging screening by CT and MRI.

AIM: To examine the prevalence and detailed radiological findings of internal anomalies in thalidomide embryopathy (TE). MATERIALS AND METHODS: Whole-body image screening for internal anomalies using unenhanced whole-body computed tomography (CT) and head magnetic resonance imaging (MRI) was performed in 22 patients (13 women and nine men; mean age, 49 years; range, 47-51 years) with TE. RESULTS: Among the 22 patients with TE, internal anomalies were detected in 19 (86.4%): anomalies of the auditory organ in 10 (45.5%), anomalies of the vascular system in six (27.3%), agenesis of the gallbladder in six (27.3%), hypoplasia or aplasia of the 7th or 8th cranial nerves in five (22.7%), block vertebrae in five (22.7%), fusion of the left lobe and quadrate lobe of the liver in three (9.1%), and others in five (22.7%), respectively. CONCLUSION: In addition to limb defects or hypoplasia, various internal anomalies can be detected at a high incidence in TE using CT and MRI. Understanding these characteristic radiological findings may help radiologists detect a wide range of radiological findings of internal anomalies associated with TE.

Pediatric liver transplantation using reduced and hyper-reduced left lateral segment grafts: a 10-year single-center experience.

Few studies have examined the long-term outcomes and prognostic factors associated with pediatric living living-donor liver transplantation (LDLT) using reduced and hyper-reduced left lateral segment grafts. We conducted a retrospective, single-center assessment of the outcomes of this procedure, as well as clinical factors that influenced graft and patient survival. Between September 2000 and December 2009, 49 patients (median age: 7 months, weight: 5.45 kg) underwent LDLT using reduced (partial left lateral segment; n = 5, monosegment; n = 26), or hyper-reduced (reduced monosegment grafts; n = 18) left lateral segment grafts. In all cases, the estimated graft-to-recipient body weight ratio of the left lateral segment was more than 4%, as assessed by preoperative computed tomography volumetry, and therefore further reduction was required. A hepatic artery thrombosis occurred in two patients (4.1%). Portal venous complications occurred in eight patients (16.3%). The overall patient survival rate at 1, 3 and 10 years after LDLT were 83.7%, 81.4% and 78.9%, respectively. Multivariate analysis revealed that recipient age of less than 2 months and warm ischemic time of more than 40 min affected patient survival. Pediatric LDLT using reduced and hyper-reduced left lateral segment grafts appears to be a feasible option with acceptable graft survival and vascular complication rates.

Effect of maintenance therapy with low-dose peginterferon for recurrent hepatitis C after living donor liver transplantation.

Approximately 30% of patients who have recurrent hepatitis C after liver transplantation achieve sustained virological response (SVR) by taking a combination therapy of pegylated interferon and ribavirin. For the remaining non-SVR patients, an effective management treatment has not yet been established. In this study, efficacy of long-term peginterferon maintenance therapy for non-SVR patients was evaluated. Forty patients who had previously received the combination therapy for hepatitis C after living donor liver transplantation were classified into one of the following three groups: the SVR group (n = 11); the non-SVR-IFN group (n =17), which received low-dose peginterferon maintenance therapy for non-SVR patients; and the non-SVR-Withdrawal group (n = 12), which discontinued the interferon treatment. We then compared histological changes among these three groups after 2 or more years follow-up. Activity grade of liver histology improved or remained stable in patients in the SVR and non-SVR-IFN groups, but deteriorated in half of the patients in the non-SVR-Withdrawal group. Fibrosis improved or remained stable in 10 of 11 SVR patients and in 13 of 17 non-SVR-IFN patients, but deteriorated in all non-SVR-Withdrawal patients. Mean changes in fibrosis stage between pretreatment and final liver biopsy were -0.18, +0.06 and +2.2 in the SVR, non-SVR-IFN and non-SVR-Withdrawal groups, respectively. Fibrosis stage deteriorated to F3 or F4 significantly more rapidly in the non-SVR-Withdrawal group than in the other two groups. In conclusion, continuing long-term maintenance therapy with peginterferon prevented histological progression of hepatitis C in patients who had undergone living donor liver transplantation.

The challenge of acute rejection in intestinal transplantation.

Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.

Preemptive living donor liver transplantation in glycogen storage disease Ia: case report.

UNLABELLED: Even with substantial progress in the management of patients with glycogen storage disease type Ia (GSD-Ia), hepatic and renal complications may still develop during long-term follow-up. Herein, we report a case of preemptive living donor liver transplantation in a patient with GSD-Ia. PATIENT: The patient was a 5-year-old boy in whom GSD-Ia was diagnosed at age 10 months. Clinical symptoms included frequent hypoglycemic episodes, hyperlipidemia, hyperuricemia, and growth retardation, which were poorly controlled using conventional treatments. At age 5 years, frequent massive nasal bleeds developed, which led to severe anemia. The patient was brought to our institute for living donor liver transplantation (LDLT). Because GSD-Ia usually responds to dietary and medical treatments, we had a long discussion to determine whether preemptive LDLT was indicated. Transplantation was performed using the left lateral liver segment from the patients mother. The weight of his native liver was almost 2 kg. After reperfusion of the graft, the blood glucose concentration rapidly increased, and regular glucose was administered throughout the operation. The posttransplantation course was uneventful. The patient had no episodes of hypoglycemia with a regular diet. Total cholesterol, triglyceride, and uric acid concentrations also reverted to normal without medication. The patient had a few episodes of nasal bleeding after transplantation, which stopped spontaneously. He was discharged from our hospital with normal liver function. CONCLUSION: Patients with GSD-Ia should be considered for preemptive LDLT to improve their quality of life when clinical symptoms do not respond to appropriate treatment.

The excellent results of spousal kidney transplantation: experience in a Japanese single center.

In coping with the shortage of deceased kidney donors, living donor kidney transplantation is mainly performed in Japan. We started our living unrelated spousal kidney transplantation program in 1989. In this analysis, we compared the results of 64 spousal transplantations performed between September 1989 and May 2007 with those of living related and deceased donor grafts. Despite the older age of the recipients and the lower HLA matching, the graft survival rates of spousal transplants were as good as those from living related donors and better than those from deceased donors, (P < .01). The graft survival rate of spousal kidney transplantation is improving with advances in immunosuppression, so spouses are considered important donors in Japan, which lacks deceased donors.

Kidney transplantation for patients on long-term hemodialysis.

Patients surviving more than 10 years on hemodialysis (HD) are at risk of developing serious morbidity from unrelated conditions and from the many complications of long-term dialysis, such as cardiovascular disease, cerebrovascular disease, malignant tumors ectopic vascular calcification, diabetes mellitus, and disuse atrophy of the bladder. Long-term dialysis affects transplant patient outcomes and long-term graft survival. We analyzed 436 patients who underwent kidney transplantations between January 1987 and December 2007 to determine the impact of long-term dialysis on kidney transplant outcomes. The 39 patients who had been treated pretransplantation with dialysis for more than 10 years had an average length of dialysis treatment of 15.8 years (range, 10.0-32.5 years); they were denoted as the long-term hemodialysis group. The remaining 397 recipients showed an average of 3.7 years period of end-stage renal disease (ESRD) (range, 0-9.8, years; short-term hemodialysis group). There were significant differences in patient survival rates between the 2 groups: 93.2% vs 98.6%, at 1 year; 79.3% vs 95.4% at 5 years; and 58.4% vs 93.1% at 10 years (P = .0034). Also, graft survival was significantly different between the 2 groups: 89.2% vs 95.8% at 1 year; 60.4% vs 88.5% at 5 years; and 33.4% vs 80.4% at 10 years (P = .0026). Our results suggest that dialysis treatment for more than 10 years produces negative effects on post-transplantation patient and graft survival.

Biliary anastomosis and biliary complications following living donor liver transplantation.

Biliary complications are one of the most important problems in liver transplantation. Regardless of various improvements of surgical technique, liver transplantation is associated with significant biliary problems. In this article, we have described a biliary anastomosis method with a continuous suture (CS) technique in the posterior wall and interrupted suture (IS) technique for the anterior wall. We performed this biliary reconstruction in 28 adult patients between September 2003 and August 2007. Prior to that time our procedure was a CS anastomosis for both the anterior and posterior walls. A 5-Fr catheter is inserted into the biliary system. The current biliary complication was 3 cases (13.0%) of stenosis at the anastomosis, which is lower than that for a CS anastomosis. This anastomosis reduced biliary complications and is simple.

Successful treatment of recurrent intracardiac thrombus in Behçet's disease with immunosuppressive therapy.

Behçet's disease (BD) is a chronic multisystem inflammatory disorder characterized by recurrent oral and genital ulcers, skin eruptions and uveitis. Neurological, gastrointestinal, and musculoskeletal systems are also involved. Although venous and arterial vasculitis occur in up to one-third of patients, intracardiac thrombus is a very rare complication. We herein report the case of a 46-year-old man with BD who presented with a large right atrial thrombus. Within a month after surgical removal, the thrombus recurred and was successfully treated with immunosuppressants that included prednisolone and cyclophosphamide.

The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation.

UNLABELLED: Recent evidence suggests that CD4+CD25+ regulatory T cells (Tregs) affect immune responses, including those to alloantigens in organ transplants. We have followed a group of liver allograft recipients with good liver graft function who have been weaned off immunosuppression (IS). The purpose of this study was to determine whether Tregs contributed functionally to the mechanisms of graft acceptance. MATERIAL AND METHODS: The functional assay used peripheral blood obtained from LTx recipients free of immunosuppression. The Whole population of CD4+ T cells and the CD4+ T cells depleted of CD4+CD25 high cells were tested for proliferation against donor versus third party stimulators. Moreover to determine the antigen-specificity of the Tregs, serially diluted numbering of CD4+CD25+ T cells were co-cultured with CD4+CD25- T cells. The proliferation responses were examined toward donor versus third party stimulators. RESULT: CD4+ T cells from all LTx recipients off immunosuppression showed hyporesponsiveness to the donor but not to third party stimulators. However, even after depletion of the CD4+CD25 high population, the cells continued to be hyporesponsive toward the donor. In four out of five cases, the suppression exhibited by CD4+CD25+ T cells was more specific for the donor. DISCUSSION: These findings suggest that donor alloantigen specific regulation by Tregs is one of multiple mechanisms that may contribute to the maintenance of liver graft survival in the absence of immunosuppression.

Proinflammatory and antiinflammatory cytokine production during ischemia-reperfusion injury in a case of identical twin living donor liver transplantation using no immunosuppression.

BACKGROUND: Bolus steroids are usually administered prior to graft reperfusion in an attempt to provide protection against ischemia reperfusion injury (IRI). However, the anti-IRI properties of steroids have not been established. Living donor liver transplantation (LDLT) between identical twins provides a unique opportunity to study the natural production of cytokines during transplantation without the confounding influences of the alloimmune response or of immunosuppression in particular steroids. METHODS: A 38-year-old male with hepatitis C virus-related cirrhosis and multiple hepatocellular carcinomas received a hepatic right lobe graft from his identical twin. No immunosuppression was administered, not even intraoperative bolus steroids. IRI was assessed by serum transaminases as well as by proinflammatory interleukin (IL) IL-1beta, tumor necrosis factor (TNF)-alpha, IL-8 cytokines and for potent regenerative/anti-inflammatory (IL-6, IL-10) mediators. RESULTS: Despite no administration of steroids, low peak levels of serum transaminases were observed. Serum IL-6 and IL-10 dramatically and rapidly increased during liver transplantation, namely, 160 and 20 times higher than baseline, respectively. In contrast, IL-1beta and TNF-alpha remained low during and after transplantation and an increase in IL-8 was less obvious. CONCLUSION: Syngeneic LDLT without intraoperative bolus steroids is feasible, yielding no penalty in terms of IRI. A predominance of protective cytokines was observed in the absence of steroids. Thus, the concept that intraoperative administration of steroids is necessary to protect liver transplants from IRI must be revisited.

New protocol of immunosuppression for liver transplantation across ABO barrier: the use of Rituximab, hepatic arterial infusion, and preservation of spleen.

INTRODUCTION: An ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) is a challenge. Until 2000 systemic multidrug immunosuppression and splenectomy was the gold standard with poor results. Application of local administration with prostagrandin E1 (PGE1) and steroids via a portal vein (PV) catheter dramatically improved the survival from 20% to 60% but PV thrombus became a problem (35%). To solve it, an hepatic arterial (HA) catheter was used instead of a PV catheter and splenectomy was omitted. Although the PV thrombus problem was resolved, the ABO antibody titers significantly increased, and two cases of uncontrollable humoral rejection (HR) were experienced. In this study, Rituximab was introduced instead of splenectomy to decrease the antibody. We report the efficacy of prophylaxis with Rituximab for ABO-I LDLT. METHODS: Eight patients received. Rituximab at 2 to 14 days before LDLT. During the operation, the spleen was preserved. Methylpredonisolone and PGE1 were administered via an HA catheter for 2 to 3 weeks after LDLT in addition to an immunosuppressive regimen consisting of tacrolimus and steroids. Antibody titers were measured serially. RESULT: There was no clinical HR. Two patients died of complications unrelated to HR. The antibody titer decreased compared to patients without splenectomy/rituximab. B cells (CD19) were depleted from peripheral blood for up to 3 months. Cytomegalovirus infections were decreased compared to patients with splenectomy (P = .085). CONCLUSION: Rituximab prophylaxis and HA infusion therapy prevented clinical HR, which may provide a breakthrough to overcome the ABO blood-type barrier in liver transplantation.

Testosterone and insulin-like growth factor (IGF) I interact in controlling IGF-binding protein production in androgen-responsive foreskin fibroblasts.

The growth of the male external genitalia is primarily regulated by androgens. However, human genital fibroblast growth is also stimulated by insulin-like growth factor (IGF) I. In this study, we report that IGF-binding protein (IGFBP) production in human foreskin fibroblasts is regulated by androgens and IGF-I. Human foreskin fibroblasts secrete IGFBP-3, IGFBP-4, and IGFBP-5. IGF-I increased the abundance of both intact IGFBP-3 and -5 in the culture medium. Testosterone increased IGFBP-3, and the combination of IGF-I and testosterone had an additive effect. Following its secretion, IGFBP-5 was degraded, but the effect of IGF-I on IGFBP-5 peptide abundance in conditioned media did not seem to be due to inhibition of proteolysis. Testosterone had no effect on IGFBP-5 degradation. Intact IGFBP-4 was decreased by IGF-I, and the combination resulted in a similar reduction. The mechanism seemed to be decreased synthesis, since IGFBP-4 messenger RNA was also decreased. The increase in IGFBP-5 synthesis was associated with an increase in the abundance of intact IGFBP-5 in the extracellular matrix. The combination of testosterone and IGF-I resulted in a synergistic stimulation of total protein synthesis by the fibroblast cultures, suggesting that a maximum anabolic response requires both hormones. These observations suggest that combined exposure to androgen and IGF-I altered the abundance of some forms of IGFBPs and that the IGFBPs that are regulated may play a role in modulating the effects of IGF-I on the anabolic response.

The influence of gonadal function and the effect of gonadal suppression treatment on final height in growth hormone (GH)-treated GH-deficient children.

One hundred and sixty-one children with idiopathic GH deficiency who received GH treatment were followed until they reached their final height. Final height was found to be influenced by gonadal function. In 108 patients who had spontaneous puberty (91 boys and 17 girls; group A), the mean final height was 151.8 +/- 6.6 (+/- SD) cm in boys and 141.7 +/- 7.4 cm in girls. In 29 patients with combined GH and gonadotropin deficiency (23 boys and 6 girls; group C), whose pubertal development was induced artificially at age 19.5 +/- 2.1 yr in the boys and 18.6 +/- 1.8 yr in the girls, the mean final height was 163.7 +/- 3.9 cm in boys and 151.0 +/- 5.1 cm in girls. The differences in final height between groups A and C were significant in both boys and girls. The shorter final height in group A was caused by the shorter pubertal duration and smaller pubertal height gain than those in normal children. In 24 patients (17 boys and 7 girls; group B) who developed early signs of puberty, gonadal suppression therapy with cyproterone acetate and/or medroxyprogesterone acetate was given. The mean SD score of the final height in these 24 patients was -2.1 +/- 0.6, significantly higher than that in group A. This beneficial effect of gonadal suppression treatment on final height was caused by increases in the duration of puberty and the pubertal height gain.

Proliferation of type II pneumocytes in the lung biopsy specimens reflecting alveolar damage.

Proliferation of type II pneumocytes may be the most sensitive pathological indicator of alveolitis, and the density of type II pneumocytes reflecting the severity of the recent alveolar damage. Twenty-nine patients were divided into three groups by the severity of ground-glass opacities on the CT scans; the severe (acute), the moderate (subacute) and the mild (chronic) groups. We compared the density of type II pneumocytes in the transbronchial lung biopsy specimens and cell analysis of bronchoalveolar lavage (BAL) fluid with the ground-glass opacities. Clinical and laboratory findings and BAL fluid analysis also corresponded well with this grouping. Type II pneumocytes were selectively stained with an antibody against Thomsen-Friedenreich and the density of the type II pneumocytes was expressed as the number per 1 mm alveolar septal length. The densities of the type II pneumocytes in the severe, the moderate, the mild, and the control groups were 21.2+/-1.1, 14.4+/-7.2, 11.0+/-3.3 and 7.5+/-0.9/mm, respectively. There were significant differences between the acute group and the other three groups, and between the control and chronic groups. The density of type II pneumocytes is a useful index for evaluating alveolar damage even in mild alveolitis.

Peripharyngeal space invasion of head and neck cancer--incidence, mechanisms, and management.

We studied the incidence and mode of development of peripharyngeal invasion from head and neck cancers by both retrospective examination of our 127 patients and tracing the dynamics of lymph flow from the hypopharyngeal wall to the peripharyngeal space. We also presented three experiences of the surgical approach to the peripharyngeal invasion by our modification of Attia's technique. Peripharyngeal space invasions occur frequently in a direct or indirect way when meso- or hypopharyngeal or posterior oral cancer invades deeply into the muscle layers and extends to the palatine arch, retromolar region, pharyngoepiglottic fold, pharyngeal tongue, or posterior buccal mucosa. The lymph flow was revealed to move quickly from the lateral hypopharyngeal wall to the base of the skull and occasionally to the opposite side. The peripharyngeal space invasions were successfully removed under a wide surgical field without injuring the important nerves and vessels and with preservation of mandibular function. We should cover all routes for extension of head and neck cancers, including the peripharyngeal space, in the diagnosis and management of these conditions.

[Retrocollis and oculogyric crisis in association with bilateral putaminal hemorrhages].

A 50-year-old man with a history of hypertension developed right hemiparesis in February, 1985. Four years later, he noted tremor and involuntary extension of the neck (retrocollis) which was aggravated by walking or emotional stimuli. In addition to retrocollis, which was most pronounced upon turning the head to the left or backward, there also was upward deviation of the eyes (oculogyric crisis) and contraction of the left orbicularis oculi muscle. Magnetic resonance imaging study revealed one small old hematoma in the left posterior putamen and two in the right lenticular nucleus (one in the posterior putamen and the other in the globus pallidus). The findings in this case and in other reported cases of symptomatic retrocollis suggest that bilateral lesions of the putamen are associated with this type of focal dystonia.