Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Radiation therapy for primary vaginal carcinoma.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2-T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2-T3 disease resulted in good local control.

Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital.

BACKGROUND: Antimicrobial stewardship has not always prevailed in a wide variety of medical institutions in Japan. METHODS: The infection control team was involved in the review of individual use of antibiotics in all inpatients (6348 and 6507 patients/year during the first and second annual interventions, respectively) receiving intravenous antibiotics, according to the published guidelines, consultation with physicians before prescription of antimicrobial agents and organisation of education programme on infection control for all medical staff. The outcomes of extensive implementation of antimicrobial stewardship were evaluated from the standpoint of antimicrobial use density, treatment duration, duration of hospital stay, occurrence of antimicrobial-resistant bacteria and medical expenses. RESULTS: Prolonged use of antibiotics over 2 weeks was significantly reduced after active implementation of antimicrobial stewardship (2.9% vs. 5.2%, p < 0.001). Significant reduction in the antimicrobial consumption was observed in the second-generation cephalosporins (p = 0.03), carbapenems (p = 0.003), aminoglycosides (p < 0.001), leading to a reduction in the cost of antibiotics by 11.7%. The appearance of methicillin-resistant Staphylococcus aureus and the proportion of Serratia marcescens to Gram-negative bacteria decreased significantly from 47.6% to 39.5% (p = 0.026) and from 3.7% to 2.0% (p = 0.026), respectively. Moreover, the mean hospital stay was shortened by 2.9 days after active implementation of antimicrobial stewardship. CONCLUSION: Extensive implementation of antimicrobial stewardship led to a decrease in the inappropriate use of antibiotics, saving in medical expenses, reduction in the development of antimicrobial resistance and shortening of hospital stay.

Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal nodal staging of lung cancer.

BACKGROUND: Recently, transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been evaluated for mediastinal nodal staging (N staging) of lung cancer, as this technique is less invasive than mediastinoscopy and possibly more accurate than 18F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT). However, EUS-FNA does not provide access to pretracheal and hilar lymph nodes. More recently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been introduced as a novel technique for accessing pretracheal and hilar lymph nodes. Although the combined endoscopic approach of EUS-FNA and EBUS-TBNA is presumably more accurate than PET-CT, only a few reports have quantitatively evaluated its diagnostic ability. Therefore, we prospectively assessed the diagnostic yield of this combined endoscopic approach for mediastinal N staging of lung cancer. METHODS: A consecutive series of 120 patients with suspected resectable lung cancer on CT findings underwent PET-CT and combined EUS-FNA/EBUS-TBNA. The accuracy and other diagnostic indices of the combined approach in mediastinal N staging were compared with those of PET-CT. RESULTS: Among the enrolled patients, a final pathological N stage was established in 110 patients. The accuracy of the combined approach using EUS-FNA and EBUS-TBNA was significantly higher than that of PET-CT (90.0 % vs. 73.6 %; P < 0.0001). The sensitivity, specificity, and positive and negative predictive values were respectively 71.8 %, 100 %, 100 %, and 86.6 % for the combined approach vs. 47.4 %, 87.5 %, 66.7 %, and 75.9 % for PET-CT. CONCLUSIONS: The combined endoscopic approach using EUS-FNA and EBUS-TBNA provided excellent diagnostic performance. Therefore, this approach is strongly recommended before surgery or mediastinoscopy to avoid futile thoracotomy and surgical intervention.

Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease.

BACKGROUND: Identification of neuronal progenitor/stem cells in the postnatal gut suggests the development of transplantation approaches to enteric nervous system (ENS) diseases. Many clinical applications would require engrafting large segments of postnatal gut in vivo. We investigated the ability of unselected gut cells vs selected enteric neural crest stem cells (eNCSCs) to engraft and differentiate in the postnatal gut in the Hirschsprung disease (HD, ednrb(sl/sl)) rat. METHODS: Total intestinal cells or eNCSCs (α(4) integrin(+), p75(++)) from embryonic day (E)14.5 rats carrying a marker transgene (human placental alkaline phosphatase, hPAP) were injected intraperitoneally (i.p.) into neonatal HD rats and their healthy littermates. The entire gut was systematically analyzed 3 weeks later for hPAP(+) cells between the serosal surface and the muscularis mucosae. Engrafted cells were examined for HuC/D, S-100B, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) expression. KEY RESULTS: No rats (0/33) injected with unselected cells had hPAP(+) cells in the ENS that expressed neuronal or glial markers. 5/11 healthy and 4/5 HD rats injected with eNCSCs showed widespread but low density engraftment in the ENS with cells expressing neuronal or glial markers. Neurons expressed nNOS and VIP. There was no engraftment in the colon of either HD or wildtype rats. CONCLUSIONS & INFERENCES: Enteric neural crest stem cells will engraft diffusely throughout the postnatal gut of HD rats and differentiate into neurons and glia. Engraftment is not uniform, likely related to age-dependent changes in the gut mesenchyme. Intraperitoneal injection is easily performed in sick neonates and may be developed as a technique to supply exogenous ENS cells to the diseased postnatal gut.

Concurrent chemoradiation alone with curative intent for limited-disease small-cell esophageal cancer in nine Japanese patients.

Small-cell carcinoma of the esophagus is a rare and aggressive tumor with early widespread dissemination. In this retrospective study, we report clinical outcomes of limited-disease small-cell carcinoma of the esophagus from the analysis of nine patients. Between 2003 and 2006, nine consecutive patients with small-cell carcinoma of the esophagus were treated in our single institution, representing 2.8% of all esophageal malignancies treated with curative concurrent chemoradiation during this period. All the patients received four cycles of etoposide (100 mg/m(2), days 1-3), combined with cisplatin (80 mg/m(2), day 1), plus radiation therapy (50 Gy in daily doses of 2 Gy, 5 days/week). At the time of analysis, the median follow-up time was 10.8 months (range: 4.2-42.8 months) and 21.8 months in five living patients (56%). Of all the nine patients, five patients (56%) had a complete response, and the actuarial 3-year overall survival rate was 55.6%. This regimen resulted in a favorable 3-year survival rate. We conclude that the optimum treatment seems to be the same as for small-cell carcinomas of the lung, that is, a multidrug combination chemotherapy regimen used with concurrent radiation.

Extensor tendon rupture associated with osteoarthritis of the distal radioulnar joint.

Non-rheumatoid osteoarthritis of the distal radioulnar joint can cause extensor tendon rupture. We analysed the radiographic morphology of the distal radioulnar joint to identify the risk factors for this complication. Forty-one wrist X-rays of 37 patients with extensor tendon rupture caused by distal radioulnar joint osteoarthritis were evaluated retrospectively for the severity of osteoarthritis by the Kellgren/Lawrence scoring system. Measurements were obtained from posteroanterior views. All but one wrist had severe osteoarthritic changes exceeding grade 3. The radiographic features that were different from those of the contralateral wrists included deepening and widening of the sigmoid notch, radial shift of the ulnar head and dorsal inclination of the sigmoid notch. There was no significant association between tendon rupture and the morphology of the ulnar head or ulnar variance. The scallop sign, dorsal inclination of the sigmoid notch and radial shift of the ulnar head are radiological risk factors for extensor tendon ruptures.

The two locations of ganglions causing radial nerve palsy.

Ganglions associated with radial nerve palsy at two different locations were identified at the elbow in 14 patients. The first type, found in 13 patients, arose from the anterior capsule of the proximal radioulnar joint and was located proximal to the proximal edge of the supinator muscle. It compressed the main radial nerve anteriorly. The second type, which has not been reported before in patients without abnormalities in the elbow joint, was found in the remaining patient. It was located in the supinator muscle, distal to the proximal edge of the supinator muscle, and compressed the posterior interosseous nerve against the proximal radius. Magnetic resonance imaging makes it possible to identify ganglions in a wide area around the elbow. This examination should be carried out in view of the possible presence of both types of ganglion. Magnetic resonance imaging also provides more accurate information than computed tomography or ultrasonography about the location and characteristics of the mass.

Closed rupture of the flexor tendons of the index finger caused by a pathological fracture secondary to an intraosseous ganglion in the lunate.

We report a rare occurrence of attritional rupture of both flexor tendons of the right index finger in a 71 year-old man with a pathological fracture of the lunate arising from an intraosseous ganglion.

Closed rupture of the flexor tendons of the little finger secondary to non-union of fractures of the hook of the hamate.

We report six patients with closed flexor tendon rupture affecting the little finger, occurring secondarily to non-union of the hook of the hamate bone. The ununited fragments were separated from the basal part of the hook by more than 1mm. The fragments were also rounded and showed marginal sclerosis. Non-union was located in the middle part of the hook in three patients, the tip in two, and the base in one. At operation, the fragments were removed in all patients. Five patients were treated by free tendon grafts using three palmaris and two plantaris grafts and one underwent tendon transfer. Postoperative total range of active motion of the little finger averaged 218 degrees (range 185-265 degrees ). All patients returned to their original employment. This series would suggest that flexor tendon rupture can occur after fracture of the hook of the hamate bone, even when the ununited fragment is small and/or rounded.

Treatment of unruptured cerebral aneurysms; a multi-center study at Japanese national hospitals.

The treatment and natural course of unruptured cerebral aneurysms were analyzed in 615 patients with 712 unruptured cerebral aneurysms registered from seven Japanese national hospitals and Zurich University hospital. For 209 aneurysms in 181 cases, the natural course of the aneurysms was observed without surgical treatment. During the follow-up period of 3,862 months (321.8 years), 11 of these aneurysms ruptured giving a rupture rate of 3.42%/year. Five of these 11 aneurysms were less than 10 mm in diameter. Seventeen aneurysms of these 209 untreated aneurysms had blebs. Seven of these 17 aneurysms ruptured yielding the high rupture rate of 28.3%/year. The likelihood of unruptured cerebral aneurysms to rupture was not exceedingly low even when the aneurysms were smaller than 10 mm. Since the risk of rupture and morbidity in relation to surgical treatment cannot be predicted by size alone, the morphology, especially the presence of blebs, should be considered when treating unruptured cerebral aneurysms. In 434 patients, 503 cerebral aneurysms were treated surgically either by craniotomy in 472 aneurysms or endovascular coil embolization in 31 aneurysms. Surgical outcome was influenced by the presence of concurrent diseases, patient age, size and location of the aneurysms. Complications after surgical treatment of 128 incidentally found aneurysms were reported in four cases; three cases of hemiparesis and one case showing disturbance of higher brain function, with a morbidity rate of 3.1%. These results suggest that surgical treatment may be acceptable in cases of incidentally found cerebral aneurysms, especially when blebs are present.

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers.

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues.

Radiation-induced cerebral aneurysm successfully treated with endovascular coil embolization.

In a 30-year-old male, multiple cerebral aneurysms developed 19 years after receiving 60 Gy of irradiation for craniophariginoma. Angiogram revealed right IC-PC and upper basilar trunk aneurysms in addition to atherosclerotic change. The right IC-PC aneurysm was wrapped and the basilar trunk aneurysm located between the origins of SCA and AICA was treated by endovascular coil embolization. The packing of the aneurysm was complete, but stenosis of the basilar artery appeared. The patient was discharged uneventfully and follow-up angiogram 6 months later demonstrated that the aneurysm had disappeared and the patency of the basilary artery had been preserved. Radiation-induced intracranial vasculopathy is a well-recognized phenomenon, but aneurysm formation is less common than arterial occlusive lesion. However, the mortality rate after bleeding is so high that immediate diagnosis and treatment by direct surgery or coil embolization are necessary.

Callus resection for brachial plexus compression following stress-induced first rib fracture.

A 27-year-old man presented with a lower trunk brachial plexus injury due to excessive callus formation following a stress-induced first rib fracture. The callus, but not the first rib, was resected through a supraclavicular approach. His symptoms resolved in 2 months, and no recurrence was seen at 2 years follow-up.

Ghrelin in neonatal rats: distribution in stomach and its possible role.

Ghrelin, a 28 amino acid peptide, has recently been isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. The fact that administration of ghrelin, centrally or peripherally, stimulates both food intake and GH secretion suggests that stomach ghrelin has an important role in the growth of rats. We used immunohistochemistry and radioimmunoassay to determine the age at which ghrelin-immunostained cells begin to appear in the rat stomach. Ghrelin-immunoreactive cells were found to be expressed in the fetal stomach from pregnancy day 18. The number of ghrelin-immunoreactive cells in the fetal stomach increased as the stomach grew. The amount of ghrelin in the glandular part of the rat stomach also increased, in an age-dependent manner, from the neonatal stage to adult. Eight hours of milk restriction significantly decreased the ghrelin concentration in the stomachs of 1-week-old rats, and increased the ghrelin concentration in their plasma. Administration of ghrelin to 1- and 3-week-old rats increased plasma GH concentrations. The daily subcutaneous administration of ghrelin to pregnant rats from day 15 to day 21 of pregnancy caused an increase in body weight of newborn rats. In addition, daily subcutaneous administration of ghrelin to neonatal rats from birth advanced the day of vaginal opening from day 30.7+/-0.94 to day 27.9+/-0.05. These results suggest that ghrelin may be involved in neonatal development.

Evaluation of the epidermal growth factor receptor (EGFR) and c-erbB-2 in superspreading-type and penetrating-type gastric carcinoma.

The expression of epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), transforming growth factor alpha (TGF alpha), and of c-erbB-2 was immunohistochemically investigated in resected gastric carcinoma (in 39 cases of superspreading type and in 11 cases of penetrating type), to understand the differential biological features of these two types of gastric carcinoma. EGF, EGFR and c-erbB-2 positive cases were preferentially found in penetrating type rather than in superspreading type (p < 0.05, p < 0.01, and p < 0.05, respectively). The positive rates of EGFR and c-erbB-2 were significantly higher in submucosal gastric carcinoma than in intramucosal gastric carcinoma (p < 0.01, p < 0.05, respectively). These results suggested that the autocrine mechanism of the growth factors and the expression of c-erbB-2 were correlated to the degree of gastric wall invasion.

Human herpesvirus 8 DNA in HIV-negative Japanese patients with multicentric Castleman's disease and related diseases.

Multicentric Castleman's disease (MCD) is a lymphoproliferative disorder characterized by systemic lymphadenopathy and hypergammaglobulinemia. Recently, a French group reported that human herpesvirus 8 (HHV8) DNA was detected in tissue samples of MCD patients. The detection rate was especially high in human immunodeficiency virus (HIV)-positive MCD patients. Thus, HHV8 infection seems to be closely related to HIV infection. In Japan, the HIV infection rate in the general population is very low. To examine whether HHV8 is actually related to MCD in Japan, we performed nested polymerase chain reaction for the HHV8 genome using DNA samples from 7 patients with MCD and 23 patients with related diseases such as POEMS syndrome, amyloidosis, myeloma and lymphoma. They were all HIV-negative Japanese. Three of 7 MCD patients were positive for HHV8. There were no clear differences in clinical characteristics between HHV8-positive patients and negative ones. All other patients were negative for HHV8. Thus, we have shown that some MCD patients in Japan are also infected with HHV8.

Glassy cell carcinoma of the uterine cervix: combination chemotherapy with paclitaxel and carboplatin in recurrent tumor.

Combination chemotherapy with paclitaxel and carboplatin every 4 weeks for 3 cycles was administered for recurrent glassy cell carcinoma of the uterine cervix in a 67-year-old Japanese female. The response rate was 56% under computed tomography (partial response). However, the effect was transient even with follow-up radiotherapy, and further cases need to be accumulated to determine a successful treatment modality.