Randomized, Open-Label, Phase IV, Korean Study of Kidney Transplant Patients Converting From Cyclosporine to Prolonged-Release Tacrolimus Plus Standard- or Reduced-Dose Corticosteroids.

BACKGROUND: This 24-week, multicenter, randomized, exploratory, comparative, open-label, phase-IV study assessed the safety and efficacy of prolonged-release tacrolimus (PR-T) with reduced-dose versus standard-dose corticosteroids in stable kidney transplant recipients in Korea after converting from cyclosporine-based therapy. METHODS: At baseline, patients were converted from cyclosporine-based to PR-T-based immunosuppression and randomized (1:1) to receive either corticosteroids maintained at prestudy dose (standard-dose group) or tapered from week 4 to 50% of the prestudy dose by week 12 (reduced-dose group). Patients were seen at baseline and weeks 1, 4, 12, and 24. The primary endpoint was change in estimated glomerular filtration rate (Modification-of-Diet-in-Renal-Disease-4) between baseline and week 24. Secondary endpoints included either acute rejection or patient-reported satisfaction with PR-T. Adverse events (AEs) were recorded. RESULTS: Overall, 150 patients were randomized into a reduced-dose group (n = 73) and a standard-dose group (n = 77). At week 24, mean ± standard deviation for corticosteroid dose was 2.5 ± 0.9 mg and 5.0 ± 1.3 mg, respectively. Mean change in estimated glomerular filtration rate from baseline to week 24 was +1.5 ± 9.1 mL/min/1.73 m2 (P = .1567) and +3.4 ± 10.6 mL/min/1.73 m2 (P = .0065), respectively, and not significantly different between groups. There were no acute rejection episodes. Most respondents (>70%) considered PR-T more convenient than cyclosporine. AE incidence was similar between groups. The most common AEs experienced by ≥3% of patients in either treatment group were gastrointestinal events (20.8% and 28.6% of patients receiving reduced- and standard-dose corticosteroids, respectively). Most AEs in both treatment groups were mild or moderate in severity. CONCLUSION: Renal function was maintained following conversion from cyclosporine to PR-T, irrespective of corticosteroid regimen; PR-T enables reduced corticosteroid dosage.

A Case Series of Asymptomatic Hemodialysis Catheter-Related Right Atrial Thrombi That Are Incidentally Detected Prior to Kidney Transplantation.

A hemodialysis (HD) catheter-related right atrial thrombus (RAT) is rarely encountered prior to kidney transplantation (KT) but necessitates a decision about whether to anticoagulate and/or delay the surgery. There is controversy surrounding the clinical implications of a RAT in this situation. It is sometimes considered fatal but other opinions consider it to be benign, especially when incidentally detected. We reviewed the clinical characteristics, management, and outcomes of a patient series with HD catheter-related RAT detected prior to KT and speculated on its clinical significance. Among 3677 cases of KT performed on 3607 patients between January 1997 and September 2015 in our single tertiary center, 11 cases of HD catheter-related RAT detected on transthoracic echocardiography (TTE) prior to KT were included for analysis. The average maximal diameter of the RAT was 23.2 ± 16.3 (SD in mm) and 9 (81.8%) of these 11 patients had no symptoms associated with the RAT. Four patients (36.3%) had their catheters replaced, 5 patients (45.5%) had their catheters removed, and the catheters were maintained in the remaining 2 patients (18.2%). Six patients (54.5%) were anticoagulated with either heparin or warfarin. However all 11 patients had a successful KT suggesting that a HD catheter-related RAT incidentally detected prior to this surgery may not be as serious as previously considered and should not be a reason for delaying the transplantation.

Development of a nomogram for predicting the probability of postoperative delirium in patients undergoing free flap reconstruction for head and neck cancer.

PURPOSE: To develop nomogram for prediction of postoperative delirium (POD) in patients undergoing ablative and reconstruction surgery for head and neck cancer. METHODS: Total 341 patients were retrospectively analyzed, and clinical variables in preoperative, intraoperative and postoperative periods were compared between delirium group (n = 89) and non-delirium group (n = 252). Multivariate logistic regression, receiver operating characteristics curve, and area under the curve (AUC) were used to generate and test a nomogram, which performance was evaluated by 10-fold cross validation (CV) procedure. RESULTS: In univariate and multivariate analysis, age, history of psychiatric disorder, marital status, preoperative numeric rating scale for pain, ASA classification, and ICU stay period were identified as significant risk factors. Using these factors, nomogram for predicting the POD was developed and it showed sensitivity of 61.8%, specificity of 75.4%, PPV of 47.0%, and NPV of 84.8% (Youden's index of 0.372). In 10-fold cross validation set, corresponding values were 44.9%, 84.1%, 50.0% and 81.2% (Youden's index of 0.337). AUC was comparable between two sets (0.7407 and 0.6898). CONCLUSIONS: Proposed nomogram showed fair discriminative power for POD risk in head and neck cancer patients undergoing major surgery.

Risk Factors for Hypertension After Living Donor Kidney Transplantation in Korea: A Multivariate Analysis.

BACKGROUND: Post-transplantation hypertension is very common and is associated with cardiovascular complications and poor graft survival in kidney transplant recipients. This study aimed to identify risk factors for hypertension after living donor kidney transplantation. METHODS: We retrospectively analyzed patients who underwent renal transplantation between January 2009 and April 2012. Hypertension was defined as the use of antihypertensive medications at 12 months post-transplantation. Student t test and chi-squared test were performed for univariate analysis. Logistic regression analysis was performed for multivariate analysis. RESULTS: Five-hundred thirty-nine patients were enrolled in the analyses. The rate of antihypertensive medication use was 67% at 12 months. In multivariate analysis, male gender (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.55-4.61), pretransplantation hypertension (OR, 4.65; 95% CI, 2.14-10.11), donor hypertension (OR, 3.23; 95% CI, 1.05-9.96), high body mass index (BMI; OR, 1.21; 95% CI, 1.12-1.29), and use of cyclosporine (OR, 2.05; 95% CI, 1.28-3.27) were associated with post-transplantation hypertension. CONCLUSION: These data show that male recipient, hypertension before transplantation, donor hypertension, high BMI, and cyclosporine use were independent factors associated with hypertension. It would be useful to predict and prevention the hypertension after kidney transplantation.

Neuregulin-1 protects against neurotoxicities induced by Swedish amyloid precursor protein via the ErbB4 receptor.

Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain and exhibits potent neuroprotective properties. However, little information on its role in Alzheimer's disease (AD) is known. The neuroprotective effect and mechanisms of NRG1 in SH-SY5Y cells overexpressing the Swedish mutant form of amyloid precursor protein (Swe-APP) and primary cortical neuronal cells treated with amyloid beta peptide(1-42) (Aß(1-42)) were investigated in this study. NRG1 attenuated Swe-APP- or Aß(1-42)-induced lactate dehydrogenase (LDH) release in a concentration-dependent manner. The mitigating effects of NRG1 on neuronal cell death were blocked by ErbB4 inhibition, a key NRG1 receptor, which suggests a role of ErbB4 in the neuroprotective function of NRG1. Moreover, NRG1 reduced the number of Swe-APP- and Aß(1-42)-induced TUNEL-positive SH-SY5Y cells and primary cortical neurons, respectively. NRG1 reduced the accumulation of reactive oxygen species and attenuated Swe-APP-induced mitochondrial membrane potential loss. NRG1 also induced the upregulation of the expression of the anti-apoptotic protein, Bcl-2, and decreased caspase-3 activation. Collectively, our results demonstrate that NRG1 exerts neuroprotective effects via the ErbB4 receptor, which suggests the neuroprotective potential of NRG1 in AD.

Neurothekeoma of the tongue: CT, MR, and FDG PET imaging findings.

We report CT, MR, and fluorodeoxyglucose-positron-emission tomography (FDG-PET) imaging findings of a case of cellular neurothekeoma of the tongue, a rare benign soft-tissue tumor with neural differentiation, occurring in a 15-year-old girl. CT and MR imaging showed a well-defined, well-enhancing submucosal soft-tissue mass in the midline dorsal tongue. There was high FDG uptake on PET scans. Although imaging findings are rather nonspecific, neurothekeoma may be one of diagnostic inclusions of soft-tissue masses of the tongue in a young female patient.

Replacement of a tracheal defect with autogenous mucosa lined tracheal prosthesis made from polypropylene mesh.

Reliable prosthetic or tissue grafts for the trachea have not, as yet, been developed for reconstruction of large, circumferential tracheal defects. Major limitations are anastomotic dehiscence and stenosis, attributed to the poor epithelialization and vascularization of the prosthetic graft. We have developed a new tracheal prosthesis that has a well vascularized and viable mucosa. The prosthesis consists of a Prolene mesh reinforced with polypropylene rings, and coated with gelatin. We lined the luminal surface of the prosthesis with transplanted autogenous oral mucosa, wrapped the prosthesis with greater omentum, and placed it in the peritoneal cavity for 2 weeks. Complete surgical resection and replacement of a segment (5 cm in length, 8 to 10 tracheal rings) of the thoracic trachea was then performed in nine adult mongrel dogs. The transplanted mucosa was well vascularized and maintained its normal histology in prereplacement analysis. Dogs with tracheal replacement regained their full activity and did not show any respiratory problems until sacrifice at 1, 2, and 6 months. After 6 months, the prostheses were completely incorporated by the host trachea in all dogs and confluent epithelialization was confirmed histologically from the upper to the lower anastomotic site of the prosthesis; furthermore, the transplanted mucosal cells had changed to ciliated columnar epithelium.

Intracellular accumulation of mannopine, an opine produced by crown gall tumors, transiently inhibits growth of Agrobacterium tumefaciens.

pYDH208, a cosmid clone from the octopine-mannityl opine-type tumor-inducing (Ti) plasmid pTi15955 confers utilization of mannopine (MOP) and agropine (AGR) on Agrobacterium tumefaciens strain NT1. NT1 harboring pYDH208 with an insertion mutation in mocC, which codes for MOP oxidoreductase, not only fails to utilize MOP as a sole carbon source, but also was inhibited in its growth by MOP and AGR. In contrast, the growth of mutants with insertions in other tested moc genes was not inhibited by either opine. Growth of strains NT1 or UIA5, a derivative of C58 that lacks pAtC58, was not inhibited by MOP, but growth of NT1 or UIA5 harboring pRE10, which codes for the MOP transport system, was inhibited by the opine. When a clone expressing mocC was introduced, the growth of strain NT1(pRE10) was not inhibited by MOP, although UIA5(pRE10) was still weakly inhibited. In strain NT1(pRE10, mocC), santhopine (SOP), produced by the oxidation of MOP by MocC, was further degraded by functions encoded by pAtC58. These results suggest that MOP and, to a lesser extent, SOP are inhibitory when accumulated intracellularly. The growth of NT1(pRE10), as measured by turbidity and viable cell counts, ceased upon the addition of MOP but restarted in a few hours. Regrowth was partly the result of the outgrowth of spontaneous MOP-resistant mutants and partly the adaptation of cells to MOP in the medium. Chrysopine, isochrysopine, and analogs of MOP in which the glutamine residue is substituted with other amino acids were barely taken up by NT1(pRE10) and were not inhibitory to growth of the strain. Sugar analogs of MOP were inhibitory, and those containing sugars in the D form were more inhibitory than those containing sugars in the L form. MOP analogs containing hexose sugars were more inhibitory than those containing sugars with three, four, or five carbon atoms. Mutants of NT1(pRE10) that are resistant to MOP arose in the zone of growth inhibition. Genetic and physiological analyses indicate that the mutations are located on pRE10 and abolish uptake of the opine.

Interleukin 12 gene therapy of cancer by peritumoral injection of transduced autologous fibroblasts: outcome of a phase I study.

A phase I dose-escalation clinical trial of peritumoral injections of interleukin 12 (IL-12)-transduced autologous fibroblasts was performed in patients with disseminated cancer for whom effective treatment does not exist. The goals of this study were to assess the safety and toxicities as well as the efficacy, and ancillarily the immunomodulatory effects, of peritumoral IL-12 gene transfer. Primary dermal fibroblasts cultured from the patients were transduced with retroviral vector carrying human IL-12 genes (p35 and p40) as well as the neomycin phosphotransferase gene (TFG-hIL-12-Neo). Patients received four injections at intervals of 7 days. Nine patients were enrolled in this dose-escalation study, with secreted IL-12 doses ranging from 300 ng/24 hr for the first three patients to 1000, 3000, and 5000 ng/24 hr for two patients in each subsequent dosage level. Although a definite statement cannot be made, there appears to be perturbation of systemic immunity. Also, the locoregional effects mediated by tumor necrosis factor alpha (TNF-alpha) and CD8+ T cells were observed with tumor regression. Treatment-related adverse events were limited to mild to moderate pain at the injection site; clinically significant toxicities were not encountered. Transient but clear reductions of tumor sizes were observed at the injected sites in four of nine cases, and at noninjected distant sites in one melanoma patient. Hemorrhagic necrosis of tumors was observed in two melanoma patients. These data indicate that gene therapy by peritumoral injection of IL-12-producing autologous fibroblasts is feasible, and promising in patients with advanced cancer.

Surgical tactics and outcome of treatment in jugular foramen schwannomas.

Seven patients with schwannomas of the jugular foramen were included our study in Samsung Medical Center between 1995 and 1999. Patients with neurofibromatosis were excluded. The records of the seven patients (six surgical case and one nonsurgical case) were retrospectively reviewed. There were six women and one man (mean age, 47 years) with a symptom duration ranging from 3 months to 14 years (mean, 47 months). The predominant symptoms were hearing difficulty, hemifacial spasm and hoarseness. Preoperative audiologic evaluation, computerised tomography (CT), magnetic resonance (MR) imaging, and angiography were performed in most patients. We classified tumours into four types using Kaye and Pellet classification on the basis of radiological and surgical findings. The tumours were: Type A (at cerebellopontine angle) in one; Type B (foraminal) in two; Type C (extracranial and/or foraminal) in two; and Type D (intra- and extracranial) in two cases. We used various surgical approaches such as retrosigmoid suboccipital craniectomy for Type A tumours, infratemporal fossa type A approach (ITFA) for Type C tumours, petro-occipital transsigmoid approach or modified transcochear approach for Type D tumours and ITFA with partial labyrinthectomy for Type B. In the selection of surgical approaches, we took consideration of tumour extension, tumour size, and preoperative hearing function. Facial nerve transposition was not used only in one case of ITFA because of small tumour size (1.5cm). Gross total removal was achieved in five cases, and subtotal removal in one case (Type D tumour) with a single-stage operation. Stereotactic radiosurgery was performed on residual mass in the subtotally removed case. Follow-up period ranged from 13 to 49 months (mean, 27.5 months). There was neither postoperative mortality nor recurrence on follow-up MR imaging. There were two cases of temporary facial nerve palsy and one aggravation of pre-existing low cranial palsy. Two case of sustained vocal cord palsy underwent thyroplasty, but there was no aspiration pneumonia. Persistent cerebrospinal fluid collection was improved with lumboperitoneal shunt. The surgical approaches of each case should be tailored according to their shape and the clinical manifestation. We obtain acceptable outcomes from one-stage operation.

CHOP followed by involved field radiation: is it optimal for localized nasal natural killer/T-cell lymphoma?

The present study aimed to analyse the treatment outcome of four cycles of CHOP (cyclophosphamide-vincristine-doxorubicin-prednisolone) followed by involved field radiation therapy (IF RT) for the treatment of stage I-II nasal natural killer (NK)/T-cell lymphoma. From March 1995 to December 1999, 17 patients (median age 41 years; range 30-66) with localized nasal NK/T-cell lymphoma were enrolled. B symptoms were noted in five patients (31%). Sixteen of seventeen patients (94%) were of low risk when classified according to the International Prognostic Index (IPI). The treatment plan consisted of four cycles of CHOP chemotherapy followed by IF RT of 45 Gy. Two patients received radiation during the first or second cycle of CHOP because of bleeding from the primary tumour site. Both patients achieved complete responses (CRs). In the remaining 15 patients, after 4 cycles of CHOP, 6 CRs and 3 partial responses (PRs) were achieved (53% of response rate). IF RT was given to six patients (four in CR, one in PR and one in PD), and all six patients achieved CR. Overall, CR was achieved in 10 of 17 patients (58%). The planned sequential chemoradiotherapy was completed in only 6 of 17 patients (35%) because of the progression during chemotherapy. None of the patients who achieved CR experienced relapse of lymphoma during follow-up. The estimated overall three-year survival rate was 59%. In univariate analysis, B symptoms and stage were significant prognostic factors for response and overall survival (P < 0.05). The present study suggests that four cycles of CHOP followed by IF RT is not satisfactory for treating patients with localized nasal NK/T-cell lymphoma, and that further exploration for improved therapy is needed.

The short head of the biceps femoris as a monitor for the free lateral thigh flap in pharyngoesophageal reconstruction.

Free flaps are frequently used to reconstruct the defect following radical resection of pharyngoesophageal malignancy but postoperative monitoring of buried flaps is difficult. We have designed a monitoring-muscle flap using the short head of the biceps femoris muscle when using a free lateral thigh flap. The third and fourth perforators of the profunda femoris artery, the main vascular pedicle of the lateral thigh flap, pass through the short head of the biceps femoris. Partial excision of the short head of the biceps femoris muscle does not result in any functional disturbance of the leg, and the viability of the buried lateral thigh flap can be monitored by observing the exposed muscle through a small window in the neck. Between April and October 1998 five patients underwent pharyngoesophageal reconstruction by this method. The short head of the biceps femoris was used to monitor the main flap in three patients and to obliterate the dead space after neck dissection in two patients. There were no recipient-site complications such as fistula or infection and no disturbance of thigh function.

Development of new tracheal prosthesis: autogenous mucosa-lined prosthesis made from polypropylene mesh.

Reliable tracheal or tissue graft has not been developed yet for the reconstruction of large, circumferential tracheal defects. Major limitations were anastomotic dehishence and stenosis, which were attributed to the poor epithelisation of the prosthetic graft. We developed a new tracheal prosthesis that has a viable lined and well-vascularized mucosa. The prosthesis consists of Prolene mesh reinforced with polypropylene rings, and is coated with gelatin. In addition, we lined the luminal surface of the prosthesis with transplanted autogenous oral mucosa and wrapped the prosthesis with greater omentum. Animal experiments were performed using 10 adult mongrel dogs. The transplanted mucosa and wrapped greater omentum tightly adhered to the prosthesis to make a single unit within two weeks. The mucosa survived well, was well vascularised by new vessels from greater omentum and showed normal histology. Complete surgical resection and replacement of a thoracic trachea (3 cm in length, 6 tracheal rings) were carried out in 2 dogs, which survived well with normal activity. We concluded that this highly biocompatible tracheal prosthesis could be very useful for step-wise reconstruction of tracheal defects.

Polymerase chain reaction detection of Mycobacterium tuberculosis from fine-needle aspirate for the diagnosis of cervical tuberculous lymphadenitis.

BACKGROUND: Despite its well-established usefulness in the diagnosis of cervical tuberculous lymphadenitis, fine-needle aspiration cytology (FNAC) has several limitations in its clinical applications, especially when the presence of acid-fast bacilli is not proven. Furthermore, fine-needle aspirate is sometimes inadequate for diagnosis, and the sensitivity and specificity of this technique for cervical tuberculous lymphadenitis has not been firmly established. OBJECTIVE: The authors performed Mycobacterium tuberculosis polymerase chain reaction (PCR) for mycobacterial DNA sequences from the remainder of fine-needle aspirate after cytological examination and evaluated its diagnostic efficacy in clinical situations. METHODS: Conventional diagnostic procedures including FNAC and M tuberculosis PCR were performed simultaneously in 29 cases that had been suspected to be cervical tuberculous lymphadenitis on patients' first visit. The results of FNAC and M tuberculosis PCR were compared with the clinical outcomes after several months of follow-up and pathological results from open biopsy of some cases. RESULTS: Among the 17 cases of cervical tuberculous lymphadenitis diagnosed in clinical situations, M tuberculosis DNA was found by PCR in 13 cases (76.4%). Negative findings on PCR were achieved in 12 cases, which revealed non-granulomatous lymphadenopathy. CONCLUSION: From these results, we conclude that M tuberculosis PCR using the remainder of aspirate for cytological examination is a very useful tool for the diagnosis of cervical tuberculous lymphadenitis, and its clinical application with FNAC could reduce the necessity for open biopsy.

Fractionated stereotactic radiation therapy for locally recurrent nasopharynx cancer: report of three cases.

BACKGROUND: This article reports on experience with fractionated stereotactic radiation therapy (FSRT) for locally recurrent nasopharynx cancer. METHODS: Three patients with locally recurrent nasopharynx cancer were given FSRT as reirradiation between September 1995 and August 1996. Application of FSRT was the third radiation therapy in two patients. Authors used the individually made relocatable Gill-Thomas-Cosman (GTC) stereotactic frame, and the radiation dose planning was performed using XKnife-3. The total doses to the recurrent tumor were 45 Gy/18 fractions in two patients, who were given concurrent chemotherapy as a radiosensitizer, and 50 Gy/20 fractions in the other patient. In all three patients the dose per fraction was 2.5 Gy, and the fraction schedule was to give five daily treatments per week. RESULTS: Authors observed satisfactory symptomatic improvement and remarkable objective tumor size decrease through the magnetic resonance (MR) images taken one month post-FSRT in all three patients. No neurological side effect was observed. All three patients died with regional and distant seeding outside the FSRT field at seven, nine, and nine months, respectively. CONCLUSION: FSRT as reirradiation for locally recurrent nasopharynx cancer seemed to be effective and safe.

Head and neck reconstruction using lateral thigh free flap: flap design.

Eleven lateral thigh free flaps were used in head and neck reconstruction, transferred on the basis of the second perforator as well as the third perforator of the profunda femoris artery. The lateral thigh free flap was useful and reliable in head and neck reconstruction and was versatile in flap design. Due to the wide cutaneous territory of the lateral thigh flap, the skin island could be designed freely in the lateral thigh region. Careful patient selection is mandatory for good results. The pinch test and an understanding of the variety of subcutaneous thicknesses in the lateral thigh region are helpful in designing a skin island of adequate thickness. Other considerations in flap design are discussed.

The significance of CT scan or MRI in the evaluation of salivary gland tumors.

Imaging modalities such as CT scan or MRI are frequently employed for the diagnosis of neoplastic lesions in the salivary glands. To evaluate the efficacy of the CT scan and the MRI in differentiating malignant neoplasm from benign lesions, 120 CT scans and 31 MRIs were retrospectively analyzed from 147 patients with salivary gland masses. All images were analyzed focusing on the presence of several relevant features. The pathologic results were matched with radiological features and also tabulated with radiological assessment. For the CT scans, the contour and margin of the lesion and tissue plane obliteration were found to be statistically significant indicators for malignant neoplasms. Among 69 CT scans interpreted as 'benign' by a radiologist, five cases (7%) were histologically diagnosed as 'malignant'. On the other hand, 20 out of 51 CT scans (39%) were misinterpreted as 'malignant'. For MRI, two out of 14 cases (14%) were radiologically misdiagnosed as 'benign' and six out of 17 patients (35%) as 'malignant'. In conclusion, whereas both the CT and MRI showed a similar level of accuracy in evaluation of salivary gland tumors, they showed a considerable tendency of misdiagnosis, especially by interpreting benign tumors as 'malignant'.