Height measurement of solder bumps using two-wavelength parallel four-step phase shifting digital holography.

Digital holography (DH) with two wavelengths (TW) that are close to each other was applied to height measurement of solder bumps having spherical specular surfaces with diameters of ∼20µm and heights of ∼20µm. We employed the parallel phase shifting method for instantaneous image capturing, and we improved the spatial resolution of our TW-DH system having two beams with different wavelengths that traveled in opposite directions in the interferometer. It gave 74-times higher repetition and 2.4-times higher spatial resolution than those in our previous DH system based on the Fourier transform method.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Gene therapy improves dental manifestations in hypophosphatasia model mice.

BACKGROUND AND OBJECTIVE: Hypophosphatasia is a rare inherited skeletal disorder characterized by defective bone mineralization and deficiency of tissue non-specific alkaline phosphatase (TNSALP) activity. The disease is caused by mutations in the liver/bone/kidney alkaline phosphatase gene (ALPL) encoding TNSALP. Early exfoliation of primary teeth owing to disturbed cementum formation, periodontal ligament weakness and alveolar bone resorption are major complications encountered in oral findings, and discovery of early loss of primary teeth in a dental examination often leads to early diagnosis of hypophosphatasia. Although there are no known fundamental treatments or effective dental approaches to prevent early exfoliation of primary teeth in affected patients, several possible treatments have recently been described, including gene therapy. Gene therapy has also been applied to TNSALP knockout mice (Alpl-/- ), which phenocopy the infantile form of hypophosphatasia, and improved their systemic condition. In the present study, we investigated whether gene therapy improved the dental condition of Alpl-/- mice. MATERIAL AND METHODS: Following sublethal irradiation (4 Gy) at the age of 2 d, Alpl-/- mice underwent gene therapy using bone marrow cells transduced with a lentiviral vector expressing a bone-targeted form of TNSALP injected into the jugular vein (n = 3). Wild-type (Alpl+/+ ), heterozygous mice (Alpl+/- ) and Alpl-/- mice were analyzed at 9 d of age (n = 3 of each), while Alpl+/+ mice and treated or untreated Alpl-/- mice were analyzed at 1 mo of age (n = 3 of each), and Alpl+/- mice and Alpl-/- mice with gene therapy were analyzed at 3 mo of age (n = 3 of each). A single mandibular hemi-section obtained at 1 mo of age was analyzed using a small animal computed tomography machine to assess alveolar bone formation. Other mandibular hemi-sections obtained at 9 d, 1 mo and 3 mo of age were subjected to hematoxylin and eosin staining and immunohistochemical analysis of osteopontin, a marker of cementum. RESULTS: Immunohistochemical analysis of osteopontin, a marker of acellular cementum, revealed that Alpl-/- mice displayed impaired formation of cementum and alveolar bone, similar to the human dental phenotype. Cementum formation was clearly present in Alpl-/- mice that underwent gene therapy, but did not recover to the same level as that in wild-type (Alpl+/+ ) mice. Micro-computed tomography examination showed that gene therapy improved alveolar bone mineral density in Alpl-/- mice to a similar level to that in Alpl+/+ mice. CONCLUSIONS: Our results suggest that gene therapy can improve the general condition of Alpl-/- mice, and induce significant alveolar bone formation and moderate improvement of cementum formation, which may contribute to inhibition of early spontaneous tooth exfoliation.

IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin.

BACKGROUND: Obesity and metabolic syndrome are the major risk factors for cardiovascular disease. Obesity is caused by increased food intake and/or decreased energy expenditure. Leptin potently inhibits food intake and promotes energy expenditure. These effects of leptin involve the activation of proopiomelanocortin (POMC) neurons in the hypothalamus arcuate nucleus (ARC). Disruption of leptin signaling in POMC neuron is considered one of the major causes for obesity. AIMS: The present study aimed to examine whether overexpression of interleukin-10 (IL-10) could substitute for the leptin action and ameliorate obesity in leptin-deficient Lep(ob/ob) mice. DESIGN: Adeno-associated virus (AAV) expressing murine IL-10 (AAV-mIL-10) was injected into the skeletal muscle to overexpress IL-10 in mice. These mice were subsequently subjected to analysis of body weight, food intake, glucose metabolism and underlying mechanisms. RESULTS: In Lep(ob/ob) mice, AAV-IL-10 ameliorated hyperphagia, obesity, glucose intolerance and insulin resistance, as well as attenuated tumor necrosis factor-α expression. The IL-10 treatment also improved glucose-induced insulin release. Furthermore, IL-10 treatment increased POMC mRNA expression in ARC and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in ARC and white adipose tissue (WAT). In neuron-specific STAT3-null mice that exhibited obesity and hyperphagia, AAV-mIL-10 administration failed to affect food intake, body weight and phosphorylation of STAT3 in WAT. CONCLUSIONS: These results demonstrate that peripheral overexpression of IL-10 induces STAT3 phosphorylation in ARC POMC neurons, and thereby ameliorates hyperphagia and obesity caused by leptin deficiency. IL-10 gene transfer may provide an effective approach for preventing progression of metabolic syndrome due to leptin resistance.

Liver Resident Macrophages (Kupffer Cells) Share Several Functional Antigens in Common with Endothelial Cells.

The identification and specific functions of Kupffer cells (KCs), a liver resident macrophage subpopulation, are still unclear. We compared KCs with peritoneal macrophages using cDNA microarray analysis and found that these cells share some antigens with endothelial cells. KCs highly express VCAM-1 and VEGF receptors (VEGF-Rs) at transcriptional and protein levels. VCAM-1 mediates the functional binding of KCs with lymphocytes and induces KC activation. Among the VEGF receptors, VEGF-R2 and VEGF-R3 were expressed on the KCs, while VEGF-R1 was expressed on other tissue macrophage subsets. VEGF120, a ligand of both VEGF-R1 and VEGF-R2, transduced strong survival and chemotactic signals through the KCs, when compared to PIGF, a VEGF-R1 ligand, indicating that VEGF-R2 plays significant roles in regulating KC activities. Expression of the VEGF-Rs was regulated by TLR4 signalling. These results suggest that the function of KCs is partly regulated by the common antigens shared with endothelial cells.

Polypharmacy of medications and fall-related fractures in older people in Japan: a comparison between driving-prohibited and driving-cautioned medications.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy is a risk factor for fall-related fractures. However, it is unclear whether polypharmacy itself is a direct risk factor. The aim of this study was to assess the association between the risk of fall-related fractures and polypharmacy of driving-prohibited and driving-cautioned medications in older outpatients. METHODS: We conducted a cross-sectional study of outpatients aged ≥65 years receiving any medication, using two sampling data sets from the October 2011 and October 2012 national insurance claims in Japan. Using logistic regression models, we analysed the association between the numbers of driving-prohibited or driving-cautioned medications administered or dispensed to patients and the occurrence of fall-related fractures. RESULTS AND DISCUSSION: In both analysis populations (n = 303 311 and n = 326 219), the adjusted odds ratio of driving-prohibited medications for the occurrence of fall-related fractures significantly increased as the number of these medications per patient increased (95% confidence interval: 0, 1-2, 3-4, 5-6, 7-8 and ≥9 medications; reference, 0·95-1·24, 1·18-1·79, 1·47-2·96, 1·26-5·21 and 1·50-15·2 in October 2011 and reference, 1·11-1·42, 1·39-2·03, 1·33-2·72, 1·53-5·49 and 1·30-13·0 in October 2012). The association was maintained even for sensitivity analyses restricted to medications administered orally or orally and by injection. However, a similar association was not observed for driving-cautioned medications. WHAT IS NEW AND CONCLUSION: Medication class is a more important risk factor for fall-related fractures rather than polypharmacy alone with no regard to medication class.

Comparison of Volumetric and Diametric Analysis in Endovascular Repair of Descending Thoracic Aortic Aneurysm.

OBJECTIVES: The aim was to evaluate computed tomography angiography (CTA) volumetric and diametric analysis after endovascular repair of descending thoracic aortic aneurysms (DTAAs) and its correlation with and applicability for clinical follow up. METHODS: Fifty-four consecutive endovascular repairs for DTAA were retrospectively evaluated from 2008 to 2014. All patients underwent pre-operative CTA and at least one post-operative CTA at 6 months. Fifty-four pre-operative and 137 post-operative CTAs were evaluated (using the Ziosoft 2 software) to analyze the aneurysm and thrombus volume, the maximum aneurysm diameter, and their changes at the last follow up CTA (mean 30.5 months; range 6.5-66.4 months). A statistical analysis was performed to assess the correlation between diameter and volume changes, as well as association with endoleaks. The cut off point to predict endoleaks was determined using a receiver operating characteristic (ROC) curve. The predictive accuracy of volume change versus diameter change for Type I endoleak was analyzed. RESULTS: The mean pre-operative aneurysm diameter, aneurysm volume, and thrombus volume were 56.7 ± 11.7 mm, 145.8 ± 120.0 mL, and 48.8 ± 54.8 mL, respectively. Within the observational period, a mean decrease of -27.9 ± 30.5% in the aortic volume and -15.9 ± 15.4% in diameter was observed. Correlation between aneurysm diameter and volume changes was good (r = 0.854). Volume and diameter changes were significantly different between groups with and without endoleaks (volume change 16.9 ± 38.8% vs. -35.6 ± 23.1%, p < .001; diameter change 8.0 ± 12.1% vs. -18.8 ± 14.3%, p < .001). A pre-operative thrombus volume percentage of <11.3% and increase in aneurysm volume +11.6% were predictive factors for Type II and Type I endoleak, respectively. The accuracy of a >10% volume increase in predicting a Type I endoleak was higher (accuracy 96.3%, sensitivity 75%, and specificity 98%) than a >5 mm diameter increase (accuracy 92.6%, sensitivity 25%, and specificity 98%). CONCLUSIONS: CT volumetric analysis is a more reliable modality for predicting endoleaks after endovascular repair for DTAA than diameter analysis.

Differentiation between primary central nervous system lymphoma and glioblastoma: a comparative study of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted MRI.

AIM: To evaluate the diagnostic performance of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted magnetic resonance imaging, including first-pass slope ratio (FSR), which is potentially easier to derive than the other proposed parameters in this study, for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: Twenty-eight patients (10 PCNSLs and 18 glioblastomas) were analysed. Six perfusion parameters - corrected cerebral blood volume ratio (cCBVR), uncorrected CBV ratio (uCBVR), FSR, leakage coefficient (K2), percentage of signal-intensity recovery measured at the end of the first-pass (PSRend), and PSR measured using mean signal-intensity after the first-pass (PSRmean) - were derived from enhancing areas selected semi-automatically. Comparisons of cCBVR and uCBVR and of PSRend and PSRmean were conducted. The differences between PCNSL and glioblastoma were compared for the six parameters, and their diagnostic performance was evaluated by receiver operating characteristic curve analysis. RESULTS: For both tumours, cCBVR was significantly higher than uCBVR, and PSRend was significantly lower than PSRmean. PCNSL demonstrated lower cCBVR, uCBVR and FSR, and higher K2, PSRend and PSRmean compared with glioblastoma (p=0.0044 or less). On receiver operating characteristic curve analysis, the areas under the curve were 0.822 for cCBVR, 0.944 for uCBVR, 0.917 for FSR, 0.917 for K2, 0.933 for PSRend, and 0.894 for PSRmean. No significant difference was observed among the parameters, except cCBVR, which was significantly inferior to uCBVR. CONCLUSIONS: PCNSL can be differentiated from glioblastoma with high diagnostic value using any of the parameters, except cCBVR. FSR demonstrates high differential performance comparable to the other parameters.

Salvage chemoradiotherapy for locally advanced esophageal carcinomas.

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.

Twenty-year trends in neonatal surgery based on a nationwide Japanese surveillance program.

AIM: To discuss the chronological changes observed in a national survey of neonatal surgery in Japan performed every 5 years by the Committee in the Japanese Society of Pediatric Surgeons. METHODS: We analyzed the data obtained for 20 years from 1993 to 2013 and herein report the chronological changes. RESULTS: The number of summarized cases was least in 1993, with 2806 cases, and subsequently increased to 3753 cases in 2013. The mortality rate among the patients with maternal transport linearly decreased (p = 0.0386). Although the proportion of extremely low birth weight infants linearly increased (p = 0.0014), with an annual rate of +0.39 %, the mortality rate linearly decreased (p = 0.0010), with an annual rate of -1.68 %. Moreover, the overall mortality rate linearly decreased (p = 0.0002), with an annual rate of -0.26 %. Most diseases were observed to exhibit a decline in the mortality rate with the same trend as overall mortality. The decline in the mortality rate was most robust with respect to congenital diaphragmatic hernia (CDH). The mortality rates, except for that of CDH, omphalocele, esophageal atresia, and intestinal perforation, declined to 5 % or lower by 2013. CONCLUSIONS: The present findings may be the result of remarkable progress in perinatal management.

Influence of cerebral fluid drainage on the pharmacokinetics of vancomycin in neurosurgical patients.

The objective of this study was to retrospectively investigate the influence of cerebral fluid drainage on the serum concentrations and pharmacokinetic parameters of vancomycin (VCM). We analyzed 55 patients with normal renal function who had been hospitalized in the neurosurgical ward and received intravenous infusions of VCM. We compared the daily doses of VCM, serum VCM concentrations, serum concentration/dose ratio (C/D ratio), and pharmacokinetic parameters calculated using the Sawchuk-Zaske method between patients who underwent cerebral fluid drainage (drainage group) and controls (non-drainage group). The patients in the drainage group showed a significantly lower trough concentration of VCM (5.8 ± 3.3 µg/mL) than that shown by the non-drainage group (9.9 ± 5.4 µg/mL, p = 0.017). Further, the patients in the drainage group showed a significantly lower trough C/D ratio (0.32 ± 0.17) than that shown by the non-drainage group (0.50 ± 0.31, p = 0.047). In conclusion, cerebral fluid drainage may influence VCM pharmacokinetics. Our findings strongly suggest that a high dose of VCM is required to maintain optimal serum concentrations of VCM in patients managed with cerebral fluid drainage.

Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein.

OBJECTIVE: When endoplasmic reticulum (ER) stress, i.e., the excessive accumulation of unfolded proteins in ER, endangers homeostasis, apoptosis is induced by C/EBP homologous protein (Chop). In osteoarthritis (OA) cartilage, Chop expression and apoptosis increase as degeneration progresses. We investigated the role of Chop in murine chondrocyte apoptosis and in the progression of cartilage degeneration. METHOD: We induced experimental OA in Chop-knockout (Chop(-/-)) mice by medial collateral ligament transection and meniscectomy and compared cartilage degeneration, apoptosis, and ER stress in Chop(-/-)- and wild-type (Chop(+/+)) mice. In our in vitro experiments we treated murine Chop(-/-) chondrocytes with the ER stress inducer tunicamycin (TM) and evaluated apoptosis, ER stress, and chondrocyte function. RESULTS: In vivo, the degree of ER stress was similar in Chop(-/-)- and Chop(+/+) mice. However, in Chop(-/-) mice apoptosis and cartilage degeneration were lower by 26.4% and 42.4% at 4 weeks, by 26.8% and 44.9% at 8 weeks, and by 26.9% and 32.3% at 12 weeks after surgery than Chop(+/+) mice, respectively. In vitro, the degree of ER stress induction by TM was similar in Chop(-/-)- and Chop(+/+) chondrocytes. On the other hand, apoptosis was 55.3% lower and the suppression of collagen type II and aggrecan mRNA was 21.0% and 23.3% less, and the increase of matrix metalloproteinase-13 mRNA was 20.0% less in Chop(-/-)- than Chop(+/+) chondrocytes. CONCLUSION: Our results indicate that Chop plays a direct role in chondrocyte apoptosis and that Chop-mediated apoptosis contributes to the progression of cartilage degeneration in mice.

Association of periodontal status with occlusal force and food acceptability in 70-year-old adults: from SONIC Study.

This cross-sectional study aimed to investigate the association of periodontal status with occlusal force and food acceptability. We hypothesised that mastication deteriorated with reduced periodontal support, even when posterior occlusal contacts with natural teeth were maintained and the patients remained clinically asymptomatic. Participants were 482 independently living 69-71-year-olds, classified as Eichner's group A, having no mobile teeth and no periodontal symptoms. The periodontal probing depth (PPD) and restoration status of each tooth were examined. Occlusal force in the intercuspal position was measured with pressure-sensitive films. Food acceptability was evaluated from the difficulty experienced in chewing apples, grilled beef, and hard rice crackers. Multivariate regression analysis was performed to investigate the association of periodontal status with occlusal force and food acceptability. A P-value of <0.05 was considered statistically significant. Multiple linear regression analysis showed that occlusal force had significant negative associations with maximal PPD (standardised partial regression coefficient (ß) = -0.121) after controlling for gender, handgrip strength, number of teeth, and percentage of restored teeth. Approximately 15% of participants were included in the compromised food acceptability group. Logistic regression analyses showed that compromised food acceptability was significantly associated with PPD, after controlling for gender, number of teeth, and percentage of restored teeth. Periodontal probing depth (PPD) was significantly correlated with occlusal force and self-rated food acceptability after controlling for the possible confounding factors in septuagenarians, even those with complete posterior occlusal contacts and no tooth mobility.

Single-shot fast cinematic imaging during merging process of multiple electron filaments in electrostatic potential well.

For the first time, details of the spatial and temporal acceptable evolution of the merging process of co-rotating electron vortices in a potential well are successfully captured using a "single-shot method" with a high temporal resolution of 10 µs. Four-electron filaments are trapped inside the Beam eXperiment-Upgrade linear trap [H. Himura, Nucl. Instrum. Methods Phys. Res. A 811, 100 (2016)] with a uniform axial magnetic field and co-axial multi-ring electrodes. Images of non-emitting electron filaments are captured using a high-speed camera with up to 1 000 000 fps, a microchannel plate, a fast-decay phosphor screen of which fluorescence duration is 0.15 µs, and a super fine metallic mesh with an open area ratio of 89%. Images captured every 10 µs clearly show the growth of multiple short-wave instabilities in the wing trailing electron vortices. The experimental methods and measurement techniques presented in this paper can contribute to revealing exactly how small vortices evolve into a large structure or turbulence in a potential well through complex processes.

Influence of hypertension on pH of saliva in older adults.

BACKGROUND: Hypertension and/or antihypertensive medication reportedly induce dry mouth; however, an immediate relationship between salivary flow and hypertension has not been elucidated. OBJECTIVES: The purpose of the present study was to examine the association of hypertension and antihypertensive medication with salivary flow rate and pH in older adults. SUBJECTS: Subjects were independently living volunteers aged 60-78 years taking no medication (n = 138) or only antihypertensive medication (n = 27). Unstimulated saliva and stimulated saliva by the mastication method were collected, and salivary pH was measured. Hypertension was defined as systolic blood pressure of ≥ 140 mmHg and/or diastolic blood pressure of ≥ 90 mmHg. RESULTS: There was no significant correlation between either hypertension or intake of antihypertensive medication and unstimulated or stimulated salivary flow rate. However, multiple regression analysis showed that hypertension was significantly associated with pH of unstimulated saliva after controlling for other variables (ß = -0.270, P = 0.003). CONCLUSION: Hypertension regardless of antihypertensive medication was related to a lower pH of unstimulated saliva. Blood pressure might be a required consideration for maintenance of oral health in older individuals.

Astaxanthin ameliorates heat stress-induced impairment of blastocyst development in vitro:--astaxanthin colocalization with and action on mitochondria--.

PURPOSE: The effects of astaxanthin (Ax) on the in vitro development of bovine embryos cultured under heat stress were investigated in combination with the assessment of its cellular accumulation and action on mitochondrial membrane potential (ΔΨm). METHODS: Bovine ≥8-cell embryos were collected on day 3 after in vitro fertilization and exposed to single (day 4) or repeated (day 4 and 5) heat stress (10 h/day at 40.5 °C). Ax was added into culture medium under the repeated heat stress and blastocyst development was evaluated. The cellular uptake of Ax in embryos was examined using bright-field and confocal laser-scanning microscopy, and high-performance liquid chromatography. The relationship between Ax and mitochondria localization was assessed using MitoTracker dye. The effects of Ax on ΔΨm were investigated using JC-1 dye. RESULTS: Blastocyst development in the repeated heat stress treatment decreased significantly (P < 0.05) compared with those in single heat stress or normal thermal treatment. The addition of Ax into culture medium did lead to a significant recovery in blastocyst development in the repeated heat-treated group. Ax was detected in cytoplasm of embryos and observed to colocalize with mitochondria. Ax recovered ΔΨm in embryos that was decreased by the heat treatment. CONCLUSIONS: Ax ameliorated the heat stress-induced impairment of blastocyst development. Our results suggest that the direct action of Ax on mitochondrial activity via cellular uptake is a mechanism of the ameliorating effects.

Evaluation of incidence, predictive factors and treatment considerations for asymptomatic genitourinary granulomas after intravesical bacillus Calmette-Guérin therapy.

INTRODUCTION AND OBJECTIVES: Although the complications of intravesical BCG treatment are well described, asymptomatic genitourinary granulomas after BCG therapy have rarely been reported and management strategy for these conditions remains controversial. The objective of this study is to evaluate the incidence rate of asymptomatic genitourinary granuloma formation mimicking bladder cancer recurrence after intravesical bacillus Calmette-Guérin (BCG) therapy and to identify the diagnostic and treatment strategies according to patient conditions. PATIENTS AND METHODS: A retrospective review was conducted on 162 patients who underwent intravesical BCG therapy. For patients who developed granulomas, we evaluated the time interval between BCG instillation and the development of granuloma, the presence of acid-fast bacteria on pathology specimens, culture/polymerase chain reaction results, management strategies for the lesions, and clinical outcomes. RESULTS: Asymptomatic genitourinary masses developed in 14 patients, of whom 5 underwent histological examinations and all were confirmed to have granulomatous inflammation. The affected organs included the kidney, bladder, prostate, and penis. While four of the five patients did not receive treatment for their granulomas, one patient was administered antituberculous medication to prevent worsening of the lesion during the perioperative period of the scheduled cystoprostatectomy. None of the patients experienced worsening or recurrence of granulomatous lesions. Patients who developed asymptomatic masses (n = 14) were significantly younger than those who did not (p = 0.0076) and multivariate analysis also showed that younger age was independently associated with the development of clinically suspicious lesions (p = 0.032); however, none of the parameters were associated with histologically confirmed granuloma formation. CONCLUSIONS: Genitourinary granulomas mimicking recurrence of carcinoma may develop in nearly 10% of patients after intravesical BCG therapy. Most patients can be managed without potentially toxic antituberculosis therapy.

In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts.

T cells recognize tumor-associated antigens under the condition of lymphopenia-induced homeostatic proliferation (HP); however, HP-driven antitumor responses gradually decay in association with tumor growth. Type I interferon (IFN) has important roles in regulating the innate and adaptive immune system. In this study we examined whether a tumor-specific immune response induced by IFN-α could enhance and sustain HP-induced antitumor immunity. An intratumoral IFN-α gene transfer resulted in marked tumor suppression when administered in the early period of syngeneic hematopoietic stem cell transplantation (synHSCT), and was evident even in distant tumors that were not transduced with the IFN-α vector. The intratumoral delivery of the IFN-α gene promoted the maturation of CD11c(+) cells in the tumors and effectively augmented the antigen-presentation capacity of the cells. An analysis of the cytokine profile showed that the CD11c(+) cells in the treated tumors secreted a large amount of immune-stimulatory cytokines including interleukin (IL)-6. The CD11c(+) cells rescued effector T-cell proliferation from regulatory T-cell-mediated suppression, and IL-6 may have a dominant role in this phenomenon. The intratumoral IFN-α gene transfer creates an environment strongly supporting the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the induction of tumor-specific immunity and suppression of immunotolerance.