An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy.

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and ß-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.

Difficulty initiating sleep in patients with heart failure: Impact of left atrial pressure.

BACKGROUND: Patients with heart failure (HF) often complain of sleep discomfort. Previous reports described that difficulty initiating sleep increased the cardiovascular risk in the general population. However, the association between difficulty initiating sleep and cardiac function in patients with HF remains unclear. This study aimed to investigate the associations between difficulty initiating sleep and clinical characteristics and cardiac function in patients with HF. METHODS: Eighty-seven patients with HF who underwent overnight polysomnography for suspected sleep-disordered breathing were included. Patients were divided into two groups of the longer sleep latency (SL) group (SL ≥14 min, n = 44) and the shorter SL group (SL <14 min, n = 43). The median value of SL was defined as the time from lights-off to falling asleep. We compared the patients' characteristics, laboratory data, and polysomnographic and echocardiographic indices between the two groups. RESULTS: The patients' median age was 67 years, and 85.1 % were men. There was lower beta blocker use [25 (56.8 %) vs. 34 (79.1 %), p = 0.046] and a higher peak mitral early filling velocity to mitral annular velocity ratio (E/e') [16.5 (14.2-21.7) vs. 13.7 (10.9-16.2), p = 0.005] in the longer SL group than in the shorter SL group. In multivariate logistic analysis, E/e' (odds ratio: 1.10, 95 % confidence interval: 1.01 to 1.19; p = 0.032) and systolic blood pressure before sleeping (odds ratio: 1.05, 95 % confidence interval: 1.00 to 1.10; p = 0.033) were significantly associated with a longer SL in patients with HF. CONCLUSIONS: Increased left atrial pressure suggested by increased E/e' and increased systolic blood pressure before sleeping is independently associated with difficulty initiating sleep in patients with HF. Management of these hemodynamic imbalances is required to improve difficulty initiating sleep in patients with HF.

Hyperthyroidism in Graves Disease Causes Sleep Disorders Related to Sympathetic Hypertonia.

CONTEXT: It is well known that Graves disease (GD) causes sleep disorders (SDs). However, the characteristics and associated factors of SD and its clinical course post hyperthyroidism normalization remain unclear. OBJECTIVE: To clarify the characteristics and associated factors of subjective SD and its clinical course after GD treatment. METHODS: From November 2017 to October 2020, we enrolled 72 participants (22 newly diagnosed with GD with untreated hyperthyroidism, 20 previously diagnosed with GD with normal thyroid function, and 30 normal controls) with no other underlying SD-related diseases. We compared the groups at enrollment and conducted prospective observations after 12 months of treatment on participants with newly diagnosed GD. Main outcome measures were differences and changes in the Pittsburgh Sleep Quality Index (PSQI) global and component sleep quality scores. RESULTS: PSQI global sleep quality scores (P = .036) and sleep disturbance scores (P = .011) were significantly different among the 3 groups, and were highest in the untreated hyperthyroidism group. Multiple regression analysis demonstrated that free thyroxine level, which was positively correlated with sympathetic tone (ST) as evaluated by pulse rate, and urinary total metanephrines was associated with poorer PSQI global sleep quality scores independently of other factors (P = .006). Prospective observation showed that PSQI global sleep quality scores (P = .018) and sleep disturbance scores (P = .011) significantly improved with thyroid function normalization and ST attenuation. CONCLUSION: Hyperthyroidism caused by GD augmented ST and exacerbated subjective SD. Normalization of hyperthyroidism caused by GD improved subjective SD.

Use of Cervical Ultrasonography in Globus Sensation Investigation: A Retrospective Cohort Study.

BACKGROUND: A globus sensation is one of the most common complaints in otolaryngological practice. Patients with no associated abnormalities detected during the usual examinations performed in ENT clinics, are being diagnosed with globus sensation. Cervical ultrasonography is usually not performed in ENT clinics; however, it is useful in screening diseases of the subcutaneous tissue/organs, whose detection is not possible with the routine ENT examinations. The purpose of our study was to elucidate whether cervical ultrasound examination identifies abnormalities in patients with globus sensation. METHODS: A single-centre retrospective cohort study. Cervical ultrasonographic examinations were performed on patients with globus sensation at the Department of Otolaryngology, Head and Neck Surgery of Tottori university hospital, a tertiary care centre, from January 2013 to September 2017. The subjects were 74 patients who complained of globus sensation with no abnormality in general otolaryngological examination including laryngoscopy. RESULTS: Ultrasonography detected structural abnormalities in 60.8% of the patients with globus sensation: thyroid disorders in 41 patients, including: 35 patients with thyroid nodules, 4 patients with Hashimoto's disease, 1 patient with Grave's disease, and 1 patient with subacute thyroiditis; Sjögren syndrome in 2 patients; and cervical lipoma in 1 patient. Furthermore, 2 patients with thyroid disorders had concomitant esophageal cancer. CONCLUSION: Cervical ultrasonography identified thyroid disorders in patients with globus sensation, despite the normal ENT status. Therefore, it would be appropriate to adopt cervical ultrasonography as a routine examination at ENT clinics for patients with globus sensation.

Safe and low-dose but therapeutically effective adenovirus-mediated hepatocyte growth factor gene therapy for type 1 diabetes in mice.

AIMS: Hepatocyte growth factor (HGF) is a multifunctional cytokine that plays important roles in pancreatic physiology. Approvals of gene therapy drugs have highlighted gene therapy as an innovative new drug modality, but the very recent reports of deaths in clinical trials have provided a warning that high-dose gene therapy can cause dangerous liver toxicity. The present study aimed to develop a safe and low-dose but therapeutically effective adenovirus-mediated HGF gene therapy for streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice. MAIN METHODS: A single intravenous injection of a low dose (3 × 108 plaque forming units) of adenoviral vector expressing the HGF gene under the transcriptional control of a strong promoter, i.e., the cytomegalovirus immediate-early enhancer and a modified chicken ß-actin promoter (Ad.CA-HGF), was given to T1D mice. KEY FINDINGS: Low-dose HGF gene therapy significantly attenuated the elevation of blood glucose concentrations at the acute phase of T1D, and this effect persisted for several weeks. Temporal upregulation of plasma insulin at the acute phase was maintained at a normal level in Ad.CA-HGF-treated mice, suggesting that the therapeutic mechanism may involve protection of the remaining ß-cells by HGF. Liver enzymes in plasma were not elevated in any of the mice, including the Ad.CA-HGF-treated animals, all of which looked healthy, suggesting the absence of lethal adverse effects observed in patients receiving high intravenous doses of viral vectors. SIGNIFICANCE: A low dose of intravenous Ad-mediated HGF gene therapy is clinically feasible and safe, and thus represents a new therapeutic strategy for treating T1D.

Optimization of adenoviral gene transfer in human pluripotent stem cells.

Human pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, have the potential to differentiate into a wide variety of cells in vitro and have applications in basic developmental biology research and regenerative medicine. To understand the process of differentiation from pluripotent stem cells to functional cells, it is necessary to efficiently and safely transfer and express exogenous genes. We attempted to optimize the efficient transfer of genes into pluripotent stem cells using adenoviral vectors. Comparative study of the activities of three representative ubiquitously active promoters revealed that only the CA promoter allowed robust transgene expression in human pluripotent stem cells. In addition, we established a protocol that allowed us to efficiently introduce target genes and ensure their expression even in small numbers of cells. Adenoviral vector infection of pluripotent stem cells in single-cell suspension culture yielded high gene transfer efficiency with low cytotoxicity, without losing the undifferentiated state of the pluripotent stem cells. This optimized system will facilitate developmental biology research and regenerative medicine using pluripotent stem cells.

Clinical Utility of Qualitative Elastography Using Acoustic Radiation Force Impulse for Differentiating Benign from Malignant Salivary Gland Tumors.

The goal of the work described here was to evaluate the utility of acoustic radiation force impulse (ARFI) imaging, a novel elastography technique, for differentiating benign from malignant salivary gland tumors. With the use of conventional strain elastography (SE) and ARFI imaging with a four-pattern scoring system, 185 tumors were examined (163 benign/22 malignant). When a score of ≥3 was used to define malignancy, the sensitivity, specificity and accuracy were higher for ARFI imaging (77.3%, 63.8% and 65.4%, respectively) than for conventional SE (54.5%, 56.4% and 56.2%, respectively). ARFI imaging findings revealed that most (92%) Warthin tumors, but only 24% of pleomorphic adenomas, were benign (score: 1 or 2). Attenuation of acoustic push pulses made it difficult to determine the stiffness of malignant tumors in the deep parotid lobes. Thus, ARFI imaging is a useful tool for screening Warthin tumors and exhibits high sensitivity for malignant tumors of salivary glands, other than deep parotid lobe tumors.

Impact of Screening for Salivary Gland by Ultrasonography.

BACKGROUND: Ultrasonography is superior to other imaging modalities for detecting salivary gland diseases. However, there have been no reports of the results of salivary gland screening with ultrasonography. In this study, the salivary glands were also observed during thyroid ultrasonography to determine the degree of salivary gland abnormalities detected by ultrasonography. METHODS: This study was conducted retrospectively using medical records. It assessed the association between the following abnormal findings detected during thyroid ultrasonography and their final diagnoses: atrophy/swelling, unclear demarcation from surrounding tissues, decreased salivary gland parenchyma echo level, heterogeneity of parenchyma, hypervascularity of salivary gland parenchyma, dilatation of the ducts, and a mass within the gland. RESULTS: Of the 908 patients who underwent thyroid ultrasonography, salivary gland abnormalities were detected in 36 (4.0%) patients. Of the 36 patients with abnormal ultrasonographic findings, 22 underwent further examination. Of the 22 patients, 16 received definitive diagnoses of salivary gland diseases.Salivary gland disorders were considered to be absent in patients with only heterogeneity of the salivary glands observed on ultrasonography. Salivary gland disorders in all patients with further abnormal ultrasonographic findings such as atrophy/swelling, unclear boundary, or hypervascularity in addition to internal heterogeneity were confirmed by further blood examinations and imaging studies. We were able to detect autoimmune sialadenitis such as Sjögren's syndrome and IgG4-related sialadenitis by ultrasonography in patients without obvious symptoms. CONCLUSION: Salivary gland screening during thyroid ultrasonography revealed abnormal findings including Sjögren's syndrome and IgG4-related sialadenitis in about 4% of the patients. Thus, ultrasonography may also be useful for early detection of autoimmune diseases of salivary glands.

Ultrasonography findings in immunoglobulin G4-related lymphadenopathy: a report of two cases.

Lymphadenopathy is frequently observed in immunoglobulin G4 (IgG4)-related disease in some cases, and such cases are known as IgG4-related lymphadenopathy. The ultrasonography findings associated with IgG4-related lymphadenopathy have not been described in previous reports. Herein, we describe ultrasonography findings in two cases of IgG4-related lymphadenopathy in conjunction with histopathological findings. Combined ultrasound scanning with Doppler examination accurately represented the specific histopathological features of IgG4-related lymphadenopathy.

Prognostic Factors for Colorectal Cancer Patients Treated With Combination of Immune-cell Therapy and First-line Chemotherapy: A Retrospective Study.

BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cells vaccination (DCs), in combination with 1st-line chemotherapies in terms of the survival of patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: A total of 198 patients who were diagnosed with advanced CRC and administered 1st-line chemotherapies were enrolled in this study. The correlation between overall survival (OS) and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analyses revealed that the prognosis was improved in CRC patients who received immune-cell therapy with PS 0, bevacizumab (BV), and capecitabine-including regimens (Cap). Finally, multivariate analysis demonstrated that PS=0, and the combination of immune-cell therapy and Cap provided a survival benefit in patients with advanced CRC. CONCLUSION: The survival benefit could be potentially obtained with better PS by the combination of immune-cell therapy and Cap as a 1st-line setting in patients with CRC.

Clinical efficacy of novel elastography using acoustic radiation force impulse (ARFI) for diagnosis of malignant thyroid nodules.

OBJECTIVE: Acoustic radiation force impulse (ARFI) imaging is a recent ultrasound elastography technique; consequently, its efficacy is not fully known. In this study, we compared ARFI imaging with conventional strain elastography (SE) and shear wave velocities (SWVs) to evaluate the utility of ARFI imaging for diagnosing thyroid nodules. SUBJECTS AND METHODS: In this study we examined 233 thyroid nodules (183 benign nodules and 50 malignant nodules) isolated from human patients. The nodules were evaluated with SE and ARFI imaging, and SWVs of the nodules were simultaneously measured. ARFI images were classified using a four-point score based on grayscale intensity of the images. The sensitivity, specificity, and diagnostic accuracy were compared between SE and ARFI imaging. Finally, SWVs for each score of SE and ARFI imaging were compared. RESULTS: The new scoring system for ARFI imaging can be divided into four virtual touch imaging (VTI) scores. Nodules with a VTI score of 3 or 4 as determined by ARFI imaging were determined to be malignant. The sensitivity, specificity, and diagnostic accuracy, respectively, were 63.2%, 66.3%, and 65.6% for SE, compared with 80.0%, 86.3%, and 85.0% for ARFI imaging. The median SWVs of the nodules were 1.57 m/s, 1.73 m/s, 1.88 m/s, and 2.09 m/s for VTI scores of 1, 2, 3, and 4, respectively. The SWVs of VTI scores 3 and 4 were significantly higher than those of VTI scores 1 and 2. CONCLUSIONS: The diagnostic accuracy of ARFI imaging for differentiating malignant thyroid nodules was higher than that of SE. The VTI scores of the nodules accurately reflected their SWVs. LEVEL OF EVIDENCE: 4.

Prognostic Factors for Pancreatic Cancer Patients Treated with Immune-cell Therapy.

BACKGROUND/AIM: The past 17 years, immune-cell therapy has been administered to 990 patients with advanced or recurrent pancreatic adenocarcinoma and 50 patients with curatively resected pancreatic adenocarcinoma. MATERIALS AND METHODS: The correlation between overall survival (OS) and various factors including sex, age, performance status (PS), distant metastasis, chemotherapy, radiotherapy, and type of immune-cell therapy were evaluated by univariate and multivariate analyses. RESULTS: The median OS of advanced or recurrent pancreatic cancer was 5.8 months, and the prognosis was improved in pancreatic cancer patients who received immune-cell therapy with PS scores of 0-1 [hazard risk (HR)=0.56; 95% confidence interval (CI)=0.46-0.68; p<0.0001], chemotherapy (HR=0.68; 95%CI=0.54-0.87; p=0.002), or radiotherapy (HR=0.76; 95%CI=0.63-0.93; p=0.006). Multivariate analysis demonstrated that distant metastasis indicated a poor prognosis for pancreatic cancer patients that were administered immune-cell therapy (HR=1.62; 95%CI=1.37-1.93; p<0.0001). Additionally, the combined immune-cell therapy with αß T cell and dendritic cell (DC) vaccine provided a survival benefit in advanced or recurrent pancreatic cancer patients (HR=0.69; 95%CI=0.57-0.83; p<0.0001). CONCLUSION: A survival benefit could be potentially obtained with better PS by the combination of αß T cell therapy, DC vaccine therapy, and chemotherapy at an early stage in pancreatic cancer.

A Novel Lateral Approach to the Assessment of Vocal Cord Movement by Ultrasonography.

BACKGROUND: Ultrasonography is a non-invasive technique that is commonly used by endocrinologists and endocrine surgeons to examine the thyroid region and could be useful for the assessment of vocal cord movement by these specialists. However, previous studies reported a low rate of successful visualization of vocal cord movement by ultrasonography. To address this issue, we devised a novel ultrasonographic procedure for assessing vocal cord movement indirectly by observing the arytenoid movement from a lateral view. METHODS: Subjects were 188 individuals, including 23 patients with vocal cord paralysis and 13 with vocal cord paresis. We performed ultrasonographic assessment of vocal cord movement using two different procedures: the conventional middle transverse procedure and the novel lateral vertical procedure. RESULTS: The rate of visualization of vocal cords with the middle transverse procedure was 70.2% and that of the arytenoid cartilage with the lateral vertical procedure was 98.4%. The lateral vertical procedure enabled visualization of all patients with vocal cord paresis/paralysis and detected all 23 patients with vocal paralysis; only one of 13 patients with vocal cord paresis was positively identified. The conventional procedure enabled visualization of 21 of 36 patients with vocal cord paresis/paralysis with high accuracy. There was no false-positive case in either procedure. CONCLUSION: The proposed lateral vertical procedure improved the rate of visualization of vocal cord movement by ultrasonography, suggesting that it is a useful technique to screen for vocal cord paralysis by ultrasonography.

Efficacy of Adoptive Immune-cell Therapy in Patients with Advanced Gastric Cancer: A Retrospective Study.

BACKGROUND: Conventional therapy for advanced gastric cancer (GC) has limited survival benefits. In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy, using in vitro-activated T-lymphocytes with and without dendritic cells (DCs), in combination with standard therapies in terms of the survival of patients with advanced GC. PATIENTS AND METHODS: A total of 242 patients who were diagnosed as having stage-IV GC were enrolled in this study to receive immune-cell therapy with or without standard therapies, such as chemotherapy, surgery, or radiation therapy. Overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. RESULTS: Immune-cell therapy increased median survival time (21.5 months) in patients with advanced GC. The patients who underwent surgery with or without chemotherapy as a prior treatment showed better prognosis than those who received other therapies (p<0.001). Patients who showed stable disease or a partial response to immune-cell therapy had a better prognosis than those with progressive disease (p<0.001). Multivariate analysis revealed that performance status, the type of immune-cell therapy, and prior treatment were independent prognostic factors for patients with GC. No serious adverse event was reported in immune-cell therapy. CONCLUSION: Immune-cell therapy might extend the survival of patients with advanced GC.

Significant Amelioration of Tracheal Stenosis following Lenvatinib in a Patient Who Has Anaplastic Thyroid Carcinoma with Bronchomediastinal Infiltration: A Case Report.

BACKGROUND: Anaplastic thyroid carcinoma has an extremely poor prognosis, and no known drugs have exhibited acceptable efficacy. In recent years, novel anticancer tyrosine kinase inhibitors have been developed. We encountered a case of tracheal stenosis due to mediastinal and tracheal infiltration of anaplastic carcinoma for which lenvatinib exhibited remarkable effects; owing to this, airway management could be performed, even though the patient's condition was considered critical. CASE REPORT: A 55-year-old man presented with locally advanced anaplastic thyroid carcinoma that was observed to have mediastinal infiltration. Tracheal stenosis due to infiltration of the trachea occurred, and the condition of the patient rapidly deteriorated. Radiation and chemotherapy consisting of cetuximab, cisplatin, and fluorouracil were ineffective, but his tracheal stenosis was relieved 2 weeks after initiation of lenvatinib, after which the patient could be discharged. However, the lenvatinib was ineffective for his liver, bone, and brain metastatic lesions, and the patient remained in a critical condition. CONCLUSION: We encountered a case in which lenvatinib was effective for locally advanced anaplastic thyroid carcinoma, leading to an improvement in quality of life and a prolonged life. The drug was effective for the primary lesion, but mixed efficacy was noted for distant metastatic lesions.

Usefulness of ultrasound for assessing the primary tumor of hypopharyngeal carcinoma.

Objectives: To clarify the usefulness of ultrasonography for detecting hypopharyngeal cancer. Study Design: Cross-sectional study. Methods: The study included 95 patients who underwent pre-treatment ultrasonography. We evaluated the usefulness of ultrasonography for detecting primary hypopharyngeal carcinoma of each T stage and subsite, and for assessing extrahypopharyngeal invasion. Additionally, we determined the efficacy of color Doppler for evaluating primary hypopharyngeal carcinoma. Results: The patients comprised 93 men and 2 women with a mean age of 67.5 years. The T stage (primary tumors) was T1 in 29 patients, T2 in 22, T3 in 9, and T4 in 35. Primary sites with a T stage over T3 were detected using ultrasonography in 17 patients.Regarding primary subsites, postcricoid tumors were assessed most easily (64%), while posterior wall tumors were the most difficult to assess (25%). In 15 of 17 patients, the evaluation of extrahypopharyngeal invasion by ultrasonography matched up precisely with computed tomography findings. In addition, abnormally increased blood flow in primary hypopharyngeal cancers was recognized by color Doppler, and could be used to predict subsites. Conclusions: Cancers at T3 and T4 hypopharyngeal primary tumors and their extrahypopharyngeal invasion were detectable using ultrasonography. Furthermore, ultrasonography was useful for assessing postcricoid tumors that were difficult to observe by flexible laryngoscopy. Level of Evidence: 4.

Usefulness of a Novel Ultrasonographic Classification Based on Anechoic Area Patterns for Differentiating Warthin Tumors from Pleomorphic Adenomas of the Parotid Gland.

Background: Ultrasonographic homogeneity is an important differential finding between Warthin tumor and pleomorphic adenoma, two types of benign parotid gland tumors, with the former likely to be heterogeneous and the latter homogeneous. However, differences in the performance of ultrasound machines or the homogeneity cut-off level affect the judgment of ultrasonographic homogeneity. Therefore, in this study, we adopted a novel system for classifying the composition of tumors via ultrasonography, using anechoic area as a substitute for differences in homogeneity to differentiate between Warthin tumors and pleomorphic adenomas. Methods: We evaluated 68 tumors that were histopathologically diagnosed as Warthin tumor or pleomorphic adenoma between July 2009 and November 2015. Ultrasonographic images of the tumors were evaluated on the basis of key differentiating features, including features on B-mode imaging and color Doppler imaging. Additionally, the tumors were classified into four groups based on anechoic area, and findings were compared between Warthin tumors and pleomorphic adenomas. Results: While 38 of the tumors were pleomorphic adenomas, 30 were Warthin tumors. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for detection of Warthin tumors using our novel classification system were 73.3%, 76.3%, 71.0%, 78.4% and 75.0%, respectively. Compared to pleomorphic adenomas, Warthin tumors showed large or sponge-like anechoic areas, rich vascularization and an oval shape even at large tumor sizes, and the difference was significant. On defining Warthin tumor as a tumor demonstrating two or more of the findings noted above, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for its detection were 73.3%, 84.2%, 78.6%, 80.0% and 79.4%, respectively. Conclusion: Our novel classification system based on anechoic area patterns demonstrated by the tumors had high sensitivity, specificity and diagnostic accuracy for differentiating Warthin tumors from pleomorphic adenomas.

Immunohistochemical Analysis of WT1 Antigen Expression in Various Solid Cancer Cells.

For a peptide-pulsed dendritic cell (DC) vaccine to work effectively in cancer treatment, it is significant that the target protein is expressed in cancer cells. Wilms' tumor 1 (WT1) has been identified as a molecular target for immune cell therapy of cancer. We evaluated the protein expression levels of WT1 in various solid tumors, as well as mucin 1 (MUC1) or major histocompatibility complex (MHC) class l molecules. Seven hundred and thirty-eight patients whose tissue samples were examined by immunohistochemical analysis agreed to undergo DC vaccine therapy. The positive staining of WT1 in tumor cells was observed in 25.3% of patients, with only 8.5% of them showing moderate to strong expression; moreover, WT1 tended to localize in the nucleus and cytoplasm. A positive staining of tumor cells by an anti-MHC class l monoclonal antibody was observed in 98.6% and by an anti-MUC1 monoclonal antibody in 76.8% of the patients. In relation to the application of cancer-specific immunotherapy, these findings provide useful information for determining the efficacy of MUC1- and WT1-targeted therapy.

Effect of Serotonin 1A Agonists and Selective Serotonin Reuptake Inhibitors on Behavioral and Nighttime Respiratory Symptoms in Rett Syndrome.

BACKGROUND: Rett syndrome is characterized by psychomotor regression during early childhood, autistic-like behaviors, and aberrant breathing patterns. Dysfunction of the serotonergic system has been postulated to play a role in the pathophysiology of these symptoms. PATIENT DESCRIPTION: We present an 11-year-old girl with Rett syndrome who exhibited marked respiratory symptoms, including frequent apneic events during sleep. She had been treated for these respiratory symptoms using noninvasive positive pressure ventilation since age six years. Treatment with serotonin 1A receptor agonist was initiated at age eight years, whereas treatment using a selective serotonin reuptake inhibitor began at age nine years. Noninvasive positive pressure ventilation therapy was effective in reducing symptoms of sleep apnea, and administration of serotonergic agents resulted in amelioration of sleep apneic events even in the absence of noninvasive positive pressure ventilation. In addition, improvements in hand stereotypy and social skills were observed after initiation of serotonin-based therapy. DISCUSSION: The respiratory difficulties our patient experienced during non-rapid eye movement (REM) sleep are characteristic of post-sigh central apnea. Exaggerated activity of expiratory neurons during such apneic events has been observed in mouse models of Rett syndrome. We suggest that prescribed serotonergic agents might serve to inhibit such activity, attenuating the imbalance between inspiratory and expiratory neurons. These agents might also be useful in the treatment of autistic-like behaviors caused by impaired serotonergic transmission in the brain.