A novel prognostic model of de novo metastatic hormone-sensitive prostate cancer to optimize treatment intensity.

BACKGROUND: The treatment and prognosis of de novo metastatic hormone-sensitive prostate cancer (mHSPC) vary. We established and validated a novel prognostic model for predicting cancer-specific survival (CSS) in patients with mHSPC using retrospective data from a contemporary cohort. METHODS: 1092 Japanese patients diagnosed with de novo mHSPC between 2014 and 2020 were registered. The patients treated with androgen deprivation therapy and first-generation anti-androgens (ADT/CAB) were assigned to the Discovery (N = 467) or Validation (N = 328) cohorts. Those treated with ADT and androgen-receptor signaling inhibitors (ARSIs) were assigned to the ARSI cohort (N = 81). RESULTS: Using the Discovery cohort, independent prognostic factors of CSS, the extent of disease score ≥ 2 or the presence of liver metastasis; lactate dehydrogenase levels > 250U/L; a primary Gleason pattern of 5, and serum albumin levels ≤ 3.7 g/dl, were identified. The prognostic model incorporating these factors showed high predictability and reproducibility in the Validation cohort. The 5-year CSS of the low-risk group was 86% and that of the high-risk group was 22%. Approximately 26.4%, 62.7%, and 10.9% of the patients in the Validation cohort defined as high-risk by the LATITUDE criteria were further grouped into high-, intermediate-, and low-risk groups by the new model with significant differences in CSS. In the ARSIs cohort, high-risk group had a significantly shorter time to castration resistance than the intermediate-risk group. CONCLUSIONS: The novel model based on prognostic factors can predict patient outcomes with high accuracy and reproducibility. The model may be used to optimize the treatment intensity of de novo mHSPC.

Use of the anterior prostatic urethral mucosa preservation technique during holmium laser enucleation of the prostate can reduce postoperative stress urinary incontinence.

INTRODUCTION: Holmium laser enucleation of the prostate (HoLEP) is an effective and safe surgery for patients with benign prostatic hyperplasia. However, some patients exhibit postoperative urinary incontinence. Here, we compared surgical outcomes and incidence of stress urinary incontinence between HoLEP with and without anterior prostatic urethral mucosa preservation (APUMP). METHODS: All patients in this study underwent HoLEP with APUMP technique (APUMP group) and without APUMP technique (no-APUMP group). Enucleation weight, enucleation time, max flow rate increase at 3 months, and urinary incontinence rates immediately after catheter removal and at 1 month after surgery were compared between the groups. RESULTS: In the APUMP (n = 340) and no-APUMP (n = 75) groups, the median enucleation weights were 34.5 and 35.0 g, respectively (p = .982). The corresponding median enucleation times were 33.0 and 46.5 min (p < .01), and median max flow rate increases at 1 month were 10.5 and 9.9 mL/s (p = .89). The urinary incontinence rates immediately after catheter removal were 4.1% and 14.7% (p < .01), and were 3.8% and 12.0% (p < .01) at 1 month after surgery. CONCLUSION: HoLEP using the APUMP technique could be performed with a shorter operative time while maintaining efficacy. The incidence of postoperative urinary incontinence could be decreased by APUMP, indicating that such preservation facilitates the maintenance of urinary continence after surgery.

Hepatic and lung methotrexate-associated polymorphic lymphoproliferative disorders arising during postoperative follow-up of renal cell carcinoma: a case report.

INTRODUCTION: Methotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult. CASE PRESENTATION: A 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed. CONCLUSION: Methotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered.

The study of the efficiency of in vitro maturation of ovarian tissue oocytes in pediatric patients.

PURPOSE: Although recent in vitro maturation (IVM) studies in pediatric patients have demonstrated successful retrieval and maturation of oocytes, the studies included only a small number of premenarchal patients. In the present study, we examined the potential use of oocyte retrieval and maturation for pediatric patients who undergo ovarian tissue cryopreservation (OTC). METHODS: We retrospectively examined the clinical records of pediatric patients who underwent OTC at our institution between October 2015 and December 2022. Data on the age, primary disease, menstrual history, pre-procedure chemotherapy, anti-Müllerian hormone (AMH) level, number of oocytes collected ex vivo from ovarian tissue, and number of mature oocytes from IVM were examined. RESULTS: Data of 60 pediatric patients (aged 1 to 17 years) were included for analysis. Oocytes were retrieved from 36 patients; the oocytes of 18 of these patients could be cryopreserved. The IVM rate was significantly lower in the premenarchal patients than in the postmenarchal patients. The number of mature oocytes retrieved from IVM was higher in the no-chemotherapy group than in the chemotherapy group. A significant positive correlation was observed between the AMH level and the IVM outcomes. CONCLUSION: Oocyte retrieval and maturation in pediatric patients undergoing OTC is particularly useful in those not receiving chemotherapy. In patients receiving chemotherapy, the AMH level may be useful for predicting the IVM outcome. Activation of the oocyte maturation process in vivo in pediatric patients and better understanding of the major regulators of oocyte maturation are necessary to improve the utility of the IVM procedure.

Epithelioid Angiomyolipoma with Tumor Thrombus into Inferior Vena Cava Presurgically Treated with Combination Therapy of Pembrolizumab and Axitinib: A Case Report.

Epithelioid angiomyolipoma (EAML) is a rare variant of AML with malignant potential. It is occasionally difficult to distinguish EAML from renal cell carcinoma (RCC) on imaging. A 72-year-old woman was admitted to our hospital for the treatment of a left renal tumor with relatively high blood flow and a tumor thrombus extending to the inferior vena cava, suggesting RCC. The patient underwent presurgical combination therapy with axitinib and pembrolizumab. This treatment significantly shortened the thrombus, and radical nephrectomy was performed. The pathological findings were compatible with EAML, and the treatment effects were observed. We report a case treated pre-surgically with a combined therapy of pembrolizumab and axitinib, with a favorable response as a treatment option for EAML.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Clinical characteristics in patients with non-alcoholic steatohepatitis in Japan: a case-control study using a 5-year large-scale claims database.

OBJECTIVES: To examine the clinical characteristics of patients with non-alcoholic steatohepatitis (NASH) and associated comorbidities. DESIGN: A case-control study using the national health insurance and the long-term elderly health insurance claims database. SETTING: Eligible patients diagnosed with NASH (ICD-10 K-75.8, other inflammatory liver disease or K-76.0, other fatty liver) between April 2015 and March 2020 were included. PARTICIPANTS: Patients who met the diagnostic definitions for NASH (n=545) were matched with non-NASH controls (n=185 264) and randomly selected according to sex, birth year and residential area. INTERVENTIONS: No interventions were made. PRIMARY AND SECONDARY OUTCOME MEASURES: ORs were estimated for the relationship between patient background, such as age and sex, body mass index (BMI), NASH-related comorbidities and lifestyle-related diseases. RESULTS: In total, 545 patients with NASH (38.3% men) and 185 264 non-NASH controls (43.2% men) were identified, with median ages of 68 (IQR 63.0-75.0) and 65 (IQR 44.0-74.0) years, respectively. BMI was significantly higher in patients with NASH than in controls (25.8 kg/m2 vs 22.9 kg/m2, p<0.001). The proportions of women, patients with hypertension, patients with dyslipidaemia and patients with type 2 diabetes were higher in the NASH group. In addition, NASH was associated with an increased risk of hepatic cirrhosis (OR 28.81 (95% CI 21.79 to 38.08)), followed by liver cancer (OR 18.38 (95% CI 12.56 to 26.89)). There was no significant association between NASH and risk for depression (OR 1.11 (95% CI 0.87 to 1.41)), insomnia (OR 1.12 (95% CI 0.94 to 1.34)) or chronic kidney diseases (OR 0.81 (95% CI 0.58 to 1.12)). CONCLUSIONS: In the daily medical care of patients, it is necessary to consider sex and age differences and to pay close attention to the risk of liver cancer, as well as other lifestyle-related comorbidities associated with NASH.

[A case of abscess-associated hepatocellular carcinoma with massive lymphoid cell infiltration].

A 76-year-old Japanese man was admitted to our hospital with chills and fever. Computed tomography revealed a 10-cm cystic tumor with peripheral ring enhancement in the left lobe of the liver and several small low-density areas with early peripheral enhancement in both lobes. The large liver mass was diagnosed as a pyogenic abscess and treated with antibiotics. However, elevation of the tumor marker, PIVKA-II, raised the possibility of hepatocellular carcinoma. A fine-needle aspiration biopsy was performed, and malignant hepatic cells were identified. The patient underwent left hepatectomy. Histological analyses of the resected surgical specimen confirmed necrotic liver abscess and residual hepatocellular carcinoma with massive lymphoid cell infiltration. Immunohistochemical analyses revealed that the lymphoid cells were positive for CD3 and CD8. The PIVKA-II level returned to normal after surgery and the hepatic lesions disappeared within 10 months. These findings suggest that the liver abscess stimulated cancer immunity, resulting in the proliferation of cytotoxic T lymphocytes and, subsequently, tumor regression.

Survey of understanding and awareness of fertility preservation in pediatric patients: Is conversation about fertility preservation unpleasant for pediatric patients?

Objective: To verify understanding and awareness of fertility preservation (FP) in pediatric patients undergoing FP treatments. Methods: A questionnaire survey was conducted before and after explanation of fertility issues and FP treatments for patients 6-17 years old who visited or were hospitalized for the purpose of ovarian tissue cryopreservation (OTC) or oocyte cryopreservation (OC), or sperm cryopreservation between October 2018 and April 2022. This study was approved by the institutional review board at St. Marianna University School of Medicine (No. 4123, UMIN000046125). Result: Participants in the study comprised 36 children (34 girls, 2 boys). Overall mean age was 13.3 ± 3.0 years. The underlying diseases were diverse, with leukemia in 14 patients (38.9%), brain tumor in 4 patients (11.1%). The questionnaire survey before the explanation showed that 19 patients (52.8%) wanted to have children in the future, but 15 (41.7%) were unsure of future wishes to raise children. And most children expressed some degree of understanding of the treatment being planned for the underlying disease (34, 94.4%). Similarly, most children understood that the treatment would affect their fertility (33, 91.7%). When asked if they would like to hear a story about how to become a mother or father after FP which including information of FP, half answered "Don't mind" (18, 50.0%). After being provided with information about FP treatment, all participants answered that they understood the adverse effects on fertility of treatments for the underlying disease. Regarding FP treatment, 32 children (88.9%) expressed understanding for FP and 26 (72.2%) wished to receive FP. "Fear" and "Pain" and "Costs" were frequently cited as concerns about FP. Following explanations, 33 children (91.7%) answered "Happy I heard the story" and no children answered, "Wish I hadn't heard the story". Finally, 28 of the 34 girls (82.4%) underwent OTC and one girl underwent OC. Discussion: The fact that all patients responded positively to the explanations of FP treatment is very informative. This is considered largely attributable to the patients themselves being involved in the decision-making process for FP. Conclusions: Explanations of FP for children appear valid if age-appropriate explanations are provided.

[A Case of Stauffer Syndrome-Like Findings Associated with Metastatic Renal Cell Cancer Improved by Molecular Targeted Therapy].

We report a case of Stauffer syndrome-like findings in a patient with metastatic renal carcinoma treated by surgery and molecular targeted therapy. The patient was a 58-year-old woman diagnosed with renal carcinoma with multiple metastases. She had hepatosplenomegaly and hepatic dysfunction with elevated serum liver enzyme and IL-6 levels. Treatment with temsirolimus and axitinib reduced the size of the local and metastatic tumors and simultaneously improved the hepatosplenomegaly. The local tumor was excised by laparoscopic nephrectomy, treated with axitinib and then with nivolumab. With the reduction in the metastatic tumor size, serum liver enzyme and IL-6 levels decreased. It was suggested that molecular targeted therapy is an effective treatment when the findings of metastatic renal cell carcinoma, are similar to those of Stauffer syndrome.

Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

Trans-tract electrocoagulation can decrease the need for postoperative nephrostomy tube after endoscopic combined intrarenal surgery.

AIM: To assess the efficacy and safety of trans-tract electrocoagulation at the end of endoscopic combined intrarenal surgery for renal or ureteral stones. METHODS: The present study included patients who underwent endoscopic combined intrarenal surgery from May 2010 to March 2018. After June 2013, the trans-tract electrocoagulation procedure, to coagulate bleeding from the access tract using a resectscope was carried out at the end of the operation. We compared the patients' background and surgical outcomes between patients with and without trans-tract electrocoagulation. RESULTS: Between the trans-tract electrocoagulation (n = 225) and non-trans-tract electrocoagulation (n = 72) groups, the stone number was significantly smaller (1:2:3 or more, 126:72:27 vs 59:10:3, P = 0.001) and the initial stone-free rates were significantly higher (80% vs 72%, P = 0.006) in the trans-tract electrocoagulation group than in the non-trans-tract electrocoagulation group. Patients experienced a higher nephrostomy tube-free rate (67% vs 26%, P < 0.0001), shorter postoperative catheterization time (2.8 ± 3.8 vs 5.4 ± 5.0 days, P = 0.002) and shorter hospital stay (6.5 ± 3.6 vs 8.8 ± 5.0 days, P = 0.0001) in the trans-tract electrocoagulation group than in the non-trans-tract electrocoagulation group. CONCLUSIONS: Trans-tract electrocoagulation in endoscopic combined intrarenal surgery is a safe and efficient procedure that decreases the need for nephrostomy tube placement after surgery.

HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.

Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.

Calpain-dependent cleavage of N-cadherin is involved in the progression of post-myocardial infarction remodeling.

Enzymatic proteolysis by calpains, Ca(2+)-dependent intracellular cysteine proteases, has been implicated in pathological processes such as cellular degeneration or death. Here, we investigated the role of calpain activation in the hearts subjected to myocardial infarction. We produced myocardial infarction in Cast(-/-) mice deficient for calpastatin, the specific endogenous inhibitory protein for calpains, and Cast(+/+) mice. The activity of cardiac calpains in Cast(+/+) mice was not elevated within 1 day but showed a gradual elevation after 7 days following myocardial infarction, which was further pronounced in Cast(-/-) mice. Although the prevalence of cardiomyocyte death was indistinguishable between Cast(-/-) and Cast(+/+) mice, Cast(-/-) mice exhibited profound contractile dysfunction and chamber dilatation and showed a significant reduction in survival rate after myocardial infarction as compared with Cast(+/+) mice. Notably, immunofluorescence revealed that at 28 days after myocardial infarction, calpains were activated in cardiomyocytes exclusively at the border zone and that Cast(-/-) mice showed higher intensity and a broader extent of calpain activation at the border zone than Cast(+/+) mice. In the border zone of Cast(-/-) mice, pronounced activation of calpains was associated with a decrease in N-cadherin expression and up-regulation of molecular markers for cardiac hypertrophy and fibrosis. In cultured rat neonatal cardiomyocytes, calpain activation by treatment with ionomycin induced cleavage of N-cadherin and decreased expression levels of ß-catenin and connexin 43, which was attenuated by calpain inhibitor. These results thus demonstrate that activation of calpains disassembles cell-cell adhesion at intercalated discs by degrading N-cadherin and thereby promotes left ventricular remodeling after myocardial infarction.

Henoch Schönlein purpura associated with pulmonary adenocarcinoma.

INTRODUCTION: Henoch-Schönlein purpura is a common immunoglobulin A-mediated vasculitis syndrome in children. Henoch-Schönlein purpura can also affect adults and is probably related to malignancy. CASE PRESENTATION: We report the case of a 61-year-old Japanese man who presented for examination after an abnormal shadow was detected by chest radiography. He received a diagnosis of pulmonary adenocarcinoma, stage IV. Purpura on the legs, abdominal pain, diarrhea, hematuria and proteinuria developed at this time. Henoch-Schönlein purpura was diagnosed, base on the clinical symptoms and histological findings of biopsy specimens of the skin, which showed vasculitis with immunoglobulin A deposits. Our patient received chemotherapy with gemcitabine after successful steroid therapy for the Henoch-Schönlein purpura. CONCLUSION: Although hematological malignancies are well-known causes of vasculitides, cases of Henoch-Schönlein purpura associated with lung adenocarcinoma are rare. Our patient was treated with corticosteroid therapy, which cleared the purpura and cytotoxic chemotherapy for the non-small cell lung cancer. However, he died from heart failure due to cardiac tamponade.

Prognosis of 100 Japanese patients with mycosis fungoides and Sézary syndrome.

BACKGROUND: Survival analysis of a large series of patients with mycosis fungoides (MF) and Sézary syndrome (SS) has not been performed in Japan. Revision to the staging system for MF and SS was recently published. OBJECTIVE: To determine the long-term prognosis of Japanese patients with MF and SS, to identify factors predictive of survival, and to evaluate the prognostic significance of the revised staging system. METHODS: We performed a retrospective cohort study of 100 Japanese patients with MF and SS managed at the dermatology division of Niigata University Hospital between April 1, 1982 and March 31, 2006. We estimated survival according to the patient's clinical characteristics including the stages, and assessed their prognostic significance. RESULTS: Survival rates of Japanese patients with MF and SS were similar to those shown in previous studies conducted in the United States and Europe. Prognosis of patients with skin tumor (stage IIB) and extracutaneous involvement (stage IV) was significantly worse than that of those with early-stage disease (stages IA-IIA), but erythrodermic MF patients without blood involvement (stage IIIA) showed excellent survival. Independent prognostic factors in multivariate analyses were higher age and the presence of skin tumor and extracutaneous disease. CONCLUSION: Patient age and stage are the most important clinical prognostic factors in Japanese patients with MF and SS. The revised staging system is useful for predicting survival of the patients, but at least a subpopulation of stage IIIA patients may have a favorable prognosis.

Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts.

Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast cell-deficient WBB6F1-KitW/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblasts. These changes were abolished by treatment with a neutralizing antibody specific for PDGF alpha-receptor (PDGFR-alpha). Consistent with these data, upregulation of atrial Pdgfa expression in pressure-overloaded hearts was suppressed by BM reconstitution from WBB6F1-KitW/W-v mice. Furthermore, injection of the neutralizing PDGFR-alpha-specific antibody attenuated atrial fibrosis and AF inducibility in pressure-overloaded hearts, whereas administration of homodimer of PDGF-A (PDGF-AA) promoted atrial fibrosis and enhanced AF susceptibility in normal hearts. Our results suggest a crucial role for mast cells in AF and highlight a potential application of controlling the mast cell/PDGF-A axis to achieve upstream prevention of AF in stressed hearts.