Usefulness of NF2 hemizygous loss detected by fluorescence in situ hybridization in diagnosing pleural mesothelioma in tissue and cytology material: A multi-institutional study.

OBJECTIVES: BAP1, CDKN2A, and NF2 are the most frequently altered genes in pleural mesotheliomas (PM). Discriminating PM from benign mesothelial proliferation (BMP) is sometimes challenging; it is well established that BAP1 loss, determined by immunohistochemistry (IHC), and CDKN2A homozygous deletion (HD), determined by fluorescence in situ hybridization (FISH), are useful. However, data regarding the diagnostic utility of NF2 FISH in PM is limited. Thus, we performed a multi-institutional study examining the utility of NF2 alterations determined by FISH for diagnosing PM in combination with BAP1 loss and CDKN2A HD. MATERIALS AND METHODS: Multi-institutional PM cases, including 106 surgical and 107 cell block samples as well as 37 tissue cases of benign mesothelial proliferation (BMP) and 31 cell block cases with reactive mesothelial cells (RMC), were collected and analyzed using IHC for BAP1 and FISH for CDKN2A and NF2. RESULTS: In PM, NF2 FISH revealed hemizygous loss (HL) in 54.7% of tissue cases (TC) and 49.5% of cell block cases (CBC), with about 90% of HL being monosomy. CDKN2A HD or BAP1 loss were detected in 75.5%/65.4% TC or 63.6%/60% CBC, respectively. BMP or RMC showed no BAP1 loss, CDKN2A HD, or NF2 HL. For discriminating PM from BMP, a combination of BAP1 loss, CDKN2A HD, and NF2 HL yielded enhanced sensitivity of 98.1% TC/94.4% CBC. BAP1 loss, CDKN2A HD, or NF2 HL were observed in 69%, 70%, or 58% of epithelioid PM, but in 9%, 91%, or 27% of sarcomatoid PM, respectively. Histotype, histological gradings, and CDKN2A deletion status showed significant differences in overall survival, while BAP1 loss and NF2 HL did not. CONCLUSION: NF2 HL, consisting predominantly of monosomy, can be detected by FISH in both TC and CBC of PM, and is effective for distinguishing PM from BMP, especially when combined with BAP1 loss and CDKN2A HD.

Challenges and limitation of MTAP immunohistochemistry in diagnosing desmoplastic mesothelioma/sarcomatoid pleural mesothelioma with desmoplastic features.

AIM: Genomic-based ancillary assays including immunohistochemistry (IHC) for BRCA-1 associated protein-1 (BAP1) and methylthioadenosine phosphorylase (MTAP), and fluorescence in situ hybridization (FISH) for CDKN2A are effective for differentiating pleural mesothelioma (PM) from reactive mesothelial proliferations. We previously reported a combination of MTAP and BAP1 IHC effectively distinguishes sarcomatoid PM from fibrous pleuritis (FP). Nevertheless, cases of sarcomatoid PM with desmoplastic features (desmoPM) are encountered where the IHC assessment is unclear. METHODS AND RESULTS: We evaluated assessment of MTAP IHC, BAP1 IHC, and CDKN2A FISH in 20 desmoPM compared to 24 FP. MTAP and BAP1 IHC could not be assessed in 11 (55 %) and 10 (50 %) cases, respectively, due to loss or faint immunoreactivity of internal positive control cells, while CDKN2A FISH could be evaluated in all cases. The sensitivities for MTAP loss, BAP1 loss, and CDKN2A homozygous deletion in desmoPM were 40 %, 10 %, and 100 %. A combination of MTAP loss and BAP1 loss yielded 45 % of sensitivity. CONCLUSIONS: MTAP IHC is a useful surrogate diagnostic marker in differentiating ordinary sarcomatoid PM from FP, but its effectiveness is limited in desmoPM. CDKN2A FISH is the most effective diagnostic assays with 100 % sensitivity and specificity in discriminating desmoPM from FP in the facilities where the FISH assay is available.

Combination of DYRK2 and TERT Expression Is a Powerful Predictive Marker for Early-stage Breast Cancer Recurrence.

BACKGROUND/AIM: DYRK2 is a dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase induces degradation of telomerase reverse transcriptase (TERT). The expression of both proteins in breast cancer were investigated as predictors of recurrence. PATIENTS AND METHODS: Two hundred and twenty-one patients with early breast cancer treated at our institute between 2000 and 2009, were included. We used immunohistochemical analyses to measure the expression of DYRK2 and TERT and correlated it with clinicopathological factors and survival. RESULTS: DYRK2 and TERT were positive in 58 (26%) and 86 (39%) of 221 patients, respectively. There was no correlation between DYRK2 and TERT expression and clinicopathological factors. Better disease-free survival was observed in the DYRK2-positive group (p=0.032), and poorer disease-free survival was noted in the TERT-positive group (p=0.023). The DYRK2-positive TERT-negative group exhibited significantly better disease-free survival than the other groups (p=0.006). CONCLUSION: The combination of DYRK2 and TERT may be a powerful tool to stratify breast cancer patients.

Replacement of a 5-cm Intrathoracic Trachea With a Tissue-Engineered Prosthesis in a Canine Model.

BACKGROUND: Critical obstacles must be addressed before clinical application of artificial tracheas. The major complications of long tracheal replacement include anastomotic dehiscence and stenosis owing to poor vascularity and incomplete reepithelialization. The objective of this report was to clarify whether preincubation of the prosthesis in the omentum could be applicable for reconstruction of a long segment of the intrathoracic trachea in a canine model. METHODS: The framework of an artificial trachea was fabricated from a polypropylene mesh tube and coated with 1% neutral atelocollagen inside and outside the lumen. The prosthesis was placed in the omentum of 9 healthy male beagle dogs for 3 weeks. Then, the pedicled prosthesis was used to replace a 50-mm-long section of intrathoracic trachea. Results were evaluated bronchoscopically, macroscopically, and histologically. RESULTS: After 3 weeks of abdominal incubation, the prostheses were incorporated into the host tissue. None of the dogs showed dehiscence of the anastomosis or infection of the prostheses during the postoperative period. Seven of the 9 dogs survived for more than 1 year. One dog died of a bowel obstruction resulting from a diaphragmatic hernia 3 months after replacement, and another died due to reasons unrelated to the prosthesis at 6 months. Bronchoscopic examination revealed no stenosis or dehiscence, and microscopic examination of all dogs showed that the luminal surface was covered by newly regenerated connective tissue and respiratory epithelium. CONCLUSIONS: Pedicled omentum-prosthesis complexes may allow successful reconstruction of a long segment of the intrathoracic trachea.

Completion Pneumonectomy for Second Primary/Primary Lung Cancer and Local Recurrence Lung Cancer.

BACKGROUND: Completion pneumonectomy (CP) for second primary/primary lung cancer (SPLC) and local recurrence lung cancer (LRLC) is still controversial. Although several case series on such a practice exist, the oncological benefit is under debate. The purpose of this study was to review available literatures on CP for SPLC and LRLC and evaluate postoperative and long-term outcomes. METHODS: MEDLINE, SCOPUS, and Web of Science were reviewed for eligible studies in January 2021. Studies were included if they indicated outcomes of patients with lung cancer undergoing CP. Overall survival (OS) was defined as the primary endpoint; secondary endpoints included operative morbidity and 30-day mortality. Random-effects meta-analysis based on a binomial distribution was used to create pooled estimates. RESULTS: Thirty-two eligible studies including 1157 patients were identified. These studies were uniformly retrospective reports. Pooled estimates for 3-year and 5-year OS were 50.6% (95% confidence interval [CI], 34.7%-66.5%) and 38.9% (95% CI, 32.2%-46.1%) in SPLC patients. When the SPLC was a stage I tumor, pooled 5-year OS was favorable with 60.7% (95% CI, 43.2%-75.9%). In LRLC, pooled 3-year and 5-year OS were 47.6% (95% CI, 36.1%-59.4%) and 33.8% (95% CI, 26.8%-41.5%), respectively. Pooled morbidity and 30-day mortality was reported in 38.2% (95% CI, 32.0%-44.9%), and 10.0% (95% CI, 8.1%-12.3%), respectively. CONCLUSIONS: CP for SPLC and LRLC is a challenging procedure with significant perioperative morbimortality. However, published evidence indicates good long-term survival for selected patients. Further studies are needed to identify patient subgroups which benefit most from CP.

Sodium-glucose cotransporter 2 inhibitor canagliflozin attenuates lung cancer cell proliferation in vitro.

Cancer is a major cause of death in patients with type 2 diabetes mellitus (T2DM) and lung cancer is one of the most prevalent cancers in patients with T2DM. In the present study, we examined the anti-cancer effect of the Sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, using a lung cancer model. In lung cancer tissues from non-T2DM human subjects, SGLT2 was detected by immunohistochemistry. SGLT2 mRNA and protein were also detected in A549, H1975 and H520 lung cancer cell lines by RT-PCR and immunohistochemistry, respectively. Canagliflozin at 1-50 µM significantly suppressed the growth of A549 cells in a dose-dependent manner. In BrdU assays, canagliflozin attenuated the proliferation of A549 cells, but did not induce apoptosis. In cell cycle analysis, S phase entry was attenuated by canagliflozin in A549 cells. In in vivo experiments, a xenograft model of athymic mice implanted with A549 lung cancer cells was treated with low and high dose oral canagliflozin. Despite the results of the in vitro experiments, tumor weight was not decreased by canagliflozin. In addition, the serum insulin level, but not body weight or blood glucose level, was decreased by canagliflozin. The number of cells positive for Ki67 was slightly decreased by canagliflozin, but this was not statistically significant. In conclusion, SGLT2 is expressed in human lung cancer tissue and cell lines, and the SGLT2 inhibitor, canagliflozin, attenuated proliferation of A549 lung cancer cells by inhibiting cell cycle progression in vitro but not in vivo.

Surgical navigation system for temporomandibular joint ankylosis in a child: a case report.

BACKGROUND: Computer-assisted surgical navigation systems were initially introduced for use in neurosurgery and have been applied in craniomaxillofacial surgery for 20 years. The anatomy of the oral and maxillofacial region is relatively complicated and includes critical contiguous organs. A surgical navigation system makes it possible to achieve real-time positioning during surgery and to transfer the preoperative design to the actual operation. Temporomandibular joint ankylosis limits the mouth opening, deforms the face, and causes an increase in dental caries. Although early surgical treatment is recommended, there is controversy regarding the optimal surgical technique. In addition, pediatric treatment is difficult because in children the skull is not as wide as it is in adults. There are few reports of pediatric temporomandibular joint ankylosis surgery performed with a navigation system. CASE PRESENTATION: A 7-year-old Japanese girl presented severe restriction of the opening and lateral movement of her mouth due to a temporomandibular joint bruise experienced 2 years earlier. Computed tomography and magnetic resonance imaging demonstrated left condyle deformation, disappearance of the joint cavity, and a 0.7-mm skull width. We diagnosed left temporomandibular joint ankylosis and performed a temporomandibular joint ankylosis arthroplasty using a surgical navigation system in order to avoid damage to the patient's brain. A preauricular incision was applied, and interpositional gap arthroplasty with temporal muscle was performed. After the surgery, the maximum aperture was 38 mm, and the limitation of the lateral movement was eliminated. CONCLUSIONS: A navigation system is helpful for confirming the exact target locations and ensuring safe surgery. In our patient's case, pediatric temporomandibular joint ankylosis surgery was performed using a navigation system without complications.

Elucidation of prognostic factors and the effect of anti-fibrotic therapy on waitlist mortality in lung transplant candidates with idiopathic interstitial pneumonias.

BACKGROUND: Lung transplantation (LTx) is the last resort for patients who fail to respond to drug therapy and progress to advanced idiopathic interstitial pneumonias (IIPs). However, more than one-third of patients registered for LTx face despair because of rapid disease progression and donor shortage. This study aimed to identify the risk factors of waitlist mortality in LTx candidates with IIPs and investigate the association of anti-fibrotic therapy with waitlist mortality. METHODS: We retrospectively investigated 56 patients with IIPs, including 29 patients with idiopathic pulmonary fibrosis (51.7%) and 11 patients with idiopathic pleuroparenchymal fibroelastosis (19.6%), registered for LTx at Fukuoka University Hospital between January 2006 and June 2020. The risk factors affecting transplantation-censored survival were evaluated. RESULTS: The waitlist mortality rate of patients with nonspecific interstitial pneumonia was significantly lower than that of others. Multivariate survival analysis using Cox's model identified a history of pneumothorax (P = 0.029) and short 6-min walk distance (6MWD) (P = 0.012) to be significant variables affecting waitlist mortality. Patients receiving anti-fibrotic therapy (n = 27, 48.2%) had a lower risk of pneumothorax (P = 0.017) and their 6MWD was longer than that of non-therapy patients (P < 0.001). The waitlist mortality rate of patients on anti-fibrotic therapy was significantly lower (P = 0.012). CONCLUSIONS: History of pneumothorax and short 6MWD were independent predictors of waitlist mortality in LTx candidates with IIPs. The anti-fibrotic therapy may potentially reduce mortality in patients with IIPs on the waiting list for LTx.

Fluorescence in situ hybridization detection of chromosome 22 monosomy in pleural effusion cytology for the diagnosis of mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is characterized by mutations in several genes, including cyclin-dependent kinase-inhibitor 2A/p16 in the 9p21 locus, BRCA1-associated protein 1 (BAP1), and neurofibromatosis type 2 (NF2) in the 22q12 locus. Recent studies indicate that fluorescence in situ hybridization (FISH) detects hemizygous loss of NF2 in tissue specimens of MPM. The authors investigated whether NF2 FISH, either alone or in combination with other diagnostic assays (9p21 FISH, methylthioadenosine phosphorylase [MTAP] immunohistochemistry [IHC], and BAP1 IHC), effectively distinguishes MPM cells from reactive mesothelial cells (RMCs) in cell blocks prepared from pleural effusions. METHODS: FISH assays were used to examine the deletion status of NF2 and 9p21, and IHC was used to determine the expression of MTAP and BAP1 in cell blocks from 54 cases with MPM and 18 cases with RMCs. RESULTS: Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) showed 51.9% sensitivity (48.1% for chromosome 22 monosomy and 3.7% for hemizygous deletion) and 100% specificity in differentiating MPM cells from RMCs. Combinations of NF2 FISH, 9p21 FISH, and BAP1 IHC assays yielded greater sensitivity (98.1%) than any assay alone (9p21 FISH, 61.1%; MTAP IHC, 52.8%; or BAP1 IHC, 60.4%). The level of hemizygous NF2 loss in cell blocks positively correlated with that in corresponding tissues. Furthermore, to overcome cytologic specimen-specific challenges, FISH combined with cytokeratin AE1/AE3 immunofluorescence was necessary in 25.9% of MPM cases for FISH assessment of predominantly scattered MPM cells. CONCLUSIONS: NF2 FISH alone or in combination with other diagnostic assays effectively differentiates MPM cells from RMCs in cell blocks prepared from pleural effusions.

MiR-21 in Lung Transplant Recipients With Chronic Lung Allograft Dysfunction.

Background: Micro-RNA-21 (miR-21) is a post-translational regulator involved in epithelial-to-mesenchymal transition (EMT). Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD. Methods: Expression of miR-21, vimentin, Notch intracellular domain (NICD) and SMAD 2/3 was investigated in explanted CLAD lungs of patients who underwent retransplantation. Circulating miR-21 was determined in collected serum samples of CLAD and matched stable recipients. Results: The frequency of miR-21 expression was higher in restrictive allograft syndrome (RAS) than in bronchiolitis obliterans syndrome (BOS) specimens (86 vs 30%, p = 0.01); Vimentin, NICD and p-SMAD 2/3 were positive in 17 (100%), 12 (71%), and 7 (42%) BOS patients and in 7 (100%), 4 (57%) and 4 (57%) RAS cases, respectively. All four markers were negative in control tissue from donor lungs. RAS patients showed a significant increase in serum concentration of miR-21 over time as compared to stable recipients (p = 0.040). Conclusion: To the best of our knowledge this is the first study highlighting the role miR-21 in CLAD. Further studies are necessary to investigate the involvement of miR-21 in the pathogenesis of CLAD and its potential as a therapeutic target.

Nuss procedure for pectus excavatum in a patient with cleidocranial dysplasia.

Cleidocranial dysplasia is an autosomal skeletal disorder resulting from delayed or abnormal ossification of bony growth. Pectus excavatum independently presented in a 9-year-old boy with cleidocranial dysplasia and was corrected using the Nuss procedure. There were no perioperative complications, and the post-operative course was uneventful. Although there were concerns regarding extraordinary late consolidation or remodeling of the bony thorax, placement of a Nuss plate for 5 years and 6 months improved the patient's concave deformity without re-depression.

Severe scoliosis with an impaired pulmonary allograft function after pediatric unilateral lung transplantation.

Left-unilateral single-lobe lung transplantation from a living donor was performed in a 4-year-old boy who suffered from severe respiratory failure caused by bronchiolitis obliterans (BO) as a result of graft versus host disease (GVHD) after peripheral blood stem cell transplantation (PBSCT). The patient grew well during his early childhood years, with an excellent lung allograft function. However, severe thoracic scoliosis occurred 7 years after lung transplantation, which ultimately resulted in compression of the lung allograft followed by severe respiratory dysfunction, and the patient became dependent on mechanical ventilation support. Posterior spinal fusion of Th2-L3 with instrumentation and bone grafting was performed to correct scoliosis in the hope of recovering his thoracic capacity. The left thoracic volume was dramatically improved immediately after spinal fusion surgery, and the patient was ultimately weaned off of mechanical ventilation after a year of pulmonary rehabilitation.

A successful surgical tracheobronchoplasty in a case of expiratory collapse of central airways associated with tracheobronchomalacia in a severely deformed single lung patient.

A 67-year-old male with a severe body deformity and a total collapse of the left lung due to infantile paralysis was admitted to a regional hospital for a spinal fracture. He suffered from cardiopulmonary arrest during the hospitalization. Although extubation was tried several times after resuscitation, he went into cardiopulmonary arrest repeatedly. The expiratory collapse of the central airways due to tracheobronchomalacia was suspected, requiring tracheostomy with persistent positive pressure ventilation. He was transferred to our hospital after several unsuccessful endobronchial interventions. Severe tracheobronchomalacia was diagnosed with dynamic bronchoscopy, and surgical tracheobronchoplasty using a polypropylene mesh was performed. A modified surgical approach was utilized to stabilize the intraoperative respiratory status in this particular patient with a severely deformed body and a single lung. Consequently, the tracheobronchoplasty was completed without intraoperative complications. The postoperative course was also uneventful, and the patient was ventilator-free on postoperative day 7.

[Comparison of the Incidence of Febrile Neutropenia in Doxorubicin/Cyclophosphamide(AC)and Docetaxel/Cyclophosphamide(TC) Perioperative Chemotherapies for Primary Breast Cancer].

Febrile neutropenia(FN)is an adverse event associated with chemotherapy. Because well-maintained dose intensity improves survival rate, suppression of FN is important. While the incidence of FN has been recognized to be higher with docetaxel/cyclophosphamide(TC)therapy, it is generally considered lower with doxorubicin/cyclophosphamide(AC)therapy, and primary prophylaxis with granulocyte-colony stimulating factor(G-CSF)is not recommended. FN with AC therapy is commonly experienced in our daily practice. Thus, we retrospectively compared the incidence of FN with AC and TC therapies. We examined the data of 48 patients with primary breast cancer, consisting of 26 patients treated with AC and 22 patients with TC as perioperative chemotherapy-from January 2014 to September 2018-to determine the incidence of FN. FN was observed in 7/26 patients who received AC(26.9%)and 5/22 patients who received TC(22.7%). Excluding patients with primary prophylaxis with G-CSF, FN was observed in 7/23 patients(30.4%)who received AC and 5/18 (27.8%)who received TC. The incidence of FN with AC therapy was higher than that with TC therapy in this study. Therefore, positive use of G-CSF is necessary for safety and to adequately maintain dose intensity for AC therapy.

Long-term survival of thoracoscopic surgery compared with open surgery for clinical N0 adenocarcinoma.

BACKGROUND: Early stage non-small cell lung cancer (NSCLC) is good candidate for video-assisted thoracoscopic surgery (VATS). Long-term outcome compared between VATS and open surgery remains unclear. The aim of this study was to assess the long-term outcome of VATS in early stage adenocarcinoma. METHODS: A retrospective study was performed in 546 patients which were operated between January 2006 and December 2010 in our institute and of those, 240 (220 lobectomies, and 20 segmentectomies) were clinical N0 adenocarcinoma. One hundred and thirty-five patients underwent VATS and 105 patients for open surgery. Long-term oncological outcomes were compared in both groups. RESULTS: There were significant differences in age, gender, Blinkman index, clinical T factor and tumor size between two groups. VATS group showed statistically longer operation time (P=0.01), less blood loss (P=0.005), shorter length of stay (P=0.001), and less dissected number of lymph nodes (P<0.001) compared with open surgery. Disease-free survival in VATS was significantly better than open surgery (5- and 10-year survival; VATS, 91.4%, 79.0%; open, 85.1%, 73.6%; respectively, P=0.04). Overall survival in VATS was not different from open (P=0.58). Propensity matched disease-free and overall survival was not significantly different between two groups. Multivariate Cox regression analysis showed that age [P=0.04, 95% confidence interval (CI): (1.02-6.81)] in overall and T factor [P=0.01, 95% CI: (1.41-17.3)] in disease-free survival was prognostic significant after propensity matching. CONCLUSIONS: Our study demonstrated that long-term outcome in VATS for early stage adenocarcinoma was equivalent to open surgery. VATS may be a treatment of choice for promising long-term prognosis.

Evaluation of regenerated tracheal cilia function on a collagen-conjugated scaffold in a canine model.

OBJECTIVES: It is unclear whether the movement and function of the regenerated cilia on collagen-conjugated artificial trachea are the same as those of normal cilia. This study assessed the ciliary beat frequency (CBF) and ciliary transport functions (CTFs) of regenerated cilia in a canine model. METHODS: A tracheal defect introduced into the anterior portion of the cervical trachea of an adult beagle dog was covered with a collagen-conjugated prosthesis. Two months later, the trachea was harvested along the long axis, both from normal and regenerated regions. The cilia were stained with isothiocyanate-conjugated wheat germ agglutinin, and their movement was monitored with a high-speed camera to analyse CBF and CTF. Four samples each were obtained from the regenerated and normal regions for CBF analysis and 7 samples each were obtained for CTF analysis. RESULTS: The wheat germ agglutinin-stained cells showed well-regulated beats in both the regenerated and normal regions of the trachea. Mean CBF in the regenerated and normal regions did not differ significantly (7.11 ± 0.41 vs 7.14 ± 1.09 Hz; P = 981). By contrast, CTF was significantly lower in the regenerated region than in the normal region (30.0 ± 6.62 vs 7.43 ± 0.58 µm/s; P = 0.005). CONCLUSIONS: Mean CBF in the regenerated and normal regions did not differ significantly at 2 months. The CTF in the regenerated region recovered partially but remained lower than those in the normal region. Methods are needed to improve the CTF of regenerated cilia.

Preliminary experimental outcomes of induced hypercapnia in treatment of obstinate singultus.

BACKGROUND: Our team found that abolishing the venous-arterial CO2 gradient can cease singultus (hiccups), in which the CO2 pressure in blood reaches no less than 50 mmHg. In order to precisely investigate the target level as a preliminary study, we made a combination gas consisting of 10% CO2 and 90% O2 to generate the conditions instantly and safely. METHODS: Thirty-five cases consisting of 26 patients with long-term chronic singultus were treated using the gas. The group consisted of 21 males and 5 females with mean singultus duration of 8.0±13.1 years. A standard oxygen mask was used for delivery of the gas to the patients, and patients breathed in the gas until they felt relief. The duration of the procedure was measured from the beginning to the point at which singultus ceased. A blood test was performed to measure the partial pressure of CO2 in venous blood at the point at which singultus ceased. RESULTS: Singultus ceased in all patients in a mean time of 5.3±1.5 minutes, with complete recurrence observed in two cases. The mean partial pressure of CO2 in the venous blood at the point the singultus stopped was 60.8±6.8 mmHg. No life-threatening complications were found in any patient. CONCLUSIONS: One of the definitive conditions for ceasing singultus is acute CO2 retention in the body, the target of which is around 60 mmHg of CO2 in venous blood. We believe that targeting acute hypercapnia can always stop singultus, although further neuroscientific investigation is necessary to reveal the physiological mechanism.

Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension.

The Na+/Ca2+ exchanger type-1 (NCX1) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+ and Ca2+. Vascular smooth muscle NCX1 plays an important role in intracellular Ca2+ homeostasis and Ca2+ signaling. We found that NCX1 was upregulated in the pulmonary arteries of mice exposed to chronic hypoxia (10% O2 for 4 weeks). Hence, we investigated the pathophysiological role of NCX1 in hypoxia-induced pulmonary arterial hypertension (PAH), using NCX1-heterozygous (NCX1+/-) mice, in which NCX1 expression is reduced by half, and SEA0400, a specific NCX1 inhibitor. NCX1+/- mice exhibited attenuation of hypoxia-induced PAH and right ventricular (RV) hypertrophy compared with wild-type mice. Furthermore, continuous administration of SEA0400 (0.5 mg/kg/day for 4 weeks) to wild-type mice by osmotic pumps significantly suppressed hypoxia-induced PAH and pulmonary vessel muscularization, with a slight reduction in RV hypertrophy. These findings indicate that the upregulation of NCX1 contributes to the development of hypoxia-induced PAH, suggesting that NCX1 inhibition might be a novel approach for the treatment of PAH.

Current status of surgery for clinical stage IA lung cancer in Japan: analysis of the national clinical database.

PURPOSE: As the number of cases of early lung cancer in Japan grows, an analysis of the present status of surgical treatments for clinical stage IA lung cancer using a nationwide database with web-based data entry is warranted. METHODS: The operative and perioperative data from 47,921 patients who underwent surgery for clinical stage IA lung cancer in 2014 and 2015 were obtained from the National Clinical Database (NCD) of Japan. Clinicopathological characteristics, surgical procedure, mortality, and morbidity were analyzed, and thoracotomy and video-assisted thoracic surgery (VATS) were compared. RESULTS: The patients comprised 27,208 men (56.8%) and 20,713 women (43.2%); mean age, 69.3 years. Lobectomy was performed in 64.8%, segmentectomy in 15.2%, and wedge resection in 19.8%. The surgical procedures were thoracotomy in 12,194 patients (25.4%) and a minimally invasive approach (MIA) in 35,727 patients (74.6%). MIA was divided into VATS + mini-thoracotomy (n = 13,422, 28.0%) and complete VATS (n = 22,305, 46.5%). The overall postoperative mortality rate was 0.4%, being significantly lower in the MIA group than in the thoracotomy group (0.3% vs 0.8%, P < 0.001). CONCLUSIONS: Our analysis of data from the NCD indicates that MIA has become the new standard treatment for clinical stage IA lung cancer.