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.

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.

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.

Hemizygous loss of NF2 detected by fluorescence in situ hybridization is useful for the diagnosis of malignant pleural mesothelioma.

Neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene located on chromosome 22q12.2, is frequently abnormal in mesothelioma. Recent studies have revealed the effectiveness of diagnostic assays for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. These include detection of homozygous deletion of the 9p21 locus by fluorescence in situ hybridization (FISH) (9p21 FISH), loss of expression of BAP1 as detected by immunohistochemistry, and loss of expression of methylthioadenosine phosphorylase (MTAP) as detected by immunohistochemistry. However, the application of FISH detection of NF2 gene deletion (NF2 FISH) in differentiation of malignant pleural mesothelioma from reactive mesothelial hyperplasia has not been fully evaluated. In this study, we investigated whether NF2 FISH, either alone or in a combination with other diagnostic assays (9p21 FISH, MTAP immunohistochemistry, and BAP1 immunohistochemistry), is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia. This study cohort included malignant pleural mesothelioma (n = 47) and reactive mesothelial hyperplasia cases (n = 27) from a period between 2001 and 2017. We used FISH to examine deletion status of NF2 and 9p21 and immunohistochemistry to examine expression of MTAP and BAP1 in malignant pleural mesothelioma and in reactive mesothelial hyperplasia. Hemizygous NF2 loss (chromosome 22 monosomy or hemizygous deletion) was detected in 25 of 47 (53.2%) mesothelioma cases. None of the mesothelioma cases showed homozygous NF2 deletion. Hemizygous NF2 loss showed 53.2% sensitivity and 100% specificity in differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. A combination of NF2 FISH, 9p21 FISH, and BAP1 immunohistochemistry yielded greater sensitivity (100%) than that detected for either diagnostic assay alone (53.2% for NF2 FISH, 78.7% for 9p21 FISH, 70.2% for MTAP immunohistochemistry, or 57.4% for BAP1 immunohistochemistry). Thus, NF2 FISH in combination with other diagnostic assays is effective for distinguishing malignant pleural mesothelioma from reactive mesothelial hyperplasia.

Laparoscopic-assisted Stamm-gastrostomy: technical modifications to ease suturing inside the minimal trocar site.

Laparoscopic gastrostomy tube placement has been increasingly adopted by pediatric surgeons. We herein report our experience with the performance of a laparoscopic-assisted Stamm-operation inside the minimal trocar site without the extension of the trocar site incision or mini-laparotomy. We present some technical modifications that facilitate suturing inside the minimal trocar site. METHODS: A retrospective chart review was conducted of cases involving patients who underwent laparoscopic-assisted gastrostomy, using a simple extracorporeal method inside the trocar site from April 1998 to March 2018. RESULTS: One hundred five gastrostomy tubes were placed in a laparoscopic-assisted operation. All but two of the cases involved patients with neurological impairment. The mean age was 12.5 years; 28 cases were > 16 years of age. Seventy-five cases underwent gastrostomy during laparoscopic fundoplication. All gastrostomy procedures were completed without intraoperative difficulties; however, 8 cases, which involved a thick abdominal wall, required extension of the trocar site. No cases required conversion to open gastrostomy. No major complications were observed. Two patients developed continuous peristomal cellulitis after surgery, due to the mismatch of the site position and an unsuitable button device size. CONCLUSION: We demonstrated that laparoscopic gastrostomy with fully extracorporeal suturing within the trocar site is feasible and beneficial, especially for the most neurologically impaired pediatric cases. Technical modification, changing the order of the process, and suturing technique in the minimal space, made it easier to perform the procedures inside the minimal trocar hole.

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.

Fusuma Sliding Flap for Lip Reconstruction of Lower Lip Cancer.

Lower lip cancer is typically treated with surgical excision, and this frequently results in a large defect and severe aesthetic problems. Local flap reconstruction is suitable for restoring appearance and function, and it causes less surgical stress than a vascularized free flap. The Fusuma sliding flap is a local flap technique introduced by Kasai et al in 2008. Here, the authors report their use of this method for lip reconstruction in a 94-year-old Japanese female after the removal of a cancerous mass.

Bone metabolism of the jaw in response to bisphosphonate: a quantitative analysis of bone scintigraphy images.

We examined the changes in the bone metabolism of the jaw in response to BP treatment, and we used bone SPECT-CT to analyze the site-specific bone metabolism between the jaw and other sites of bone. We compared the changes in the bone metabolism of each part of bone in response to BP treatment by performing a quantitative analysis of bone scintigraphy images between patients treated with low-dose BP for osteoporosis (LBP group; n = 17), those treated with high-dose BP for metastatic bone tumor (HBP group; n = 11), and patients with other oral disease who required bone scintigraphy, with no history of BP treatment (control group; n = 40). The study endpoint was the mean standardized uptake value (SUV) of the uptake of Tc-99 m methylene diphosphonate (MDP) in each group. The mean SUVs of the HBP group were significantly lower at the axial bone of the cervical vertebra, thoracic vertebra, sternum, and rib compared to those of the LBP and control groups. The LBP group's mean SUV was significantly higher at the temporal bone, the anodontia part of the alveolar bone in maxilla, the vital teeth part of alveolar bone in the mandible, and the temporomandibular joint. There was no significant difference among the three groups at the mandibular angle and mandibular ramus. Our analyses revealed that the bone metabolism of the jaw and temporal bone in the BP-treated patients was enhanced, and no suppression of bone remodeling in the jaw by BP was observed.

[Pulmonary Mucormycosis with Reversed Halo Sign on Computed Tomography of Patient with Leukemia].

The patient was a male in his 60s, who had undergone bone marrow transplantation because of lymphoblastic leukemia. He suffered from chest pain two weeks after the transplantation. A chest computed tomography(CT) showed reversed halo sign( RHS) in the right upper lobe of the lung. A bronchoscopic lung biopsy revealed mycelia, and the patient was diagnosed with pulmonary mucormycosis. Although antifungal drugs were administered, no significant improvements were observed. A right upper lobectomy of the lung was successfully performed, and no postoperative complications occurred. Pathological examination found nodular lesions with extensive necrotic foci inside, and inflammatory granulation tissue and mucormycosis with hyphae (+) were found through Grocott staining. RHS in leukemia patients with neutropenia is specific to pulmonary mucormycosis. Pulmonary mucormycosis is a life-threatening disease, and urgent treatment intervention including surgical treatment is advisable.

[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.

[Automatic Linear Stapler].

The automatic linear stapler becomes the necessary device in today's chest surgery. These made simple and uniform suture techniques possible, but it is important to fully understand the usage and characteristics of automatic linear stapler for safe stapling. In this paper, we focus on the currently used stapler and describe its mechanism and its characteristics.

[Primary Lung Cancer Initially Suspected of Pulmonary Extranodal Marginal Zone Lymphoma of Mucosa Associated Lymphoid Tissue(MALT)].

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is associated with pre-existing infections or autoimmune disorders. We report a case of lung cancer initially suspected of MALT lymphoma. The patient was a 73-year-old woman. Complete screening examinations identified a tumor in the right middle lobe. Transbronchial lung biopsy revealed the infiltration of CD20+/CD79a+ lymphocytes invading the structure of the alveolus. MALT lymphoma was suspected, and the middle lobe was resected. The tumor was primarily invasive mucinous carcinoma, and lymphocytic infiltration was observed around the tumor. The monoclonal expansion of B cells and genetic and chromosomal abnormalities which are criteria for the diagnosis of MALT lymphoma were not demonstrated and the lesion was diagnosed as reactive lymphoid infiltrates. Marked lymphocytic infiltration regardless of neoplastic or reactive may suggest the presence of latent lesions.

The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration.

The duration of antiresorptive therapy is an important risk factor for medication-related osteonecrosis of the jaw. We performed a pilot study using quantitative analysis by bone scintigraphy to test the hypothesis that mandibular metabolism is affected by long-term bisphosphonate (BP) therapy. Our primary objectives were to assess changes in bone metabolism of the mandible in response to long-term BP therapy and compare the bone metabolism changes of the mandible with other bone sites. We compared the metabolic difference at the site in the mandible unaffected by disease, the humerus and the femur between 14 osteoporosis patients who were being treated with BP (BP group) and 14 patients who were not being treated with BP (control group) using a quantitative analysis and bone scintigraphy. Study endpoints were the mean and maximum bone uptake values (BUVs) quantified using bone scintigraphy images of the mandible, humerus and femur. Quantified images of the site in the mandible unaffected by disease had significantly higher mean and maximum BUVs compared to the controls (mean, 0.74 vs. 0.49, p = 0.019; max., 1.29 vs. 0.85, p = 0.009, respectively). The mean and maximum BUV of femur ROIs in the BP group were significantly lower than those in control patients (mean BUV, 0.23 vs. 0.30, p = 0.039; max. BUV, 0.43 vs. 0.53, p = 0.024, respectively). This is the first report of mandible changes in response to long-term BP treatment, using bone scintigraphy. The results using bone scintigraphy demonstrated that the bone metabolism of the intact mandible is affected by a long-term administration of BP.

[Benign Metastasizing Leiomyoma of the Lung;Report of a Case].

A 71-year-old woman, in whom computed tomography revealed a solitary mass shadow at the base of the left lung, underwent resection of the mass. Histopathological examination showed estrogen receptor-positive leiomyoma cells growing in cords and mixed with glandular structures composed of alveolar cells. These findings led to a diagnosis of benign metastatic leiomyoma. Benign metastatic leiomyoma is a rare disease in which histologically benign uterine leiomyoma cells metastasize to different sites of the body. However, in this patient, the presence of uterine myoma was not confirmed in the past or at present. She had a history of cervical conization, which suggests that a small amount of the leiomyoma component contained in cervical tissue may have been forced into blood vessels during surgical manipulation, causing lung metastasis.

BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests.

Differentiation of malignant pleural mesothelioma (MPM) from benign mesothelial proliferation remains problematic. Loss of nuclear staining of BRCA1-associated protein 1 (BAP1; detected using immunohistochemistry (IHC)) and homozygous deletion (HD) of p16 (detected using fluorescence in situ hybridization (FISH)) are useful for differentiation of MPM from reactive mesothelial hyperplasia (RMH), but the correlation between BAP1 expression loss and p16 HD has not been fully described. We performed BAP1 IHC and p16-specific FISH for 40 MPM and 20 RMH cases, and measured proportions of cells showing BAP1 expression and p16 HD for each case. The diagnostic accuracy for MPM and the cut-off values of the two methods were assessed using receiver operating characteristic (ROC) analysis. BAP1 expression loss, p16 HD and coexistence of both were present in 27 (67.5 %), 27 (67.5 %) and 17 (42.5 %) MPM cases, respectively. Three MPM cases (7.5 %) and all 20 RMH cases had neither BAP1 loss nor p16 HD. There was no correlation between the results of the two methods. Their combination showed higher sensitivity (92.5 %, 37/40) and estimated probability than BAP1 IHC and p16-specific FISH used alone. BAP1 IHC and p16-specific FISH have independent diagnostic value, and have increased reliability when used in combination, for MPM diagnosis.

[Prevention and Treatment Strategy for Infectious Complication after Lung Transplantation].

The most frequent cause of death within a year after lung transplantation is infectious complications, which shifts to chronic allograft rejection or chronic lung allograft dysfunction(CLAD) thereafter. It is no doubt that minimization of the dose of immunosuppression within the acceptable therapeutic range is a best strategy to avoid infectious complications however, adequate dose of immunosuppressant is mandatory to protect lung allografts from acute or chronic rejection. Carefully balanced therapy of immunosuppression and infection control is extremely important for patient's long term survival after lung transplantation. Total 344 transplants were performed in Japan until the end of 2013, and the 5-year post-operative survival was reported as more than 70% which is superior than North American or European registry data. However, more than 30% of death is still caused by infectious complications thus appropriate prevention and treatment for infection is important for better long term results. Here in this paper, the 1st 10-year experience of Fukuoka University Lung Transplant Program was reported and discussed especially focusing on infectious complications.

Deletion status of p16 in effusion smear preparation correlates with that of underlying malignant pleural mesothelioma tissue.

Differentiating malignant pleural mesothelioma (MPM) cells morphologically from reactive mesothelial hyperplasia cells is problematic. Homozygous deletion (HD) of p16 (CDKN2A), detected by FISH, is a good marker of malignancy and is useful to differentiate between these cells. However, the correlation between the p16 status of effusion smears and that of the underlying MPM tissues has not been investigated. We used p16-specific FISH to investigate 20 cases of MPM from which both effusion cytologic smears and histologic specimens were available. In five cases, histologic specimens included both an invasive component and surface mesothelial proliferation. In 14 cases (70%), MPM cells in both tissue sections and effusion smears were p16 HD-positive. Conversely, MPM cells in the remaining six tumors (30%) were p16 HD-negative in both tissue sections and effusion smears. For all five MPM cases with surface mesothelial proliferations and invasive components, the effusion smears, surface mesothelial proliferations, and invasive MPM components all displayed p16 deletion. Moreover, the extent to which p16 was deleted in smears highly correlated with the extent of p16 deletion in tissues. The p16 deletion percentages were also similar among smears, tissue surface proliferations, and invasive components. In cases with clinical and radiologic evidence of a diffuse pleural tumor, detection of p16 deletion in cytologic smear samples may permit MPM diagnosis without additional tissue examination. However, the absence of p16 deletion in cytologic smear samples does not preclude MPM.

Is the Geriatric Nutritional Risk Index a Significant Predictor of Postoperative Complications in Patients with Esophageal Cancer Undergoing Esophagectomy?

BACKGROUND: The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced for predicting the risk of nutrition-related complications. The GNRI has mainly been reported as a simple and accurate tool to assess the nutritional status and prognosis of elderly patients. So far, there have been no reports of the GNRI in patients with gastrointestinal cancer. Our objective was to examine the association between the GNRI and short-term outcomes, especially postoperative complications, in patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. MATERIALS AND METHODS: The present study enrolled 122 consecutive patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. The GNRI at admission to the hospital was calculated as follows: (1.489 × albumin in g/l) + (41.7 × present/ideal body weight). The characteristics and short-term outcomes were compared between two groups: the high (GNRI ≥90) and the low (GNRI <90) GNRI group. The mortality and morbidity rates, especially the rates regarding respiratory complications and anastomotic leakage, were investigated. RESULTS: The mean age of the 122 patients was 63.9 ± 9.1 years (range 43-83). There were no significant differences in either patient or operative characteristics. The low GNRI group had a significantly higher rate of respiratory complications (p = 0.002). A multivariate analysis demonstrated that the GNRI was the only independent significant factor predicting respiratory complications (hazard ratio 3.41, 95% confidence interval 1.19-9.76; p = 0.022). CONCLUSION: The GNRI is considered to be a clinically useful marker that can be used to assess the nutritional status and predict the development of postoperative respiratory complications in patients with esophageal cancer undergoing esophagectomy and gastric tube reconstruction.

[Diagnosis and Treatment of Hemothorax].

Most cases of hemothorax are related to blunt trauma, procedures, neoplasm such as schwanommas of von-Recklinghausen disease and soft-tissue tumors, and vascular ruptures. Spontaneous pneumothorax is also a caused of spontaneous hemothorax. Hemothorax may result in respiratory distress, respiratory failure, retained clot, fibrothorax, empyema and extended hospitalization. We should attempt to clear the chest cavity as early in the hospital course as the patient's physiology will allow. The management of hemothorax has been a complex problem since it was 1st described over 200 years ago. Traditionally, lrage hemothorax is treated primarily by closed thoracic drainage by inserting a large-caliber chest tube in stable patients. In hemodynamically unstable patients with more than 1,000 ml of blood drainage from the initial thoracotomy or ongoing blood losses of more than 100 to 200 ml/h, an early surgical approach with ongoing resuscitation is needed. Video-assisted thoracoscopic surgery (VATS), minimally invasive surgery, grows and finds new applications for the patients with hemothorax as both diagnostic and therapeutic interventions recently. VATS is an accurate, safe, and reliable operative therapy in the 5-day post event window, but there is a decreasing success rate after this time period.