Withdrawal from Hemodialysis in a Patient with IgD Type Multiple Myeloma: A Case-based Review.

Several previous case reports have shown that patients with immunoglobulin D (IgD) multiple myeloma (MM) can be withdrawn from hemodialysis, however, the characteristics that can predict withdrawal in these patients have not yet been elucidated. A 57-year-old Japanese woman required hemodialysis because of renal dysfunction due to IgD-λ and Bence Jones protein-λ MM. Bortezomib-based chemotherapy nine days after admission led to her withdrawal from hemodialysis on Day 50. In our case-based review, younger age and early initiation of bortezomib-based chemotherapy emerged as possible predictors of successful hemodialysis withdrawal.

Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.

To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B-cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B-cell and T-cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.

Time to Incurable Recurrence for Patients Treated With Pulmonary Metastasectomy for Colorectal Cancer.

BACKGROUND: Probability of cure is important for patients with lung metastasis who must decide whether to undergo metastasectomy. Although progression-free survival (PFS) is thought to reflect this, it does not include curative effects by repeat metastasectomy. Thus, the authors developed a new indicator, time to incurable recurrence (TTIR), in which only incurable recurrence was set as an event that included death, with incurable recurrence defined as recurrence not treated by definitive local therapy (DLT), recurrence treated by DLT but with PFS maintained less than 2 years, or recurrence followed by re-recurrence. METHODS: This multi-institutional study included 339 patients who underwent lung metastasectomy for colorectal cancer between 1990 and 2008. RESULTS: Among the 339 patients, 191 experienced recurrence, 77 received DLT for recurrence, 38 had a PFS of 2 years or longer after the treatment, and 33 had maintained a PFS at the last follow-up date. The patients had PFS ranging from 39 to 212 months (median, 101 months). The 5-year OS, PFS, and TTIR rates were respectively 63.4%, 42.2%, and 51.9%. The TTIR curve was similar to the OS curve 7 years after the initial metastasectomy. The difference between TTIR and PFS at 7 years was 9.7%, indicating probability of cure by repeat DLT. Multivariable analysis showed different prognostic factors among OS, PFS, and TTIR. CONCLUSION: At the initial metastasectomy, TTIR may reflect probability of a cure, including cure by repeat DLT, and can be used to analyze prognostic factors associated with cure.

Added Diagnostic Value of Cerebrospinal Fluid Carcinoembryonic Antigen in a Patient with Leptomeningeal Carcinomatosis as the Initial Manifestation of Gastric Cancer.

A 77-year-old woman with no history of malignancy presented with anorexia and bilateral lower extremity weakness. Her consciousness level worsened daily, so we performed a lumbar puncture. Cerebrospinal fluid (CSF) analysis indicated meningitis, but three rounds of CSF cytology showed no malignant cells. The patient's carcinoembryonic antigen (CEA) level was highly elevated in CSF, but normal in serum. Through gadolinium-enhanced brain/spinal magnetic resonance imaging and gastrointestinal endoscopy, she was diagnosed with leptomeningeal carcinomatosis (LC) from gastric cancer. CEA level in CSF facilitated the diagnosis of LC from gastric cancer because there were no malignant cells on CSF cytology.

Usefulness of Plasma Exosomal MicroRNA-451a as a Noninvasive Biomarker for Early Prediction of Recurrence and Prognosis of Non-Small Cell Lung Cancer.

OBJECTIVES: The aim of this study was to clarify the usefulness of plasma exosomal microRNA-451a (miR-451a) as a novel biomarker for the early prediction of recurrence and prognosis in non-small cell lung cancer (NSCLC) patients after curative resection. METHODS: Before surgery, plasma samples were collected and exosomal microRNA (miRNA) levels were evaluated. We first profiled specific exosomal miRNAs related to recurrence in 6 NSCLC patients with stage IA cancer by miRNA microarray. We then validated the usefulness of selected miRNAs as biomarkers using the other 285 NSCLC patients. RESULTS: Plasma exosomal miR-451a showed the highest upregulation in the NSCLC patients with recurrence in the miRNA microarray analysis. A significant positive correlation was demonstrated between exosomal miR-451a levels and NSCLC tissue miR-451a levels. Exosomal miR-451a showed a significant association with lymph node metastasis, vascular invasion, and stage. In stage I, II, or III patients, the overall survival (OS) and disease-free survival (DFS) rates among the high-exosomal-miR-451a patients were significantly worse than those among the low-exosomal-miR-451a patients. In Cox multivariate analysis, exosomal miR-451a showed significance for OS and DFS. CONCLUSION: Plasma exosomal miR-451a might serve as a reliable biomarker for the prediction of recurrence and prognosis in NSCLC patients with stage I, II, or III cancer.

Nuclear factor-kappa B influences early phase of compensatory lung growth after pneumonectomy in mice.

BACKGROUND: Compensatory lung growth (CLG) is a well-established lung regeneration model. However, the sequential mechanisms, including unknown molecular triggers or regulators, remain unclear. Nuclear factor- kappa B (NF-κB) is known to be essential for inflammation and tissue regeneration; therefore, we investigated the role of NF-κB in CLG. METHODS: C57BL/6 J mice underwent either a left pneumonectomy or a thoracotomy (n = 77). Gene microarray analysis was performed to detect genes that were upregulated at 12 h after pneumonectomy. NF-κB protein expression was examined by immunohistochemistry and Western blot. To investigate the influence of NF-κB on CLG, either an NF-κB inhibitor SN50 or saline was administered following pneumonectomy and the degree of CLG was evaluated in each group by measuring the lung dry weight index (LDWI) and the mean linear intercept. RESULTS: Gene microarray analysis identified 11 genes that were significantly but transiently increased at 12 h after pneumonectomy. Among the 11 genes, NF-κB was selected based on its reported functions. Western blot analysis showed that NF-κB protein expression after pneumonectomy was significantly higher at 12 h compared to 48 h. Additionally, NF-κB protein expression at 12 h after pneumonectomy was significantly higher than at both 12 and 48 h after thoracotomy (p < 0.029 for all). NF-κB protein expression, evaluated through immunohistochemistry, was expressed mainly in type 2 alveolar epithelial cells and was significant increased 12 h after pneumonectomy compared to 48 h after pneumonectomy and both 12 and 48 h after thoracotomy (p < 0.001 for all). SN50 administration following pneumonectomy induced a significant decrease in NF-κB expression (p = 0.004) and LDWI compared to the vehicle administration (p = 0.009). CONCLUSIONS: This is the first report demonstrating that NF-κB signaling may play a key role in CLG. Given its pathway is crucial in tissue regeneration of various organs, NF-κB may shed light on identification of molecular triggers or clinically usable key regulators of CLG.

Predictors of long-term compensatory response of pulmonary function following major lung resection for non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: Long-term pulmonary function which might include compensatory response (CR) significantly influences quality of life of long-term survivor after major lung resection. We investigated long-term pulmonary function after major lung resection. METHODS: A total of 137 patients who had undergone lobar resection for non-small cell lung cancer (NSCLC) from May 2013 to June 2014 had spirometry at 10-14 months after surgery. Actual post-operative forced expiratory volume in 1 s (FEV1 ) (FEV1apo )/predicted post-operative FEV1 (FEV1ppo ), actual post-operative forced vital capacity (FVC) (FVCapo )/predicted post-operative FVC (FVCppo ), its relationship with clinicopathological factors and immunohistochemistry for pro-surfactant protein C (pro-SPC), thyroid transcription factor-1 (TTF-1) and vascular endothelial growth factor receptor 2 (VEGFR2) were investigated. RESULTS: FEV1apo /FEV1ppo showed strong correlation with FVCapo /FVCppo (r = 0.628; P < 0.001). We defined greater CR as both FEV1apo /FEV1ppo and FVCapo /FVCppo were >120%. Greater CR was significantly associated with decreased smoking index (P < 0.001) and greater resected subsegments (P = 0.037). The never-smoker group revealed significantly greater CR compared with the smoker group in both FEV1apo /FEV1ppo (119.9 ± 12.5% vs 107.5 ± 14.2%; P = 0.030) and FVCapo /FVCppo (117.9 ± 9.98% vs 107.2 ± 13.1%; P = 0.046) in case-matched comparison. The expression of pro-SPC, TTF-1 and VEGFR2 in the normal lung parenchyma of greater CR group was significantly higher than those of lesser CR group (P < 0.001 for each). In addition, pro-SPC, TTF-1 and VEGFR2 expressions showed a significant correlation to the degree of CR especially in the smoker group (r = 0.631, 0.705 and 0.732, respectively; P < 0.001 for each). CONCLUSION: Our data suggest that smokers may develop lesser long-term CR after major lung resection. Decreased expression of pro-SPC, TTF-1 and VEGFR2 may indicate decreased capacity of CR, especially in patients who smoke.

Outcome and risk factors of recurrence after thoracoscopic bullectomy in young adults with primary spontaneous pneumothorax.

PURPOSE: To investigate the risk factors of recurrence of pneumothorax following thoracoscopic bullectomy in young adults. METHODS: Between January, 2005 and September, 2015, 167 patients aged ≤40 years underwent initial thoracoscopic bullectomy for primary spontaneous pneumothorax (PSP) at our hospital. Recurrence-free probability was calculated from the date of surgery to recurrence or last follow-up, using the Kaplan-Meier method. RESULTS: Sixteen (9.6%) of the 167 patients suffered a recurrence (collective total, 16 recurrences). The recurrence-free intervals were 3-107 months (median 25.8 months), and the 5-year recurrence-free probability was 85.9%. Multivariate Cox analysis demonstrated that age ≤23 years (p = 0.029) and a history of ipsilateral pneumothorax before surgery (p = 0.029) were significantly associated with higher risk of recurrence. The 5-year recurrence-free probability was 72.3% for patients aged ≤23 years and a history of ipsilateral pneumothorax before surgery and 94.1% for those with neither of these factors (p = 0.001). Recurrence developed within 3 years after surgery in 14 of the 16 patients. CONCLUSIONS: Patients ≤23 years of age with a history of ipsilateral pneumothorax before surgery are at significantly high risk of its recurrence, frequently within 3 years; thus, the risk of postoperative recurrence of a pneumothorax must be kept in mind.

[Management of Postoperative Wound Infection and Empyema].

Postoperative wound infection and empyema after pulmonary surgery is considered surgical site infection. Postoperative empyema (PE) is a rare but potentially fatal complication of pulmonary resections and proper management is essential. Appropriate antibiotics and surgical treatment is necessary to cure the PE. PE is often associated with bronchopleural fistula, which makes the management of PE difficult. The treatment of empyema has the basic way of thinking, but there are various cures, closed tube thoracostomy, video-assisted thoracoscopy, emergency open window thoracostomy, and Endoscopic conservative treatment may necessary.

Optimized magnitude of cryosurgery facilitating anti-tumor immunoreaction in a mouse model of Lewis lung cancer.

BACKGROUND: Cryosurgery has reemerged as a less invasive local treatment with possible immune-regulatory effects. However, the optimal magnitude of cryosurgery for achieving immune-regulatory responses at abscopal tumor sites remains unclear. We aimed to investigate appropriate magnitude of cryosurgery for this goal using a mouse model. METHODS: C57BL/6J mice were inoculated with Lewis lung carcinoma cells or B16 melanoma cells in bilateral flanks. The left-sided tumor was cryoablated with repeated freeze/thaw cycles either once, twice, or thrice. The peritumoral injections of LPS were performed. Abscopal tumor volumes were measured, immunohistochemistry was performed for CD4, CD8, Foxp3, and Ki-67, and proinflammatory cytokines were measured in lavage fluid of cryoablated tumor. RESULTS: The growth rate of the abscopal tumor was slowest in the Cryosurgery ×2 group among the five experimental groups. The proportions of CD4(+) T cells and CD8(+) T cells in the abscopal tumor were also significantly higher in the Cryosurgery ×2 group. The levels of IL-1ß, IL-2, IL-6, IL-12ß, IFN-γ, and TNF-α in the peritumoral lavage fluid in Cryosurgery ×2 + LPS group were significantly increased compared with the other groups. CONCLUSIONS: This study suggested that achievement of approximately 73 % damaged area in the cryoablated tumor by two cycles of cryosurgery generates the most favorable immune-regulatory response for abscopal tumors via activation of anti-tumor immune cells as well as increased secretion of proinflammatory cytokines.

Neutrophil-Lymphocyte Ratio as a Prognostic Marker for Lung Adenocarcinoma After Complete Resection.

BACKGROUNDS: The neutrophil-lymphocyte ratio (NLR) is a simple and low-cost index that may be a benchmark for systemic inflammatory response and antitumor immunity. The goal of the study was to investigate the prognostic value of preoperative NLR in patients with lung adenocarcinoma after complete resection. METHODS: The subjects were 361 consecutive patients with lung adenocarcinoma who underwent complete resection between 2000 and 2009. Perioperative clinical and laboratory data were evaluated retrospectively. The cohort was divided using the cut-off value for preoperative NLR identified in receiver operating characteristic analysis. Correlations of NLR with clinicopathological characteristics and prognosis were examined. RESULTS: A high NLR was significantly correlated with a smoking history >10 pack-years (p = 0.023), pathological stage II or III (p < 0.001), lymphatic invasion (p = 0.003), and pleural invasion (p = 0.039). In univariate analysis, the high NLR group had significantly lower 5-year overall survival (86.0 vs. 77.1 %, p < 0.001) and 5-year recurrence-free survival (75.1 vs. 59.9 %, p < 0.001). Multivariate analysis showed that NLR was an independent prognostic factor (hazard ratio 1.822, 95 % confidence interval 1.133-2.931, p = 0.013). CONCLUSION: These results show that preoperative NLR is an independent prognostic factor in patients with lung adenocarcinoma after complete resection. NLR may reflect host immunity and systemic inflammation that facilitates tumor growth.

Efficacy and hemodynamic response of pleural carbon dioxide insufflation during thoracoscopic surgery in a swine vessel injury model.

PURPOSES: Thoracoscopic anatomical lung resection is a minimally invasive technique, but intraoperative massive bleeding is a critical complication. We investigated the hemostatic efficacy and safety of intrapleural carbon dioxide (CO2) insufflation in thoracoscopic surgery in a swine vessel injury model. METHODS: Swines were assigned to one of four groups subjected to thoracoscopic surgery under target intrathoracic pressures of 0, 5, 10, or 15 mmHg CO2 insufflation, respectively. A pin-hole injury of the right cranial lobe pulmonary vein was inflicted thoracoscopically and we compared the blood loss and hemodynamic changes in each group. RESULTS: There were no signs or echographic findings of air embolus. Both the blood loss per minute and total blood loss during the experiment were significantly lower in the 10 and 15 mmHg groups than in the 0 mmHg group (p > 0.05, respectively). The hemodynamic signs, including heart rate, mean arterial pressure, and peripheral oxygen saturation, were not significantly different in the 0 and 10 mmHg groups at most times, although they were significantly correlated with the insufflation pressure during the experiments (p < 0.05). CONCLUSIONS: CO2 insufflation in thoracoscopic major lung resection appears to be safe, even in the short term, and can help to control vessel injury.

Toll-like receptor 3 ligand specifically induced bronchial epithelial cell death in caspase dependent manner and functionally upregulated Fas expression.

BACKGROUND: Viral infections are the most common cause of asthma exacerbation. Virally infected epithelial cells undergo apoptosis. Although in healthy conditions, apoptosis may have a host-defensive role in limiting virus spread, this process may have a detrimental effect on damaged epithelium in asthma. Toll-like receptors (TLRs) are the receptors for various pathogens, and viruses possess several components that can activate TLR3, TLR4, and TLR7/8. However, as it has not been determined as to which component is responsible for virus-induced epithelial cell apoptosis, we comprehensively analyzed the effects of all TLR ligands on apoptosis. METHODS: BEAS-2B cells or primary cultured human bronchial epithelial cells (PBECs) were stimulated by TLR 2, 3, 4, 5, 7/8, and 9 ligands and cell death was analyzed by flow cytometry. Chemokine generations induced by these ligands were also analyzed. RESULTS: The TLR3 ligand polyinosinic-polycytidylic acid (poly I:C) specifically induced chemokine generation and apoptosis, while other TLR ligands including those for TLR5, 7/8, and 9 had no effect. The response to poly I:C had two phases, which included rapid secretion of chemokines and subsequent apoptosis in a later phase. Poly I:C induced apoptosis in a caspase-dependent manner and functionally upregulated the expression of Fas. CONCLUSIONS: Previous findings indicating that viruses induced caspase-dependent death and upregulated Fas expression were reproduced by poly I:C, suggesting the central role of dsRNA/TLR3 in virus-induced apoptosis. Since these processes may have detrimental effects on pre-existing epithelial damage, the dsRNA/TLR3 pathway may be potential novel treatment target for virus-induced exacerbation of asthma.

[Anti-PD-1 Antibody Drugs - Potential of Plasma PD-L1 Protein as a Biomarker].

The superior therapeutic effects of antibodies targeting immune checkpoints have been reported in the treatment of various cancers including non-small cell lung cancer(NSCLC)and malignant melanoma. However, the risk of reactivity against selfantigens and the high prices of these drugs are major concerns. Previously, PD-L1 protein expression and the number of infiltrating T cells in tumor tissues were investigated by immunohistochemical staining, as biomarkers for therapeutic anti-PD- 1 antibodies. However, further research into the clinical significance of PD-L1 expression in tumor tissues is still required. A promising and comprehensive gene mutation analysis of tumor tissues and T cell repertoire analysis has recently been undertaken. Liquid biopsy, which has the benefit of being minimally invasive, has also been investigated. We are currently, investigating the utility of plasma PD-L1 protein levels as a predictive biomarker of prognosis in NSCLC. Furthermore, it is important to explore useful biomarkers and develop reliable companion diagnostics for the individualized treatment with immune checkpoint drugs.

Leptin enhances ICAM-1 expression, induces migration and cytokine synthesis, and prolongs survival of human airway epithelial cells.

There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and a human airway epithelial cell line, BEAS-2B. Flow cytometry showed enhanced ICAM-1 expression by both of those cells in response to leptin, and that effect was abrogated by dexamethasone or NF-κB inhibitor. Flow cytometry and quantitative PCR showed that airway epithelial cells expressed leptin receptor (Ob-R), whose expression level was downregulated by leptin itself. Multiplex cytokine analysis demonstrated enhanced production of CCL11, G-CSF, VEGF, and IL-6 by BEAS-2B cells stimulated with leptin. Furthermore, transfection of Ob-R small interference RNA decreased the effect of leptin on CCL11 production as assessed by quantitative PCR. Finally, leptin induced migration of primary airway epithelial cells toward leptin, suppressed BEAS-2B apoptosis induced with TNF-α and IFN-γ, and enhanced proliferation of primary airway epithelial cells. In summary, leptin was able to directly activate human airway epithelial cells by binding to Ob-R and by NF-κB activation, resulting in upregulation of ICAM-1 expression, induction of CCL11, VEGF, G-CSF, and IL-6 synthesis, induction of migration, inhibition of apoptosis, and enhancement of proliferation.

Prognostic Significance of Preoperative Neutrophil-Lymphocyte Ratios in Patients with Stage I Non-small Cell Lung Cancer After Complete Resection.

BACKGROUND: The immune system has been shown to play an important role in preventing cancer progression. The neutrophil-lymphocyte ratio (NLR) has been proposed to be an indicator of a systemic inflammatory response. We investigated the prognostic significance of NLR in patients with completely resected stage I non-small lung cancer (NSCLC). METHODS: A series of 343 pathological stage I NSCLC patients, completely resected between 2000 and 2008 at a single institution, were evaluated retrospectively. Perioperative clinical and laboratory data were collected, and the cohort was divided into two groups according to preoperative NLR. We examined the correlation between NLR and clinicopathological parameters and determined the prognostic significance. RESULTS: High NLR was significantly correlated with patients of older age (p = 0.045), preoperative hypoalbuminemia (p = 0.030), and nonadenocarcinoma histology (p = 0.045). Upon univariate analysis, the high NLR group had significantly lower 5-year recurrence-free survival (81.2 vs. 59.9 %, p < 0.001) and 5-year overall survival (89.2 vs. 72.8 %, p < 0.001) than the low NLR group. Multivariate analysis showed that NLR was an independent prognostic factor (hazard ratio 2.141, 95 % confidence interval; 1.306-3.515, p = 0.003). In terms of initial recurrent sites, the proportion of patients who developed distant metastasis was significantly higher in the high NLR group than in the low NLR group (p < 0.001). CONCLUSIONS: Preoperative high NLR is a significant predictor of poor prognosis and is associated with more frequent distant metastasis in patients with completely resected stage I NSCLC. This readily available and simply calculated ratio provides useful information for the clinician to consider in terms of perioperative management.

Pregabalin reduces post-surgical pain after thoracotomy: a prospective, randomized, controlled trial.

PURPOSE: A new perioperative management method was explored by assessing the safety and the efficacy of pregabalin for the treatment of intercostal neuralgia after thoracotomy. METHODS: The study was conducted on 68 adult patients scheduled to undergo thoracotomy. Patients were randomly divided into two groups; a NSAIDs group, where 34 patients were orally administered loxoprofen three times daily and a pregabalin group, where 34 patients were orally administered 75 mg of pregabalin twice daily, starting on the day of surgery and continuing for 2 weeks. The pain scores, sleep interference and the incidence of neuropathic pain were evaluated on days 1, 3 and 7, and at weeks 4, 8 and 12 after surgery. The frequency of pain medication use in the first week after surgery and the adverse effects in each group were also examined. RESULTS: The pain scores, sleep interference and incidence of neuropathic pain were significantly lower (p < 0.001) at all time points in the pregabalin group. The use of additional pain medication during the first week after surgery was not significantly different between the groups. The only significant adverse effect was a stomach ache in the NSAIDs group, while mild drowsiness was reported in the pregabalin group. CONCLUSION: Pregabalin is considered to be an effective and safe drug for the treatment of pain after thoracotomy.

Mediastinal hemorrhage due to ectopic parathyroid hyperplasia with long-term hemodialysis: report of a case.

Secondary hyperparathyroidism can sometimes occur among long-term hemodialysis patients. We herein present the case of a 48-year-old female who underwent surgical resection to treat a mediastinal hemorrhage from an ectopic parathyroid. She had been receiving dialysis for the past 16 years due to renal failure. She visited the hospital due to chest pain, and a CT scan revealed a tumorous lesion in the anterior mediastinum. An increase in size of the tumorous lesion, accompanied by bilateral pleural fluid, was observed. Emergency surgery was performed due to a diagnosis of a mediastinal hemorrhage from the tumorous lesion, accompanied by a decrease in the Hb value. The pathological findings of the hematoma revealed parathyroid hyperplasia. This is a rare case report of an ectopic parathyroid developing hyperplasia which caused a mediastinal hemorrhage due to secondary hyperparathyroidism.