Postprandial hypoglycemia caused by the combination of clarithromycin and rifampicin in a patient with nontuberculous mycobacterial pulmonary disease.

Most cases of nontuberculous mycobacterial pulmonary disease (NTM-PD) have a progressive clinical course, and initiation of treatment is recommended rather than watchful waiting. The NTM-PD medications are frequently associated with adverse reactions, occasionally serious. Optimization of the methods for monitoring and managing adverse events in NTM-PD treatment is thus an important medical issue. Here we report a first case of postprandial hypoglycemia caused by the combination of clarithromycin (CAM) and rifampicin (RFP) in a patient with NTM-PD. A 73-year-old Japanese woman with NTM-PD was hospitalized for treatment with a combination of oral CAM, RFP, and ethambutol. She took the first doses of antibiotics before breakfast, and 3 h later went into a hypoglycemic state. Postprandial hypoglycemia occurred with high reproducibility and was accompanied by relative insulin excess. Continuous glucose monitoring with or without food and in combination with various patterns of medication revealed that the combination of CAM and RFP specifically induced postprandial hypoglycemia. Shifting the timing of administration of the CAM and RFP combination from morning to before sleep corrected the hypoglycemia and enabled continuation of the antimicrobial treatment. In conclusion, our report suggests the importance of introducing NTM-PD medication under inpatient management in order to closely monitor and early detect postprandial hypoglycemia and other serious adverse events.

GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity.

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr-/-) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr-/- mice survived longer than controls after LPS-induced lung injury. Ghsr-/- mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr-/- mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

Clinical application of ghrelin for chronic respiratory failure.

Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure.

Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced in the human stomach. Although ghrelin has therapeutic potential for cancer cachexia, ghrelin treatment may have a concern about accelerating cancer progression. Here, using the human lung adenocarcinoma cell line HLC-1, we investigated the effects of ghrelin on molecular mechanisms linked to cancer progression, including cell viability, proliferation, resistance to apoptosis, and mitochondrial activity. Both types of mouse alveolar epithelial cells (types I and II) expressed the GHSR, as did the human normal airway cell lines BEAS-2B and HLC-1. Treatment with ghrelin (10-2, 10-1, 1, 10 µM) did not affect cell viability or proliferation. Pretreatment of HLC-1 cells with ghrelin (10 µM) did not affect resistance to paclitaxel-induced apoptosis. The parameters of mitochondrial respiration, including basal respiration, proton leak, ATP production, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration, of the HLC-1 cells pretreated with or without ghrelin were unchanged. Taken together, ghrelin does not influence cancer progression in lung adenocarcinoma cells.

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections.

Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence-clearance-regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

Ghrelin administration for chronic respiratory failure: a randomized dose-comparison trial.

BACKGROUND: Repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. We investigated the optimal ghrelin dose for underweight patients with chronic respiratory failure. METHODS: In this multicenter, randomized, dose-comparison exploratory study, 44 cachectic patients with chronic respiratory failure were randomly assigned pulmonary rehabilitation with intravenous twice-daily administration of 1 or 2 µg/kg ghrelin for 3 weeks. The primary endpoint was improvement in 6-min walking distance (6 MWD). The secondary endpoint was change in peak VO2. RESULTS: Twenty-one patients were assigned to the 1 µg/kg ghrelin group and 23 to the 2 µg/kg ghrelin group. Change from baseline 6 MWD after treatment was similar between groups(1 µg/kg: 53.9 m, 2 µg/kg: 53.9 m, p = 0.99). Mean change in peak VO2 was significantly greater in the 2 µg/kg group (63.1 ml/min) than in the 1 µg/kg group (-63.8 ml/min, p = 0.048). Food intake and lean body mass significantly increased in both groups, and the St. George Respiratory Questionnaire score, body weight, and body mass index were remarkably improved in only the 2 µg/kg group, although there was no significant difference between groups. No treatment-related serious events were reported for either group. CONCLUSION: Improvements in the oxygen uptake capacity were greater in patients receiving 2 µg/kg ghrelin twice daily for 3 weeks than in those receiving 1 µg/kg, although exercise tolerance was similar between groups at the end of the 3-week treatment period. Thus, a twice daily dose of 2 µg/kg ghrelin is recommended over 1 µg/kg ghrelin for patients with chronic respiratory failure and weight loss.

Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner.

Acute lung injury (ALI) is a critical syndrome consisting of acute respiratory failure associated with extensive pulmonary infiltrates. The pathological characterization of ALI includes injuries of alveolar epithelial cells (AECs), alveolar neutrophilic infiltration, and increases in proinflammatory cytokines, which cause destruction of the alveolar capillary barrier and subsequent devastating lung fibrosis. Rikkunshito (RKT), a traditional Japanese herbal medicine, is widely used for the treatment of patients with gastrointestinal symptoms and is known to stimulate ghrelin secretion. The therapeutic effects of RKT on organ inflammation and fibrosis remain unknown. We investigated the pharmacological potential of RKT in the treatment of ALI by using a bleomycin-induced ALI model in mice. RKT or distilled water (DW) was given to mice daily starting 12 h after bleomycin administration. The RKT-treated mice showed a definitively higher survival rate than the DW-treated mice after injury. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of proinflammatory cytokines, activation of the NF-κB pathway, apoptosis of AECs, and subsequent lung fibrosis were notable in the RKT-treated mice. RKT administration increased the plasma ghrelin levels in wild-type mice, and it also mitigated the ALI response in both ghrelin-deficient mice and growth hormone secretagogue receptor-deficient mice after lung injury. Our results indicate that RKT administration exerts protective effects against ALI by protecting the AECs and regulating lung inflammation independently of the ghrelin system, and they highlight RKT as a promising therapeutic agent for the management of this intractable disease.

Epithelial Pten controls acute lung injury and fibrosis by regulating alveolar epithelial cell integrity.

RATIONALE: Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVES: To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS: Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Δ/Δ) (SOPten(Δ/Δ)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: SOPten(Δ/Δ) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Δ/Δ) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-ß1 expressions. Akt inactivation definitively saved SOPten(Δ/Δ) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

Resolvin D4 mitigates lipopolysaccharide-induced lung injury in mice.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition involving severe lung inflammation. The excessive oxidative stress and persistent inflammation that occur in ARDS lead to decreased epithelial integrity and hypoxemia due to pulmonary edema via increased vascular permeability. Resolvin D4 (RvD4) is one of the lipid mediators that is biosynthesized from omega-3 polyunsaturated fatty acids. It plays a role in the resolution of inflammation and reduces oxidative stress and cell death. We investigated the therapeutic potential of the administration of RvD4 in a murine model of lipopolysaccharide (LPS)-induced ARDS. Concurrent with the intratracheal administration of LPS, RvD4 or saline was administered to mice via the caudal vein every 12 h. This treatment with RvD4 alleviated the LPS-induced infiltration of inflammatory cells in lungs, inhibited increased pulmonary vascular permeability, decreased the levels of IL-1ß, IL-6, and TNF-α in bronchoalveolar lavage fluid (BALF), and suppressed the reduction of the expression levels of the tight junction protein, Zonula occludens-1 (Zo-1) and the NAD+-dependent deacetylase, Sirtuin-3 (Sirt3). In vitro experiments revealed that in LPS-stimulated BEAS-2B cells, treatment with RvD4 suppressed the increases in the expressions of pro-inflammatory cytokines and maintained the epithelial cell barrier function and cell viability. The silencing of SIRT3 abolished both the anti-inflammatory effect and the retention of cell integrity in BEAS-2B cells. Together these results indicate that treatment with RvD4 can (i) protect against LPS-induced lung injury by inhibiting inflammation, and (ii) maintain epithelial barrier function via a reduction in the downregulation of SIRT3.

Identification of a urinary CD276 fragment for detecting resectable pancreatic cancer using a C-terminal proteomics strategy.

This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using exploratory and validation cohorts. Urinary fragments were examined by iTRAQ-labelling of tryptic peptides and concentrations of C-terminal fragments were evaluated. Only the urinary CD276 fragment showed a fold change (FC) of > 1.5 with a significant difference of P < 0.01 between healthy (H) and PDAC participants in both the exploratory (H, n = 42; PDAC, n = 39) and validation cohorts (H, n = 36; resectable PDAC, n = 28). The sensitivity and specificity of the CD276 fragment for diagnosing resectable PDAC were 75% and 89%, respectively, in the validation cohort. Postoperative urinary levels of the CD276 fragment were low as compared to those before surgery (n = 18, P < 0.01). Comprehensive C-terminus proteomics identified an increase in the urinary CD276 fragment level as a feature of patients with PDAC. The urinary CD276 fragment is a potential biomarker for detecting resectable PDAC.

A rare case of concomitant Lambert-Eaton myasthenic syndrome and syndrome of inappropriate antidiuretic hormone secretion in a patient with small cell lung carcinoma.

Small cell lung carcinoma (SCLC) is a neuroendocrine carcinoma with a poor prognosis and is a common cause of paraneoplastic syndromes. Paraneoplastic syndromes are characterized by neurological and endocrinological problems in patients with malignancy and are often associated with difficulty in induction of chemotherapy. Here we report the case of a patient with SCLC concomitant with two paraneoplastic syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS), who was treated with a platinum-doublet chemotherapy regimen. A 66-year-old male patient presented with a 1-month history of progressive proximal muscle weakness, ataxia gait and 5 kg of body weight loss. The laboratory tests revealed hyponatremia due to SIADH and the existence of antibodies against P/Q-type voltage-gated calcium channels. The nerve conduction study showed a low amplitude of compound muscle action potential (0.38 mv), a 34% decrement on 3-Hz stimulation, and a 1939% increment after maximum voluntary contraction in 10 seconds (7.75 mv). The endobronchial ultrasound transbronchial needle aspiration biopsy revealed the pathological findings of SCLC. A 2-cycle chemotherapy regimen of irinotecan plus cisplatin resulted in temporary tumor shrinkage that lasted 2 months, but the improvement of proximal muscle weakness and hyponatremia were maintained over the tumor re-progression period after chemotherapy. Although paraneoplastic syndromes accelerate the decrease in performance status, chemotherapy for SCLC may improve symptoms related to paraneoplastic syndromes and could be considered in similar cases.

A case of bilateral invasive mucinous adenocarcinoma of the lung with severe productive cough and dyspnea successfully treated with palliative lung lobectomy.

Invasive mucinous adenocarcinoma (IMA) of the lung is a chemo-refractory type of lung cancer with frequent intrapulmonary dissemination. Patients with IMA of the lung often suffer from a productive cough and rapid deterioration of performance status (PS). There is currently no standard therapeutic strategy against this unrelenting condition. Here we report a patient with bilateral IMA of the lung with severe productive cough and dyspnea successfully controlled by palliative lung lobectomy. A 67-year-old Japanese man presented with a 3-month history of productive cough. Chest computed tomography (CT) revealed a mass lesion in the left lower lobe and a small nodule and multiple thin-walled cystic lesions in the right lung. He was diagnosed with stage IIB IMA of the lung. Over the next two weeks, his productive cough and dyspnea drastically worsened and his PS declined from 0 to 4. Chest CT showed increases in size of both the nodule and cystic lesions in the right lung and the mass lesion in the left lower lobe. He was re-diagnosed as stage IVA. Given the extreme heterogeneity of the tumor distribution, we decided to perform palliative resection of the left lower lobe. After the surgery, he experienced complete relief of respiratory symptoms, and his PS improved dramatically, enabling chemotherapy. Thirty-one months after surgery, he maintains good PS. In conclusion, our report suggests that aggressive introduction of palliative lung lobectomy played a substantial role for in the excellent outcome of our patient with relatively well confined, advanced-stage IMA.

Clinico-radiologic Characteristics of Pulmonary Visceral Larva Migrans Caused by Ascaris suum.

Objective Visceral larva migrans (VLM) caused by Ascaris suum is a major health problem in pig farming regions. The clinical characteristics of pulmonary VLM caused by A. suum, however, are unclear. We assessed the clinico-radiologic features of this disease. Methods Medical records, including the results of chest radiography and high-resolution computed tomography (HRCT), were retrospectively reviewed from January 2000 through June 2019, at the University of Miyazaki Hospital and Kyoritsuiin Hospital in Miyazaki Prefecture, Japan. Results Seven patients with VLM caused by A. suum were identified. All seven patients had a unique habit of consuming raw foods, such as organic vegetables, chicken, turkey, wild boar, and venison. All but one patient, who had eosinophilic pneumonia with a fever and severe fatigue, had only mild or no respiratory symptoms. All 7 patients had remarkable eosinophilia (median, 1,960/µL) and high serum IgE levels (median, 1,346 IU/mL). Chest HRCT revealed multiple nodules and multiple nodular ground-glass opacities in 57% and 29% of the patients, respectively. The pulmonary lesions were located predominantly in subpleural areas. All seven patients were treated with albendazole, which led to improvement within two to three months. Neither eggs nor parasites were detected in the feces or sputum of any patient. Conclusion Consumption of raw organic vegetables or raw meat is a possible route of A. suum infection. Infected patients exhibit mild respiratory symptoms, and multiple nodules with a halo in the subpleural area are a common finding on chest HRCT. Treatment with albendazole was effective in these cases.

Transition From Distinct Types of KRAS Mutation-Harboring Multifocal Lung Adenocarcinoma to Rhabdoid Tumor: A Longitudinal Follow-Up.

BACKGROUND Rhabdoid tumor (RT) of the lung is a rare and aggressive malignancy. The origin of and the mutation responsible for RT are entirely unknown. The distinction between RT associated with subtypes of lung cancer and SMARCA4-deficient thoracic sarcomas is also unknown. CASE REPORT Three pulmonary subsolid nodules in the right S6, left S6, and left S8 were identified in a 78-year-old Japanese woman. At 3 and 9 months later, a chest CT showed unchanged sizes, but at 15 months the development of a 37-mm mass in the right S6 was observed. The patient's systemic condition deteriorated rapidly, and she died 1 month later. An autopsy revealed that the mass consisted of 90% RT and 10% lung adenocarcinoma. There were another 2 adenocarcinoma lesions in the left lung. KRAS mutation analyses revealed the same KRAS mutation (G12D) in the adenocarcinoma and RT components in the identical mass and metastatic RT, indicating that all of these components had the same clonality. A different KRAS mutation in each of the 3 adenocarcinoma lesions was detected (right S6: G12D, left S6: A59G, left S8: G12C), indicating that the multiple adenocarcinoma lesions were truly multifocal lung adenocarcinoma. The adenocarcinoma and RT components retained SMARCA4 expression. CONCLUSIONS This is the first evidence of RT originating from multifocal lung adenocarcinoma. KRAS mutation is thought to be responsible for the RT's emergence via the epithelial-mesenchymal transition. Patients with multiple subsolid nodules should be followed closely; aggressive surgical intervention should be considered given concerns about the evolution of this aggressive malignancy.

Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome.

Fibrotic scarring is an important prognostic factor of acute respiratory distress syndrome (ARDS). There are currently no antifibrotic drugs or other therapeutic agents for ARDS. Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring by facilitating collagen cross-linking. Recent clinical trials revealed that a monoclonal inhibitory antibody against LOXL2 failed to show benefit over placebo in patients with fibrotic disorders involving the lungs. These clinical results raise the possibility that targeting the extracellular enzymic activity of LOXL2 is not in itself sufficient to prevent fibrotic scarring. We investigated the role of LOXL2 in the pathogenesis of ARDS in vivo, in vitro, and in samples from patients with ARDS. After lung injury, LOXL2 was unevenly expressed in the nuclei of lung fibroblasts and myofibroblasts in the fibrotic phase. Nuclear LOXL2 expression was upregulated in lung fibroblasts after transforming growth factor-beta1 (TGF-ß1)-treatment. LOXL2 silencing abrogated the TGF-ß1-induced expression of a myofibrogenic-progenitor marker, the appearance of proto-myofibroblasts, and the evolution of differentiated myofibroblasts in lung fibroblasts. Nuclear upregulation of Snail was evident in myofibroblasts during the fibrotic phase after lung injury. We detected high levels of LOXL2 protein in the lungs of ARDS patients, specifically during the proliferative and fibrotic phases. Our results highlight nuclear LOXL2 in fibroblasts as a primary causative driver of cell-fate decision toward myofibroblasts and of the progression of fibrotic scarring. A nuclear-LOXL2-targeted agent could be a promising therapeutic strategy against fibrotic disorders including ARDS.

[A case of pulmonary epithelioid hemangioendothelioma that required differentiation from malignant mesothelioma].

A 77-year-old woman presented with a 3-month history of right chest pain and a low-grade fever. Right pleural effusion had been detected at another hospital. Her chest CT scan revealed right pleural effusion, right pleural thickening, and bilateral multiple lung nodules. No specific findings were obtained from an examination of the pleural effusion. Thoracoscopic pleural and lung biopsies were conducted. Histologically, the tumor had an infiltrative growth pattern in the fibrously-thickened parietal pleura, visceral pleura, and lung parenchyma. The tumor was composed of epithelioid and spindle cells, and in some sections, the tumor cells had intracytoplasmic vacuoles, and had formed an immature vascular lumen. Proliferation in a papillary fashion in the alveolar spaces and vascular involvement of tumor were also seen. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD31, and CD34, and negative for calretinin and WT-1. The tumor was therefore diagnosed as pulmonary epithelioid hemangioendothelioma (PEH), which is a rare, low-to-moderate grade vascular tumor of the lung. This disease should be included in the differential diagnosis together with malignant pleural mesothelioma, in cases demonstrating unusual pleural thickening.

A case of impaired consciousness due to large cystic metastatic brain tumors from lung adenocarcinoma successfully controlled with Ommaya reservoir placement.

Large cystic brain metastases from lung cancer are rare but cause substantial central nervous system symptoms that often deprive patients of opportunities to receive anticancer therapy. There are no standard therapeutic strategies against this relentless condition. Here we report a patient with large cystic brain metastases from lung adenocarcinoma successfully controlled with Ommaya reservoir placement and subsequent gamma knife surgery (GKS). A 62-year-old Japanese man presented with left upper extremity paresis. Magnetic resonance imaging revealed large cystic masses in both cerebral hemispheres and multiple brain nodules. Computed tomography of the chest showed irregular nodular shadows in the lower lobe of the right lung with multiple swollen lymph nodes. His performance status (PS) and level of consciousness worsened rapidly. Thus, at that time, we could not perform bronchoscopy with the goal of establishing a pathological diagnosis. Intracystic placement of an Ommaya reservoir followed by GKS dramatically improved his PS and level of consciousness. We were subsequently able to perform bronchoscopy, which resulted in a diagnosis of lung adenocarcinoma with 100% positivity of programmed cell death-1 ligand-1 expression. The patient was started on a 3-week cycle of pembrolizumab. Substantial reduction in tumor size was observed after one course of pembrolizumab treatment. The patient had a partial remission. He has been still receiving pembrolizumab with long-term efficacy. In conclusion, our report suggests that aggressive Ommaya reservoir placement should be considered for large cystic metastatic brain tumors, even in patients with undiagnosed cancer, poor PS, and impaired consciousness.

Allergic bronchopulmonary aspergillosis complicated by eosinophilic chronic rhinosinusitis successfully treated with mepolizumab.

A 67-year-old woman was admitted to our hospital because of frequent asthma attacks and refractory chronic rhinosinusitis. She was diagnosed with allergic bronchopulmonary aspergillosis (ABPA) concomitant with eosinophilic chronic rhinosinusitis (ECRS) on the basis of peripheral blood eosinophilia, precipitating antibodies against Aspergillus fumigatus, elevated total serum IgE, pulmonary infiltration, central bronchiectasis, mucoid impaction, and bilateral rhinosinusitis with nasal polyps, which showed remarkable eosinophil accumulation histologically, especially in the ethmoid sinuses. Treatment with mepolizumab, 100 mg every 4 weeks, was initiated for both the ABPA and ECRS. Consistent with the decrease in the peripheral eosinophil count, the asthma and rhinosinusitis symptoms were drastically ameliorated. Not only her airway symptoms but also her exercise tolerance and pulmonary function test results remarkably improved. Mepolizumab therapy enhanced the quality of life for this patient with intractable ABPA and ECRS.

Successful treatment with mepolizumab in a case of allergic bronchopulmonary aspergillosis complicated with nontuberculous mycobacterial infection.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction that is associated with an allergic immunological response to Aspergillus species via Th2-related inflammation. The long-term use of a systemic corticosteroid is often needed for the treatment of ABPA. However, systemic corticosteroid treatment imposes a risk of the onset of a nontuberculous mycobacterial infection. Here we report the case of a patient with ABPA who required the long-term use of an oral corticosteroid because her repeated asthmatic attacks were successfully treated with mepolizumab, an anti-interleukin-5 monoclonal antibody. The patient, a 60-year-old Japanese female, had been treated with an oral corticoid and itraconazole. Despite the success of the initial treatment for ABPA, it was difficult to discontinue the use of the oral corticosteroid. In addition, Mycobacterium avium was detected from her bronchial lavage. We initiated mepolizumab treatment to taper the amount of corticosteroid and control the asthma condition. The patient's number of blood eosinophils, serum IgE level, fractional exhaled nitric oxide level, dosage of oral prednisolone, and need for inhaled budesonide/formoterol all improved, without an exacerbation of her asthma attacks. Although further research regarding mepolizumab treatment is needed, we believe that mepolizumab could be considered one of the agents for treating refractory ABPA.

Plasma desacyl ghrelin-to-acyl ghrelin ratio is a predictor of postoperative complications and prognosis after pancreaticoduodenectomy.

The current study aimed to clarify the significance of the preoperative desacyl ghrelin (DG)-to-acyl ghrelin (AG) ratio in patients undergoing pancreaticoduodenectomy (PD). Ghrelin, a peptide hormone mainly produced in the stomach, possesses unique functions. Recently, studies have determined the involvement of plasma gherlin in certain postoperative outcomes, particularly in surgical resections of the stomach. Although PD involves gastric resection, few reports have determined the involvement of ghrelin following PD. From April 2003 to December 2011, 195 patients underwent PD for tumors of the pancreatic head, bile duct and ampulla of Vater at the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine (Miyazaki, Japan). Of these, 83 patients were enrolled into the present study as their plasma gherlin levels were measured. AG, DG, total ghrelin (TG) and the DG-to-AG ratio (D/A) were subsequently assessed. Furthermore, the prognostic nutritional index (PNI) and high-sensitivity modified Glasgow Prognostic Score (HS-mGPS) were determined. Morbidity was examined in all 83 patients, but mortality was only determined in 69 individuals after 14 patients were excluded due to the presence of benign disease. The results revealed that the TG of patients undergoing standard PD (SPD) was significantly lower than that of patients undergoing pylorus-preserving PD or subtotal stomach-preserving PD. It was also determined that TG levels declined significantly in SPD patients at 2 weeks after surgery. Negative associations were identified between plasma ghrelin levels and PNI, and between serum albumin and HS-mGPS. Patient morbidity was determined to be 31.3% and the severe complications exhibited by patients included pancreatic fistula (14.5%), intra-abdominal abscess (15.7%), intra-abdominal bleeding (6.0%) and liver abscess (1.2%). Multivariate analysis revealed that disease location and low D/A were independent risk factors for severe complications. The 5-year overall survival (OS) rate was 41.5%. Multivariate analysis also demonstrated that diabetes mellitus, long postoperative hospital stay and low D/A were independent risk factors for OS. The present study revealed the D/A may serve as a useful predictive factor for postoperative complications and prognosis after PD.