Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment.

CASE PRESENTATION: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection. CONCLUSION: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.

Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab.

PURPOSE: Radiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. METHODS: We performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. RESULTS: Patients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. CONCLUSION: Radiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

Th2-biased immune responses are important in a murine model of chronic hypersensitivity pneumonitis.

BACKGROUND: Chronic hypersensitivity pneumonitis (HP) can lead to irreversible pulmonary fibrosis. A good animal model is essential to elucidate the mechanisms of this disease. We previously reported that a Th2 predominance may play an important role in the fibrogenesis in chronic HP patients. A study was undertaken to evaluate whether Th2-biased immune responses were crucial during the processes of lung fibrosis in a murine model of chronic HP. METHODS: Instillation of pigeon dropping extracts (PDE) was conducted 3 days a week for 6 or 12 weeks in C57BL/6, BALB/c and A/J mice to establish models of chronic HP. We evaluated the histopathological features, immunohistochemistry, collagen content, bronchoalveolar lavage fluid (BALF) profiles and Th1/Th2 cytokines in BALF or lung tissue with RT-PCR and ELISA. RESULTS: Thickening of the alveolar walls and structural alterations were observed only in the A/J mice after 12 weeks of exposure to PDE. The fibrosis scores were significantly increased in 12-week A/J mice compared to those in the other strains. Immunohistochemistry evaluation showed that PDE was engulfed by alveolar macrophages that were incorporated into the alveolar septa of 12-week A/J mice. Interleukin (IL)-4 mRNA increased significantly in 6- and 12-week A/J mice. IL-13 mRNA showed a significant increase in 12-week A/J mice compared with 6-week A/J mice. TGF-ß1 mRNA at 12 weeks was significantly increased in A/J mice compared with the other groups. CONCLUSION: Th2-biased genetic backgrounds may play an important role in fibrosing processes in the present chronic HP model.

Churg-Strauss syndrome versus chronic eosinophilic pneumonia on high-resolution computed tomographic findings.

OBJECTIVES: The aim of this study was to compare the high-resolution computed tomographic findings between Churg-Strauss syndrome (CSS) and chronic eosinophilic pneumonia (CEP). METHODS: We retrospectively reviewed the clinical records of 16 patients with CSS and 34 patients with CEP. RESULTS: Twelve (35%) of the 34 patients with CEP had a history of asthma. Although the subpleural distribution of ground-glass opacities (GGOs) and consolidation was common both in CSS and CEP, the midzone distribution was more frequent in CSS (44%) than in CEP (12%). Centrilobular nodules within GGOs were significantly more frequent in CSS (56%) than in CEP (18%). In contrast, traction bronchiectasis associated with volume loss was demonstrated more frequently in CEP (74%) than in CSS (25%). CONCLUSIONS: On high-resolution computed tomography, the presence of the midzone distribution and nodules within GGOs without traction bronchiectasis suggests CSS rather than CEP.

Prediction Accuracy of Mechanism-Based Oral Absorption Model for Dogs.

The purpose of the present study was to evaluate the prediction accuracy of a mechanism-based oral absorption model for the fraction of a dose absorbed (Fa) in dogs, focusing on poorly soluble drugs. As an open mechanism-based model, the gastrointestinal unified theoretical framework was used in this study. The prediction accuracy of the gastrointestinal unified theoretical framework was evaluated using Fa data in dogs (63 data sets for marketed drugs and proprietary compounds). For neutral compounds, Fa was accurately predicted, suggesting that the physiological parameters of dogs were appropriate except for gastrointestinal pH. An extensive literature survey on the small intestinal pH of dogs was then conducted. The result suggested that the pH value ranged between 6.5 and 7.5, with the midst value of 7.0, but there was a great variation among the literature. To confirm the appropriateness of this pH value, the Fa of free acid compounds was predicted by setting the small intestinal pH to 6.5, 7.0, and 7.5. The proportions of compounds with <2-fold error were 57%, 90%, and 76%, respectively. The results of the present study would enable an appropriate use of a mechanism-based model for drug discovery and development.

[Randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel in patients with advanced nonsmall cell lung cancer].

PURPOSE: To evaluate the chemotherapeutic regimens suitable for the outpatient settings, we conducted a randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel. METHODS: Group CP(n=25): carboplatin AUC 6.0 day 1 and paclitaxel 70 mg/m2 day 1, 8, 15 every 4 weeks followed by gemcitabine 1.0 g/m2 day 1, 8, 15 every 4 weeks; group CG(n=26): carboplatin AUC 2.0 and gemcitabine 0.8 g/m2 day 1, 8 every 3 weeks followed by docetaxel 60 mg/m2 day 1, 8 every 3 weeks. RESULTS: The response rate of the first line therapy was 18.0% in group CP and 21.7% in group CG and that of the second line therapy was 10.0% and 14.3%, respectively. Time to progression of the first line therapy was 4.0 months in group CP and 4.3 months in group CG, that of the second line therapy was 2.1 months and 2.8 months, respectively. The median survival time was 10.9 months in group CP and 10.3 months in group CG. No statistically significant differences were documented in the response rate, time to progression, and overall survival between these two groups. Severe hematologic toxicity was rare in both groups and no symptomatic peripheral neuropathy was documented in carboplatin/paclitaxel therapy. CONCLUSION: Carboplatin /paclitaxel followed by gemcitabine and carboplatin/gemcitabine followed by docetaxel were well tolerated and equal in efficacy. Both regimens in this study seemed to be suitable for the outpatient settings because of their mild hematologic toxicity and peripheral neuropathy.

Effect of cigarette smoking on the development of murine chronic pigeon breeder's lung. The difference between a short-term and a long-term exposure.

Previous reports suggested that cigarette smoke had a protective effect of on the development of hypersensitivity pneumonitis (HP). However, smoking rate in chronic pigeon breeder's lung (PBL) seemed to be high in our clinical experiences. We developed a murine model of PBL by intranasal instillation with pigeon dropping extracts (PDE) for 4 weeks (short-term exposure) and 17 weeks (long-term exposure) to investigate the effect of cigarette smoke on disease processes. In this model, lung inflammation associated with the production of anti-PDE antibodies and antigen dependent lymphocyte proliferation was induced. Long-term exposure to PDE without cigarette smoking resulted in an increase in lung weight/body weight ratio, total cell number in bronchoalveolar lavage (BAL) fluid, and content of hydroxyproline in the lung compared to shortterm exposure. After a short-term exposure, cigarette smoke lessened the lymphocytosis in BAL fluid, and lymphocyte proliferation. On the other hand, after a long-term exposure cigarette smoke increased lung hydroxyproline. These results suggest that a short-term cigarette smoking attenuates lung inflammation, but a long-term cigarette smoking enhances lung inflammation with fibrosis.

The characterization of gefitinib sensitivity and adverse events in patients with non-small cell lung cancer.

BACKGROUND: Factors predicting gefitinib sensitivity and adverse events in non-small cell lung cancer (NSCLC) remain controversial. PATIENTS AND METHODS: Correlations among clinicopathological characteristics, gefitinib sensitivity and adverse events were studied in 154 patients with NSCLC, whereas epidermal growth factor receptor (EGFR) mutations were analyzed in 44 patients. RESULTS: Female, non-smoker, adenocarcinoma of stage I-II, and gefitinib effectiveness correlated with longer time to progression (TTP) and overall survival (OS), while the rate of interstitial lung disease in patients undergoing thoracic radiotherapy and stomatitis in females or those who never smoked were significantly higher. EGFR mutations were identified in 18 cases, and among 34 gefitinib-treated patients, 16 patients harboring mutations tended to do better, both in terms of TTP and OS. The results of the mutation analysis from surgical and non-surgical specimens were identical. CONCLUSION: Certain clinicopathological characteristics and EGFR mutations can be either predictive of gefitinib sensitivity or adverse events.

Proinflammatory and anti-inflammatory cytokine gene polymorphisms in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immunologically-mediated lung disease caused by repeated inhalation of dispersed antigen. Various cytokines have been reported to be involved in the immunopathogenesis of HP Recently, some reports suggested an association between the genetic control of cytokine production and disease susceptibility. To evaluate whether cytokine gene polymorphisms are associated with HP, we performed a case-control association study involving 61 patients with HP, consisting of summer-type HP (SHP) and bird fancier's lung (BFL, also named bird fancier's disease), as well as 101 healthy controls. Polymorphisms of the genes for tumor necrosis factor (TNF)-alpha (-308G/A, -857C/T, -863C/A, -1031T/C), interleukin (IL)-10 (-592C/A, -819C/T, -1082G/A), transforming growth factor (TGF)-beta1 (-509C/T, +869T/C), and IL-6 (-634C/G) were examined by restriction fragment length polymorphism analysis. There were no significant differences in allele frequency and genotype distribution among control, SHP, and BFL group. When HP group was divided into acute or chronic, no significant differences were detected between any groups. LPS-stimulated IL-6 secretion by whole blood cells was similar between subjects with GG genotype and non-GG genotype in IL-6 -634C/G polymorphism. In conclusion, the association between HP susceptibility and cytokine polymorphisms studied was not demonstrated.

Usefulness of cyclosporine A on rapidly progressive interstitial pneumonia in dermatomyositis.

BACKGROUND: Interstitial pneumonia in polymyositis and dermatomyositis (PM/DM) is recognized to be a major complication of PM/DM. Rapidly progressive interstitial pneumonia (RPIP) in DM is frequently refractory to steroids and is the prognosis-determining factor in DM. Recently cyclosporine A (CyA) has emerged as an available treatment for interstitial pneumonia in PM/DM, but its efficacy on RPIP is unclear. AIM OF THE WORK: To evaluate the usefulness of CyA in the treatment of RPIP in DM. METHODS: We reviewed the medical charts of 10 cases with RPIP in DM to whom CyA was administered. RESULTS AND CONCLUSIONS: Combined administration of oral CyA and steroids with/without immuno-suppressants was likely to be beneficial in 4 of 10 cases that were refractory to the conventional preceding therapy. The values of PaO2/FIO2 when CyA were initiated were suggested to be a prognosis-determining factor for the outcome of the disease, showing that initiation of CyA should be considered in the early stage of RPIP in DM. The dosage of steroids was tapered in 3 out of 4 CyA-responsive cases without re-exacerbation. Therefore administration of CyA might be useful in lowering the dosage of steroids.

Cyclosporin A followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a slowly progressive disease with a poor prognosis. Acute exacerbation is the worst stage in the clinical course of IPF, as the condition is unresponsive to most conventional therapies. Corticosteroids and other immunosuppressive drugs have been attempted for the treatment of acute exacerbation, but only with very limited effectiveness. This study was performed to examine the effect of cyclosporin A (CsA) on acute exacerbation of IPF. PATIENTS AND METHODS: Thirteen patients with acute exacerbation of IPF were retrospectively studied. All 13 patients received pulse-therapy with methylprednisolone (1,000 mg per day for 3 days), followed by oral prednisolone (40-60 mg per day). Seven patients were received CsA (1.0-2.0 mg/kg per day) after the treatment with corticosteroids. We attempted to keep the blood trough level of CsA between 100 and 150 ng/ml. RESULTS: Among the 7 patients treated with CsA, 4 patients have survived for 60, 120, 276 and 208 weeks, respectively; 2 did not respond to pulse-therapy with methylprednisolone and died within 8 weeks after the start of CsA treatment. The other patient experienced re-exacerbation and died 87 weeks after the discontinuation of CsA due to the development of viral encephalitis. In contrast, all 6 patients treated without CsA died within 66 weeks after the onset of acute exacerbation. Four of these patients responded to pulse-therapy with methylprednisolone, but their condition deteriorated again while the subsequent prednisolone was being tapered. CONCLUSION: CsA seems to prevent re-exacerbation of IPF and improve the patients' chances for long-term survival.

A clinical study of hypersensitivity pneumonitis presumably caused by feather duvets.

BACKGROUND: Bird fancier's lung (BFL) is a type of hypersensitivity pneumonitis induced by the inhalation of bird-related antigens. The BFL induced by feathers is difficult to diagnose because feathers are generally unrecognized as a causative antigen. OBJECTIVE: To determine the clinical features of BFL presumably induced by feather duvets (feather duvet lung) to provide clues for diagnosis. METHODS: We performed a retrospective review of the medical records of patients with feather duvet lung evaluated between April 1, 2000, and June 30, 2003, at the Tokyo Medical and Dental University Hospital in Japan. RESULTS: Seven patients with feather duvet lung were included in this study; 4 patients had acute disease and 3 had chronic BFL. Duration of contact with feather duvets was 1 month to 10 years. Serum KL-6 and surfactant protein D levels were elevated in all the patients. Specific antibodies against avian antigens were positive in acute BFL but negative in chronic BFL. Antigen-induced lymphocyte proliferation in peripheral blood or bronchoalveolar lavage cells was positive in all the patients. The diagnosis was confirmed by an environmental or inhalation provocation test. CONCLUSIONS: Feather duvets can induce acute and chronic BFL. Physicians should be aware of feather duvets as a cause of BFL because feather duvets are becoming more prevalent.

Significance of methicillin-resistant Staphylococcus aureus (MRSA) survey in a university teaching hospital.

We experienced a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in two wards at our medical school teaching hospital during the period of July-September 1997. To determine whether these MRSA clinical isolates were associated with environmental factors, we conducted two sequential MRSA surveys of the hospital staff and surroundings in wards with outbreaks (wards 1 and 2) and in one ward without an outbreak (ward 3) in April 1998 (ward 1 only) and in March 1999 (wards 1, 2, and 3). In the two sequential surveys, MRSA strains were detected mainly from white coats. MRSA strains isolated from fingers in the first survey were decreased in the second survey. The pulsed-field gel electrophoresis (PFGE) patterns of the strains isolated in the two surveys were classified into five types (A-E). Type D, including the outbreak pattern of the MRSA in ward 1 in 1997, was reduced between the first and second surveys by managing microbiological hygiene, suggesting that the outbreak was controlled in ward 1. On the other hand, the strains isolated in the second survey in ward 2 were mainly type E, which was also common among clinical isolates from ward 2 during the latter half of 1998 to 1999. This suggested a high probability of cross-infection between the patients and the hospital staff in the ward. Our observations suggest that doctors and nurses should be cautious that their coats might be contaminated with the prevailing strains of MRSA. We also concluded that the surveys were very useful for the successful management of MRSA infections.

Chromosome 9p deletion in squamous metaplasia in cystic lesion of the lung.

A 70-year-old man presented with squamous cell carcinoma of the lung. Examination of the resected specimen showed a tumour and a thickly walled cyst not immediately adjacent to the main tumour. The surface of the cyst was lined by squamous metaplastic epithelium. Microsatellite analysis of microdissected specimens was performed with seven markers from four chromosomal regions. In the squamous cell carcinoma, a non-informative homozygosity at two markers on 3p, loss of heterozygosity (LOH) at D5S346 on 5q, and LOH at D9S146, D9S150, and D9S1748 on 9p were detected. In the metaplastic epithelium of the cyst, LOH was detected at D9S1748 on 9p21. This appears to be the first report providing possible evidence of genetic changes by demonstrating allelic loss on 9p21 in the metaplastic epithelium of a cyst. This allelic loss might be related to an early step in carcinogenesis in lung cysts.

Feather duvet lung.

BACKGROUND: Bird fancier's lung (BFL) is a type of hypersensitivity pneumonitis, which is induced by inhalation of bird related antigens. The diagnosis of BFL induced by feathers is difficult because feathers are generally not recognized as a causative antigen of BFL. We report a female case of chronic BFL presumably due to a feather duvet, which presents as pulmonary fibrosis. CASE REPORT: A 73 year-old woman presented with exertional dyspnea for the last three years. She had raised two pigeons for three years (1971-1973) in her forties and had been using a feather duvet for the last eight years (1992-2000). A chest X-ray showed reticular infiltrates in the both peripheral lung field and an HRCT scan showed scattered consolidation, micronodules, and peribronchial ground-glass opacities. Lymphocyte proliferation to the feather antigen was positive and inhalation provocation test using a bird antigen was also positive. Thoracoscopic biopsy specimens showed organization, cholesterol clefts, alveolitis around terminal and respiratory bronchioles--all of which are consistent with chronic hypersensitivity pneumonitis. Clinical findings have spontaneously improved after she stopped using her feather duvet. CONCLUSIONS: Feather beds including duvets, pillows, and cushions are now popular all over the world. Physicians should be aware of feathers as a cause of BFL since this induction seems to be more prevalent.

Clinical features of recurrent and insidious chronic bird fancier's lung.

BACKGROUND: Chronic bird fancier's lung (BFL) can be subgrouped into two types. One subgroup of patients develops interstitial pulmonary fibrosis after recurrent acute episodes (recurrent BFL), and the other subgroup of patients has no history of acute episodes but has slowly progressive chronic respiratory disease (insidious BFL). OBJECTIVE: To define the clinical characteristics of both types of BFL and to provide clues for diagnosis. METHODS: We performed a retrospective review of the medical records of patients with chronic BFL who were evaluated between October 1992 and March 2001 at the Tokyo Medical and Dental University Hospital in Japan. Patients were evaluated for their clinical characteristics, including history, laboratory, and immunologic findings; imaging; bronchoalveolar lavage; and histologic findings. RESULTS: Thirty-two patients with chronic BFL were included in this study; 15 patients had recurrent BFL and 17 had insidious BFL. The patients with recurrent BFL tended to breed dozens of pigeons in a loft, whereas the patients with insidious BFL were likely to be exposed to smaller birds kept indoors. Specific antibodies against pigeon dropping extracts or budgerigar dropping extracts were positive in 87% of the recurrent BFL cases and 35% of the insidious BFL cases. Antigen-induced lymphocyte proliferation was positive in more than 90% of both groups. The upper lung field was frequently involved in both groups as demonstrated by chest radiographic findings. In all of the patients with insidious BFL, the diagnosis was confirmed by positive laboratory-controlled inhalation test results. CONCLUSIONS: Insidious BFL may be misdiagnosed as idiopathic pulmonary fibrosis if a careful history is not taken and antigen-induced lymphocyte proliferation, careful imaging evaluation, and laboratory-controlled inhalation challenge testing are not conducted. In contrast, the clinical findings of recurrent BFL are consistent with hypersensitivity pneumonitis induced by other antigens.

The effect of seratrodast on eosinophil cationic protein and symptoms in asthmatics.

Thromboxane A2 (TXA2), an arachidonate derivative, is a potent bronchoconstrictor; therefore, blocking TXA2 should attenuate airway narrowing. Seratrodast, a TXA2 receptor antagonist, is expected to be a potent antiasthmatic. It was reported that seratrodast reduced bronchial hyperresponsiveness. However, it is controversial whether it reduces airway inflammation. We studied some additional effects of oral seratrodast to inhaled corticosteroids on 10 adult asthmatics in an open-label, crossover design study. Eosinophil cationic protein (ECP) levels in serum and sputum, peak expiratory flow rate (PEF), clinical symptoms, and airway responsiveness were evaluated. Clinical symptom scores were improved by administration of seratrodast (p < 0.05). The addition of seratrodast to asthmatic patients significantly improved mean PEF (p < 0.05). In addition, withdrawal of seratrodast resulted in deterioration of PEF. Airway hyperresponsiveness to acetylcholine measured by Astograph was improved by administration of seratrodast (p < 0.01), and returned to the level of "run-in period" after withdrawal. Administration of seratrodast decreased the concentration of ECP in sputum significantly (p < 0.05), and sputum ECP significantly increased again after withdrawal of (p < 0.05). These results suggest that seratrodast improves clinical symptoms andairway hyperresponsiveness by reducing airway inflammation. Seratrodast may be useful as an anti-inflammatory agent and beneficial when added to inhaled corticosteroids in the treatment of bronchial asthma.