Norihiro Kaneko

Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer.

Background We previously reported the role of IL-6 in a murine model of cancer cachexia and currently documented a patient in whom tocilizumab, anti-IL-6 receptor antibody, dramatically improved cachexia induced by IL-6 over-expressing lung cancer. Despite this potential to alleviate cancer cachexia, tocilizumab has not been approved for this clinical use. Therefore, preceding our planned clinical trial of tocilizumab, we designed the two studies described here to evaluate the levels of IL-6 in patients with lung cancer and the effect of tocilizumab in a murine model of human cancer cachexia. Methods First, we measured serum IL-6 levels in patients with lung cancer and analyzed its association with cachexia and survival. Next, we examined the effect of a rodent analog of tocilizumab (MR16-1) in the experimental cachexia model. Results Serum IL-6 levels were higher in patients with cachexia than those without cachexia. In patients with chemotherapy-resistant lung cancer, a high IL-6 serum level correlated strongly with survival, and the cut-off level for affecting their prognosis was 21 pg/mL. Meanwhile, transplantation of IL-6-expressing Lewis Lung Carcinoma cells caused cachexia in mice, which then received either MR16-1 or 0.9% saline. Tumor growth was similar in both groups; however, the MR16-1 group lost less weight, maintained better food and water intake and had milder cachectic features in blood. MR16-1 also prolonged the survival of LLC-IL6 transplanted mice (36.6 vs. 28.5 days, p = 0.016). Conclusion Our clinical and experimental studies revealed that serum IL-6 is a surrogate marker for evaluating cachexia and the prognosis of patients with chemotherapy resistant metastatic lung cancer and that tocilizumab has the potential of improving prognosis and ameliorating the cachexia that so devastates their quality of life. This outcome greatly encourages our clinical trials to evaluate the safety and efficacy of tocilizumab treatment for patients with increased serum IL-6.

Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis

Objectives Biological therapy represents important advances in alleviating rheumatoid arthritis (RA), but the effect on interstitial lung disease (ILD) has been controversial. The objective of this study was to assess the risk of such treatment for patients with ILD. Design Case–control cohorts. Setting Single centre in Japan. Participants This study included 163 patients with RA who underwent biological therapy. Outcome measured We assessed chest CT before initiation of biological therapy and grouped 163 patients according to the presence of ILD (with (n=58) and without pre-existing ILD (n=105)). Next, we evaluated serial changes of chest CT after treatment and visually assessed the emergence of ILD or its progression, which was referred to as an ‘ILD event’. Then, we also classified the patients according to the presence of ILD events and analysed their characteristics. Results Tumour necrosis factor (TNF) inhibitors were administered to more patients with ILD events than those without ILD events (88% vs 60%, p<0.05), but recipients of tocilizumab or abatacept did not differ in this respect. Of 58 patients with pre-existing ILD, 14 had ILD events, and that proportion was greater than for those without pre-existing ILD (24% vs 3%, p<0.001). Of these 14 patients, all were treated with TNF inhibitors. Four patients developed generalised lung disease and two died from ILD progression. Baseline levels of KL-6 were similar in both groups, but increased in patients with ILD events. Conclusions TNF inhibitors have the potential risk of ILD events, particularly for patients with pre-existing ILD, and KL-6 is a valuable surrogate marker for detecting ILD events. Our data suggest that non-TNF inhibitors are a better treatment option for these patients.

Relapsed small cell lung cancer: treatment options and latest developments

According to recent analyses, there was a modest yet significant improvement in median survival time and 5-year survival rate of limited stage small cell lung cancer (SCLC) in North America, Europe, Japan and other countries over the last 30 years. The median survival time of limited stage SCLC is 15–20 months and 5-year survival rate is 15% or less. In terms of extensive stage SCLC, a median survival time of 9.4–12.8 months and 2-year survival of 5.2–19.5% are still disappointing. Despite being highly sensitive to first-line chemotherapy and radiotherapy treatments, most patients with SCLC experience relapse within 2 years and die from systemic metastasis. While several clinical trials of cytotoxic chemotherapies and molecular targeting agents have been investigated in the treatment of relapsed SCLC, none showed a significant clinical activity to be able to exceed topotecan as second-line chemotherapy. There are problematic issues to address for relapsed SCLC, such as standardizing the treatment for third-line chemotherapy. Topotecan alone was the first approved therapy for second-line treatment for relapsed SCLC. Amrubicin is a promising drug and a variety of trials evaluating its efficacy have been carried out. Amrubicin has shown superiority to topotecan in a Japanese population, but was not superior in a study of western patients. There are some controversial issues for relapsed SCLC, such as treatment for older patients, third-line chemotherapy and efficacy of molecular targeting therapy. This article reviews current standard treatment, recent clinical trials and other topics on relapsed SCLC.

Effect of glucocorticoid monotherapy on pulmonary function and survival in Japanese patients with scleroderma-related interstitial lung disease

BACKGROUND Scleroderma-related interstitial lung disease (SSc-ILD) is a chronic, progressive condition that is characterized by a restrictive ventilator defect. Cyclophosphamide (CYC), with or without glucocorticoid, effectively alters the course of SSc-ILD. However, the effect of glucocorticoid monotherapy remains unclear. METHODS Seventy-one patients with SSc-ILD were classified into 2 groups: 21 in the treatment group (glucocorticoid monotherapy [n=14] or immunosuppressive agents [n=7]) and 50 in the non-treatment group. Their backgrounds and prognoses were analyzed retrospectively. We also classified these patients into survival (n=55) and non-survival (n=16) groups to assess prognostic factors. RESULTS The median follow-up period was 9.8 years. The treatment group had a greater proportion of patients with diffuse systemic sclerosis or respiratory symptoms than the non-treatment group. The treatment groups annual change in forced vital capacity (FVC) compared to baseline, which was 170.4mL (157.8mL for the glucocorticoid monotherapy subgroup and 191.3mL for the immunosuppressive agent subgroup), was better than that of the non-treatment group, -60.8mL (p<0.01). Still, in terms of 5- and 10-year survival, there was no statistically significant difference between these groups. No incidence of SSc renal crisis was reported in the treatment group. The non-survival group included more patients with pulmonary hypertension than the survival group, but multivariate analysis showed no other statistically significantly difference between these groups. CONCLUSIONS Similar to CYC, glucocorticoid alone improved pulmonary function of Japanese SSc-ILD patients, suggesting that this monotherapy is a good alternative when CYC is contraindicated.

Is emphysema a risk factor for pneumothorax in CT-guided lung biopsy?

IntroductionComputed tomography (CT)-guided lung biopsy is commonly used to make a histological diagnosis for pulmonary lesions. Its most common complication is pneumothorax. While it is thought that CT-guided lung biopsy should be avoided in patients with emphysema, however, there is no scientific report documenting the relationship the occurrence of pneumothorax and the severity of emphysema.Purpose and methodsTo investigate the relationship between the severity of emphysema and the frequency of pneumothorax, we retrospectively reviewed all the patients who received CT-guided lung biopsy. Severity of emphysema is evaluated by Goddard classification, a visual scale by which areas of vascular disruption and low attenuation value were scored for each lung field of high resolution CT.Patients’ characteristics, prognostic accuracy of this method, size and location of the lesion, length of intrapulmonary biopsy paths, and frequency of complications such as pneumothorax or intrapulmonary hemorrhage were evaluated.ResultsOne hundred-two patients (69 males and 33 females) received 102 procedures. Diagnostic accuracy was 90.2%. Pneumothorax occurred in 41 of 102 biopsies (40.2%). Chest tube placement was required in 3 out of the 41 cases (7.3%) complicated by pneumothorax (2.9% of all the biopsies). The longer lesion depths from pleura were, the more frequently pneumothorax occurred (6.67 vs 3.66 mm, p=0.019). No correlation was found between location of lesions and frequency of pneumothorax. No significant differences of COPD staging or LAA score were seen between the patients with and without pneumothorax (5.73 vs 4.32 points, p=0.339).ConclusionWe suggest that severity of emphysema such as stage I or II COPD may not be related to the frequency of pneumothorax.

Efficacy and safety of amurubicin for the elderly patients with refractory relapsed small cell lung cancer as third-line chemotherapy

BACKGROUND While more elderly patients are being diagnosed with lung cancer every year, no anti-lung cancer therapy designed specifically for the elderly has been established yet. This is the first retrospective study to examine the efficacy and safety of amurubicin (AMR) for elderly patients with refractory relapsed small cell lung cancer (SCLC) as second or third-line chemotherapy. MATERIALS AND METHODS Thirty-six patients were eligible for analyzing the frequency of hematologic and non-hematologic toxicities and effectiveness of AMR for refractory relapsed SCLC in both elderly (≥ 70 years) and non-elderly (<70 years) groups. RESULTS Among these patients as third-line chemotherapy, the response rate and the disease control rate of refractory relapsed cases were 44.4 and 55.6%, respectively. The median of progression-free survival time was 3.0 months and the median of overall survival time was 5.1 months. There were no significant differences in the frequency of the grade 3-5 hematologic or non-hematologic toxicity between the elderly (≥ 70 years) and non-elderly (<70 years) patients or second and third-line chemotherapies. CONCLUSIONS AMR could be one of the effective tools in the treatment of elderly patients with refractory relapsed SCLC as third-line chemotherapy, and the recommended dose is 30 mg/m 2 for three consecutive days.

Um caso de pneumonia por vírus parainfluenza 3 simulando pneumonia por influenza tratada com sucesso

Portanto, a terapia anti-influenza deve ser iniciada empiricamente caso haja suspeita de pneumonia por influenza.Sabe-se que o virus da parainfluenza (VPI) causou doenca semelhante a gripe durante as pandemias de influenza suina.(2) Relatou-se que o VPI 3 (VPI3) pode causar pneumonia em pacientes imunossuprimidos, tais como adultos que receberam transplantes.(3)Relatamos um caso, tratado com sucesso, de pneumonia por VPI3 simulando pneumonia por influenza em uma paciente asmatica de 31 anos de idade. A paciente apresentou febre alta (39.5°C), fadiga geral, dor articular sistemica e anorexia durante dois dias antes de ser encaminhada a nosso centro medico. Era fumante e apresentava historia de tabagismo (20 anos-maco) e de asma bronquica (sem uso atual de medicacao). A paciente tambem apresentava diabetes mellitus mal controlada e indice de massa corporal de 30 kg/m2. A radiografia de torax revelou opacidades em vidro fosco difusas em ambos os pulmoes (Figura 1). Exames laboratoriais revelaram reacao inflamatoria grave (proteina C reativa = 19,2 mg/dL e VHS = 83 mm/h). A paciente apresentou insuficiencia respiratoria grave e SpO2 de 80% em ar ambiente na primeira visita e passou a receber oxigenoterapia com ventilacao nao invasiva com pressao positiva. Devido a insuficiencia respiratoria grave, nao foi realizada lavagem broncoalveolar. Embora o resultado de um teste rapido para deteccao de antigeno de influenza tenha sido negativo, a paciente recebeu diagnostico de pneumonia por influenza com base em sintomas semelhantes aos da gripe e em achados radiologicos, tais como opacidades difusas em vidro fosco (Figura 2).A paciente passou a receber tratamento empirico com peramivir (600 mg/dia) durante 5 dias (para a infeccao por influenza) associado a pulso de esteroide e eritromicina i.v. (1.000 mg/dia) durante 5 dias (para a insuficiencia respiratoria aguda). Sua funcao respiratoria melhorou gradualmente, e a ventilacao nao invasiva com pressao positiva foi interrompida no 5o dia. A paciente passou entao a receber prednisolona oral (80 mg/dia), e a dose foi sendo gradativamente reduzida uma vez a cada tres dias, da seguinte maneira: para 40 mg/dia no 6o dia; para 30 mg/dia no 9o dia; para 15 mg/dia no 12o dia e suspensa

Non-HIV Pneumocystis pneumonia: do conventional community-acquired pneumonia guidelines under estimate its severity?

BackgroundNon-HIV Pneumocystis pneumonia (PCP) can occur in immunosuppressed patients having malignancy or on immunosuppressive agents. To classify severity, the A-DROP scale proposed by the Japanese Respiratory Society (JRS), the CURB-65 score of the British Respiratory Society (BTS) and the Pneumonia Severity Index (PSI) of the Infectious Diseases Society of America (IDSA) are widely used in patients with community-acquired pneumonia (CAP) in Japan. To evaluate how correctly these conventional prognostic guidelines for CAP reflect the severity of non-HIV PCP, we retrospectively analyzed 21 patients with non-HIV PCP.MethodsA total of 21 patients were diagnosed by conventional staining and polymerase chain reaction (PCR) for respiratory samples with chest x-ray and computed tomography (CT) findings. We compared the severity of 21 patients with PCP classified by A-DROP, CURB-65, and PSI. Also, patients’ characteristics, clinical pictures, laboratory results at first visit or admission and intervals from diagnosis to start of specific-PCP therapy were evaluated in both survivor and non-survivor groups.ResultsBased on A-DROP, 18 patients were classified as mild or moderate; respiratory failure developed in 15 of these 18 (83.3%), and 7/15 (46.7%) died. Based on CURB-65, 19 patients were classified as mild or moderate; respiratory failure developed in 16/19 (84.2%), and 8 of the 16 (50%) died. In contrast, PSI classified 14 as severe or extremely severe; all of the 14 (100%) developed respiratory failure and 8/14 (57.1%) died. There were no significant differences in laboratory results in these groups. The time between the initial visit and diagnosis, and the time between the initial visit and starting of specific-PCP therapy were statistically shorter in the survivor group than in the non-survivor group.ConclusionsConventional prognostic guidelines for CAP could underestimate the severity of non-HIV PCP, resulting in a therapeutic delay resulting in high mortality. The most important factor to improve the mortality of non-HIV PCP is early diagnosis and starting of specific-PCP therapy as soon as possible.

Rapidly Progressive Interstitial Lung Disease Associated with Dermatomyositis Treated with Combination of Immunosuppressive Therapy, Direct Hemoperfusion with a Polymyxin B Immobilized Fiber Column and Intravenous Immunoglobulin

Rapidly progressive interstitial lung disease (ILD) is associated with dermatomyositis (DM) and has a high mortality rate even with immunosuppressive agents. For such cases, there is no evidence on the combined effect of direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin. We herein report a case of 61-year-old woman who presented with respiratory failure. She showed ILD associated with DM which did not improve with immunosuppressive agents, but was improved with the addition of both direct hemoperfusion with a Polymyxin B immobilized fiber column and intravenous immunoglobulin.

Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating lung cancer recurrence

For patients with non-small cell lung cancer (NSCLC) classified as stage I using the tumor-node-metastasis (TNM) staging system (T1N0M0 or T2N0M0), the standard treatment is complete resection of the affected lobes and associated lymph nodes. However, lung cancer is usually inoperable in elderly patients, mostly because of their poor performance status. In general, resection of these early-stage tumors, typically by lobectomy, has been associated with three-year and five-year survival rates ranging from 60% to 80%. (1,2) Unfortunately, significant complications have been associated with lobectomy in elderly patients or in those with medical comorbidities, such as limited pulmonary reserve and cardiovascular disease. (3-6) With the popularization of CT screening, lung cancers have been increasingly detected at an early stage.