Possible Effect of Blonanserin Transdermal Patch on Antiemetic Control in Patients With Terminal Cancer with Refractory Nausea.

Background: Haloperidol is widely used for antiemetic control in advanced cancer. However, due to its limited administration methods (oral or injection), its management is frequently challenging in palliative home care. Recently, a blonanserin transdermal patch was developed as the first antipsychotic percutaneous agent. Objectives: This study aimed to evaluate its effectiveness and safety for refractory nausea. Methods: We conducted an observational study of 21 terminal cancer patients who had been initiated for refractory nausea in their homes. Results: After its initiation, none of the patients experienced aggravated nausea, and the number of patients with severe nausea decreased dramatically (52.4% vs. 9.5%, p = 0.008). Of 16 patients without ascites, 12.5% had not improved their nausea, which was lower than in patients with ascites (80.0%). Conclusions: Blonanserin transdermal patch has a possible effect on antiemetic control in cancer patients, and its efficacy might be particularly prominent in patients without ascites.

Efficacy of blonanserin transdermal patch on terminal delirium in patients with respiratory diseases.

BACKGROUND: Delirium is a common distressing symptom observed in patients with terminal respiratory diseases and is treated with antipsychotic medications such as haloperidol. Its management is difficult, especially in palliative home care, because its administration is limited to oral or injection methods. Recently, the blonanserin transdermal patch was developed as the first antipsychotic percutaneous agent. After it became available, we recognized its potential for the management of delirium and the alleviation of uncontrolled dyspnea in clinical practice. Thus, this study aimed to assess its efficacy in patients with terminal respiratory diseases. METHODS: This retrospective study included 113 patients with respiratory diseases who were cared for at home. The efficacy was evaluated through the prevalence of terminal delirium before and after its treatment initiation for uncontrolled dyspnea. RESULTS: Blonanserin transdermal patch treatment for uncontrolled dyspnea improved the prevalence and severity of terminal delirium (from 70.4% to 16.3%, p < 0.001) and reduced the number of doctors' visits to patients' homes within a week before their death (from 4.0 to 3.0, p = 0.086). A sub-group analysis of 23 patients with interstitial pneumonia revealed that the treatment prevented dyspnea progression by inhibiting terminal delirium. CONCLUSIONS: Blonanserin transdermal patch performed similarly to haloperidol, as previously reported, for managing terminal delirium. Our study suggests that a blonanserin transdermal patch potentially prevents terminal delirium and alleviates uncontrolled dyspnea in patients with respiratory diseases. Our findings encourage clinical trials to evaluate the safety and efficacy of blonanserin transdermal patches for patients with terminal illnesses.

Survival after surgery for clinical stage I non-small-cell lung cancer with interstitial pneumonia.

OBJECTIVES: To evaluate the surgical outcomes after surgery in patients with stage I lung cancer and idiopathic interstitial pneumonia (IIP). MATERIAL AND METHODS: This retrospective cohort study was conducted in 2131 patients with clinical stage I non-small-cell lung cancer (NSCLC) who underwent pulmonary resection between 2009 and 2018. Based on computed tomography (CT) findings, 233 patients had IIP. Lobectomy was performed in 180 patients with IIP and 1227 patients without IIP. Surgical outcomes, recurrence sites, and cause of death were investigated. In addition, we measured the distance between the tumor and hilum in patients with IIP and assessed the feasibility of sublobar resection. RESULTS: The overall survival and cancer-specific survival of patients with IIP were significantly poorer than those of non-IIP patients. The five-year overall survival rates of patients with clinical stage IA/IB lung cancer with and without IIP were 58.1%/47.3% and 88.8%/68.9%, respectively. Furthermore, 9.4% of patients with IIP and 0.9% of patients without IIP died from respiratory-related causes within 2 years after surgery. Multivariate analyses revealed that volume capacity <80% (odds ratio: 3.259), usual interstitial pneumonia pattern by CT finding (odds ratio: 1.891), and nodal metastasis (odds ratio: 3.304) were prognostic factors for overall survival in patients with IIP. Unexpected nodal metastases were observed in 22.3% of patients with IIP. By CT judgment, sublobar resection was not feasible in 68% of patients with IIP who underwent lobectomy. CONCLUSIONS: The overall survival of patients with early NSCLC after pulmonary resection with IIP was poor; this is related to the high prevalence of cancer-specific and respiratory-related deaths. Sublobar resection is not always feasible, the procedure on patients with IIP should be selected carefully according to the characteristics of each case. Nodal dissection should be performed to evaluate for metastasis, regardless of the extent of lung resection.

Outcomes of lung cancer surgery for patients with interstitial pneumonia and coronary disease.

PURPOSE: To evaluate the surgical outcomes of lung cancer patients with idiopathic interstitial pneumonia (IIP) and/or coronary artery disease (CAD). METHODS: The subjects of this retrospective study were 2830 patients who underwent surgical resection for lung cancer between 2009 and 2018. Seventy-one patients (2.6%) had both IIP and CAD (FC group). The remaining patients were divided into those with IIP only (group F), those with CAD only (group C), and those without IIP or CAD (group N). We compared mortality and overall survival (OS) among the groups. RESULTS: The 90-day mortality and OS were poorer in group FC than in groups C and N, but equivalent to those in group F. Multivariate analyses revealed that IIP (odds ratio [OR] 3.163; p = 0.001) and emphysema (2.588; p = 0.009) were predictors of 90-day mortality. IIP (OR 2.991, p < 0.001), diabetes (OR 1.241, p = 0.043), and a history of other cancers (OR 1.347, p = 0.011) were all predictors of OS. CONCLUSIONS: Short-term and long-term mortality after lung cancer surgery were not dependent on coexistent CAD but were related to IIP. Thus, computed tomography (CT) should be done preoperatively to check for IIP, which is a risk factor for surgical mortality.

Advantages and disadvantages of corticosteroid use for acute exacerbation of interstitial pneumonia after pulmonary resection.

OBJECTIVES: Acute exacerbation of interstitial pneumonia (AE-IP) is the top cause of 30-day mortality in surgery for lung cancer patients. The general treatment for AE-IP is corticosteroid; however, there are some disadvantages of corticosteroid use after surgery. This study was conducted to report the clinical course of AE-IP after surgery and evaluate the effect of corticosteroid use. METHODS: This retrospective study was performed on 337 patients with interstitial pneumonia who underwent surgical resection for lung cancer at our institute between 2009 and 2018. AE-IP were observed in 14 patients (4.2%) and their management and clinical outcome were investigated. RESULTS: All patients received methylprednisolone pulse therapy. Six patients (42.9%) became convalescent after pulse therapy and eight (57.1%) died within 90 days after surgery due to lack of therapeutic efficacy. Oxygenation and ground-glass opacities of the survivors improved within 3 days after starting pulse therapy. Patients who responded to the first pulse also responded to the second pulse. Four patients developed complications including two with bronchopulmonary fistulas that may be related to steroid treatment. Even if the corticosteroid was effective, all AE-IP patients died within 1 year after surgery. CONCLUSIONS: Corticosteroid therapy is effective for AE-IP after surgery; however, it may lead to severe complications after surgery.

Lobe-specific outcomes of surgery for lung cancer patients with idiopathic interstitial pneumonias.

OBJECTIVE: Idiopathic interstitial pneumonias (IIPs) are predominantly encountered in the lower lobe, and frequently with concomitant emphysema that is predominantly in the upper lobe. However, the impact of the resection site on surgical outcomes of lung cancer with IIPs remains unclear. This study was conducted to evaluate the surgical outcome between patients undergoing upper or lower lobe resection. METHODS: This retrospective study was performed on 1972 patients who underwent surgical resection for lung cancer at our institute between 2009 and 2018. Review of CT findings revealed that 337 (14.1%) patients had IIPs. Morbidity, mortality, and postoperative pulmonary function test (PFT) were compared between patients who underwent upper or lower lobectomy and stratified by presence or absence of emphysema (CPFE and non-CPFE). RESULTS: Surgical mortality and morbidity were not statistically different between the two groups regardless of CPFE. The difference between actual and predicted postoperative PFTs was statistically larger in the upper lobectomy compared to the lower lobectomy among the non-CPFE patients. (FVC: p = 0.019, FEV1.0: p = 0.001, %DLCO: p = 0.090) CONCLUSIONS: Site of the resected lobe in lung cancer is not a prognostic factor of surgical mortality and morbidity in patients with IIPs. However, the impact of upper lobectomy on postoperative respiratory function reduction is larger than lower lobectomy in non-CPFE patients.

The maximum dimension of the inferior vena cava is a significant predictor of postoperative mortality in lung cancer patients with idiopathic interstitial pneumonia.

PURPOSE: Several vascular measurements in computed tomography (CT) were reported to be indicators of pulmonary hypertension in chronic obstructive pulmonary disease (COPD) patients. We evaluated the usefulness of these parameters as predictors of postoperative mortality in lung cancer patients with IIP. METHODS: This retrospective study was performed on 1888 patients. The following CT findings were evaluated: diameter of the main pulmonary artery, ascending aorta, and the short axis of the inferior vena cava (IVC). Univariate and multivariate analyses were conducted to determine predictors of surgical mortality. RESULTS: In the IIP patients, the 90-day mortality was 0.8%, and the 2-year mortality was 5.8%. Regarding the 90-day mortality in patients with IIP, a multivariate analysis revealed a short axis of IVC > 21 mm [odds ratio (OR) 6.4, p < 0.01) and the risk score reported by Japanese Association for Chest Surgery (JACS) (OR 1.4, p = 0.01) as independent predictors. Regarding the 2-year mortality in patients with IIP, a multivariate analysis revealed IVC > 21 mm (OR 2.3, p < 0.04), %VC < 80% (OR 2.4, p = 0.02), and pathological cancer stages II and III vs. I (OR 7.2, p < 0.001) as independent predictors. CONCLUSIONS: Enlargement of the IVC as measured by CT was a significant predictor of mortality after surgery for lung cancer with IIP patients.

Study on Perioperative Administration of a Neutrophil Elastase Inhibitor for Interstitial Pneumonias.

BACKGROUND: Although acute exacerbation of idiopathic interstitial pneumonias (IIPs) is a lethal complication after pulmonary resection for lung cancer with IIPs, there are no established methods to prevent its occurrence. This prospective randomized study was conducted to evaluate whether perioperative administration of the neutrophil elastase inhibitor sivelestat prevents acute exacerbation after surgery. METHODS: The IIP patients with suspected lung cancers were randomly assigned to two groups before surgery: in group A (n = 65), sivelestat was perioperatively administered for 5 days; in group B (n = 65), no medications were administered. The primary endpoint was the frequency of acute exacerbation of IIPs. The secondary endpoints were perioperative changes in the lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, surfactant protein D and surfactant protein A values, and the safety of preoperative administration of sivelestat. Multivariate analyses were performed using a logistic regression model to identify the factors that predicted acute exacerbation. RESULTS: Acute exacerbation developed in 2 patients in group A and 1 patient in group B (p = 0.559). Administration of sivelestat did not contribute to decreasing the acute exacerbation as well as short- and long-term mortality. The differences were not statistically significant in perioperative lactate dehydrogenase, C-reactive protein, sialylated carbohydrate antigen, and surfactant protein D and A levels. No subjective adverse events were observed. A preoperative partial pressure oxygen level of less than 70 mm Hg was the only predictive factor identified in the logistic analysis (p = 0.019, hazard ratio 19.2). CONCLUSIONS: Perioperative administration of neutrophil elastase inhibitor appeared to be safe; however, it could not prevent the development of acute exacerbation after surgery in lung cancer patients with IIPs.

Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant inherited disorder caused by germline mutations in the FLCN gene, and characterized by skin fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax, and renal neoplasms. Pulmonary manifestations frequently develop earlier than other organ involvements, prompting a diagnosis of BHDS However, the mechanism of lung cyst formation and pathogenesis of pneumothorax have not yet been clarified. Fibroblasts were isolated from lung tissues obtained from patients with BHDS (n = 12) and lung cancer (n = 10) as controls. The functional abilities of these lung fibroblasts were evaluated by the tests for chemotaxis to fibronectin and three-dimensional (3-D) gel contraction. Fibroblasts from BHDS patients showed diminished chemotaxis as compared with fibroblasts from controls. Expression of fibronectin and TGF-ß1 was significantly reduced in BHDS fibroblasts when assessed by qPCR Addition of TGF-ß1 in culture medium of BHDS lung fibroblasts significantly restored these cells' abilities of chemotaxis and gel contraction. Human fetal lung fibroblasts (HFL-1) exhibited reduced chemotaxis and 3-D gel contraction when FLCN expression was knocked down. To the contrary, a significant increase in chemotactic activity toward to fibronectin was demonstrated when wild-type FLCN was overexpressed, whereas transduction of mutant FLCN showed no effect on chemotaxis. Our results suggest that FLCN is associated with chemotaxis in lung fibroblasts. Together with reduced TGF-ß1 expression by BHDS lung fibroblasts, a state of FLCN haploinsufficiency may cause lung fibroblast dysfunction, thereby impairing tissue repair. These may reveal one mechanism of lung cyst formation and pneumothorax in BHDS patients.

Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses.

Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells.

Isolation of individual cellular components from lung tissues of patients with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease entailing cystic destruction of the lungs and progressive respiratory failure. LAM lungs are histologically characterized by the proliferation of smooth muscle-like cells (LAM cells) and an abundance of lymphatic vessels. To elucidate the pathophysiological processes of LAM, cell-type-specific analyses are required. However, no method exists for isolating the individual types of cells in LAM lesions. Therefore, we established a fluorescence-activated cell sorting (FACS)-based method for the direct isolation of LAM cells and other various cellular components from LAM-affected lung tissue. We obtained LAM-affected lung tissue from resections or transplant recipients and prepared single-cell suspensions. FACS, immunohistochemical, and molecular analysis were used cooperatively to isolate HMB45-positive LAM cells with tuberous sclerosis complex (TSC) 2 loss of heterozygosity (LOH). Using a combination of antibodies against an epithelial cell adhesion molecule (EpCAM) and podoplanin, we fractionated CD45-negative lung cells into three groups: lymphatic endothelial cells (LEC) (EpCAM(-)/podoplanin(hi) subset), alveolar type II cells (EpCAM(hi)/podoplanin(-) subset), and mesenchymal cells (EpCAM(-)/podoplanin(-/low) subset). During subsequent analysis of HMB45 expression, as a LAM-specific marker, we clearly identified LAM cells in the mesenchymal cell population. We then discovered that CD90(+)/CD34(-) cells in the mesenchymal cell population are not only positive for HBM45 but also had TSC2 LOH. These isolated cells were viable and subsequently amenable to cell culture. This method enables us to isolate LAM cells and other cellular components, including LAM-associated LEC, from LAM-affected lung tissues, providing new research opportunities in this field.

Risk of the preoperative underestimation of tumour size of lung cancer in patients with idiopathic interstitial pneumonias.

OBJECTIVES: Sublobar resection of lung cancer (LC) is a valuable procedure in patients with idiopathic interstitial pneumonias (IIPs). Having adequate surgical margins is the key to successful sublobar resection, and evaluation of the precise extent of LC is mandatory. However, tumour extent in IIPs is difficult to evaluate. This study assessed the risk of underestimating tumour size by preoperative computed axial tomography (CAT) scan in LC patients with IIPs. METHODS: A retrospective study was performed on 1221 patients who underwent surgical resection of primary LC at our institute between 2009 and 2013. Review of CAT findings revealed that 136 (11.1%) patients were complicated with IIPs. The discrepancy between radiological and pathological tumour dimensions was measured and underestimation was defined as 10 mm or more in pathological tumour dimension. The rate and cause of preoperative underestimation were also compared between patients with and without IIPs. Univariate and multivariate analyses were performed using a logistic regression model to predict underestimation of the preoperative tumour size. RESULTS: Maximum tumour dimension was underestimated in 14 (10.3%) patients with IIPs and 35 (3.2%) patients without IIPs. A multivariable analysis revealed that IIP was the only predictive factor for tumour size underestimation identified in this study (hazard ratio = 3.52, P = 0.017). Underestimation of tumour size in patients with IIPs was mainly due to extension of tumour cells in the honeycomb lung. CONCLUSIONS: IIPs pose a high risk for underestimating tumour size of LCs in preoperative measurements. Thus, tumour extent should be assessed carefully in order to maintain adequate surgical margins.

Lung Transplantation for Lymphangioleiomyomatosis in Japan.

BACKGROUND: Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported. METHODS: In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network. RESULTS: Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053). CONCLUSIONS: Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus.

Detection of low-prevalence somatic TSC2 mutations in sporadic pulmonary lymphangioleiomyomatosis tissues by deep sequencing.

Lymphangioleiomyomatosis (LAM) (MIM #606690) is a rare lung disorder leading to respiratory failure associated with progressive cystic destruction due to the proliferation and infiltration of abnormal smooth muscle-like cells (LAM cells). LAM can occur alone (sporadic LAM, S-LAM) or combined with tuberous sclerosis complex (TSC-LAM). TSC is caused by a germline heterozygous mutation in either TSC1 or TSC2, and TSC-LAM is thought to occur as a result of a somatic mutation (second hit) in addition to a germline mutation in TSC1 or TSC2 (first hit). S-LAM is also thought to occur under the two-hit model involving a somatic mutation and/or loss of heterozygosity in TSC2. To identify TSC1 or TSC2 changes in S-LAM patients, the two genes were analyzed by deep next-generation sequencing (NGS) using genomic DNA from blood leukocytes (n = 9), LAM tissue from lung (n = 7), LAM cultured cells (n = 4), or LAM cell clusters (n = 1). We identified nine somatic mutations in six of nine S-LAM patients (67 %) with mutant allele frequencies of 1.7-46.2 %. Three of these six patients (50 %) showed two different TSC2 mutations with allele frequencies of 1.7-28.7 %. Furthermore, at least five mutations with low prevalence (<20 % of allele frequency) were confirmed by droplet digital PCR. As LAM tissues are likely to be composed of heterogeneous cell populations, mutant allele frequencies can be low. Our results confirm the consistent finding of TSC2 mutations in LAM samples, and highlight the benefit of laser capture microdissection and in-depth allele analyses for detection, such as NGS.

Potential Role of CT Metrics in Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension.

PURPOSE: Recent imaging studies demonstrated the usefulness of quantitative computed tomographic (CT) analysis assessing pulmonary hypertension (PH) in patients with chronic obstructive lung disease (COPD-PH). The aim of this study was to investigate whether it would be also valuable for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH. METHODS: We analyzed a correlation between the extent of cystic destruction (LAA%) and total cross-sectional areas of small pulmonary vessels less than 5 mm(2) (%CSA <5) in many CT slices from each of four COPD-PH patients before and after the initiation of pulmonary vasodilator. To evaluate those generalized data from patients with COPD, we evaluated multiple slices from 42 patients whose PH was not clinically suspicious. We also selected five PH patients with idiopathic interstitial pneumonia (IIP-PH) and analyzed serial changes of pulmonary artery enlargement (PA:A ratio). RESULTS: In 42 COPD patients without PH, LAA% had a statistically significant negative correlation with %CSA <5. However, three of four COPD-PH patients manifested no such correlation. In two patients, clinical findings were dramatically improved after the initiation of pulmonary vasodilator. Notably, LAA% and %CSA <5 in those patients correlated significantly after its treatment. In COPD-PH, the PA:A ratio was significantly decreased after the initiation of pulmonary vasodilator therapy (1.25 ± 0.13 vs. 1.13 ± 0.11, p = 0.019), but not in IIP-PH. CONCLUSIONS: Our study demonstrates that the use of quantitative CT analysis is a plausible and beneficial tool for predicting and evaluating the effect of pulmonary vasodilators in patients with COPD-PH.

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.

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.

Relationship between quantitative CT metrics and pulmonary function in combined pulmonary fibrosis and emphysema.

PURPOSE: Combined pulmonary fibrosis and emphysema (CPFE) is increasingly recognized, as current reports of its clinical features show. To determine CPFE's physiologic and radiologic features, we conducted quantitative assessment of computed tomography scans to compare with those of chronic obstructive pulmonary disease (COPD). METHODS: In 23 patients with CPFE and 42 patients with COPD, we measured the extent of emphysema (LAA %), parenchymal density, and total cross-sectional areas of pulmonary vessels smaller than 5 mm(2) (%CSA <5) and 5-10 mm(2) (%CSA 5-10). RESULTS: For CPFE, airflow was better, but diffusing capacity for carbon monoxide (DLCO) was worse than for COPD, whereas LAA % was similar for both groups. The %CSA <5 was greater but %CSA5-10 was less in CPFE than COPD. COPD involved a negative correlation between DLCO and LAA % at all lung sites; those factors correlated for CPFE only in the upper lobe (r = -0.535). In contrast, CPFE had a negative correlation between DLCO and parenchymal density in lower lobes (r = -0.453), but COPD showed no correlation in any such sections. In CPFE, no correlation was apparent between LAA in upper lobes and parenchymal density in lower lobes. The annual rate of FVC decline (-169.26 ml/year) in CPFE patients correlated with parenchymal density (r = -0.714). CONCLUSIONS: In CPFE, fibrosis and emphysema apparently existed independently, but both correlate with and likely contribute to the disproportionate reduction in gas exchange. Our study also suggested that pulmonary fibrotic changes may be more important contributors than emphysema for disease progression.