Incidence of and predictive factors for lung cancer in patients with rheumatoid arthritis: A retrospective long-term follow-up study.

OBJECTIVE: To determine the incidence and predictive factors of lung cancer in rheumatoid arthritis (RA). METHODS: We conducted a retrospective follow-up study of patients who were diagnosed with RA at our institution between April 2001 and December 2022. Pulmonary complications were evaluated using high-resolution computed tomography at RA diagnosis. Patients were followed until the diagnosis of lung cancer, diagnosis of other malignancies, death, loss to follow-up, or the end of the study. RESULTS: Among 771 RA patients, 3.5% were diagnosed with combined pulmonary fibrosis and emphysema (CPFE), 4.9% with interstitial lung disease (ILD) alone, and 6.0% with emphysema alone. During follow-up (mean of 9.3 years), the crude incidence rates of lung cancer per 1,000 patient-years were 2.9 in all patients, 47.8 in CPFE patients, 10.5 in ILD patients, 11.9 in emphysema patients, and 0.8 in patients without these complications. The standardized incidence ratios (95% confidence intervals [CI]) compared with the general population were 2.53 (1.29-3.77) for male patients and 0.89 (0.57-1.16) for female patients. In Fine-Gray regression analysis, adjusted hazard ratios (95% CI) of lung cancer were 13.48 (3.14-57.85) for CPFE, 6.42 (1.42-29.09) for ILD alone, and 4.65 (1.18-18.30) for emphysema alone versus without these complications, and 1.02 (1.01-1.04) per additional 1 pack-year for smoking history. These factors were not associated with the risk of other malignancies. CONCLUSION: Close monitoring of lung cancer is needed for RA patients with smoking history and pulmonary complications, especially CPFE.

Impact of combined pulmonary fibrosis and emphysema on lung cancer risk and mortality in rheumatoid arthritis: A multicenter retrospective cohort study.

OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome characterized by the coexistence of emphysema and fibrotic interstitial lung disease (ILD). The aim of this study was to examine the effect of CPFE on lung cancer risk and lung cancer-related mortality in patients with rheumatoid arthritis (RA). METHODS: We conducted a multicenter retrospective cohort study of patients newly diagnosed with lung cancer at five community hospitals between June 2006 and December 2021. Patients were followed until lung cancer-related death, other-cause death, loss to follow-up, or the end of the study. We used the cumulative incidence function with Gray's test and Fine-Gray regression analysis for survival analysis. RESULTS: A total of 563 patients with biopsy-proven lung cancer were included (82 RA patients and 481 non-RA patients). The prevalence of CPFE was higher in RA patients than in non-RA patients (40.2% vs.10.0%) at lung cancer diagnosis. During follow-up, the crude incidence rate of lung cancer-related death was 0.29 and 0.10 per patient-year (PY) in RA and non-RA patients, and 0.32 and 0.07 per PY in patients with CPFE and patients without ILD or emphysema, respectively. The estimated death probability at 5 years differed between RA and non-RA patients (66% vs. 32%, p<0.001) and between patients with CPFE and patients without ILD or emphysema (71% vs. 24%, p<0.001). In addition to clinical cancer stage and no surgery within 1 month, RA and CPFE were identified as independent predictive factors for increased lung cancer-related mortality (RA: adjusted hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.65-4.76; CPFE: adjusted HR 2.01; 95% CI 1.24-3.23). CONCLUSIONS: RA patients with lung cancer had a higher prevalence of CPFE and increased cancer-related mortality compared with non-RA patients. Close monitoring and optimal treatment strategies tailored to RA patients with CPFE are important to improve the poor prognosis of lung cancer.

HEG1, BAP1, and MTAP are useful in cytologic diagnosis of malignant mesothelioma with effusion.

BACKGROUND: The specificity and sensitivity of HEG1 for malignant mesothelioma (MM) is high. The use of BAP1/MTAP immunohistochemistry (IHC) is recommended to separate benign and malignant mesothelial proliferations. We determined how ancillary techniques can be used for the cytological diagnosis of MM with effusion. METHODS: Cell blocks from effusions from cases with MM, reactive mesothelial cells (RMCs), and carcinomas were analyzed by IHC with HEG1, BAP1, and MTAP and with homozygous deletion (HD) of CDKN2A by fluorescence in situ hybridization. Staining scores were calculated for IHC by adding the number of categories for the staining intensity and the staining extension. RESULTS: HEG1 was positive in all (41/41) MMs, but negative in carcinomas, except for ovarian carcinomas. Overall 76.9% (20/26) of RMCs and 28.6% (6/21) of ovarian carcinomas expressed HEG1. BAP1 loss was found in 71.1% of MMs, but none was found in RMCs. MTAP loss was found in 76.2% of MMs, but none was found in RMCs. 73.9% of MMs harbored HD of CDKN2A. There was concordance between loss of MTAP and HD of CDKN2A in 95% of MMs. CONCLUSION: HEG1 is a good marker for mesothelial differentiation in effusion cytology. HD of CDKN2A is frequently observed in cell blocks from effusions of MMs, and MTAP IHC may act as a surrogate for HD of CDKN2A. Cell block analysis is recommended for effusions of unknown origins with the following methods: IHC with HEG1 and claudin 4 to validate the mesothelial origin, followed by BAP1 and MTAP IHC to confirm malignancy.

A surgical case of lung cancer with poor general status associated with parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP), which is released in the presence of malignant disease, is associated with hypercalcemia. Complete resection of the tumor in such patients is rarely performed because of their poor general condition. We herein report a case of lung cancer associated with PTHrP in a patient whose condition dramatically improved after surgery. We also review the literature on the benefits of various surgical options. Although only a few cases of complete resection in such patients have been reported, the mental and physical condition of the patients improved postoperatively and the median survival time was longer than 12 months. A poor general status is frequently considered a contraindication for surgery, even in a palliative setting; however, we conclude that resection of lung cancer may lead to improved symptom control and survival when the patient's condition is induced by hypercalcemia secondary to PTHrP secretion from the tumor.

CT assessment of axillary lymphadenopathy in patients with rheumatoid arthritis: association with disease activity and severity.

BACKGROUND: Axillary lymph nodes (ALNs) are often seen on chest computed tomography (CT) in rheumatoid arthritis (RA) patients. Early reports described lymphadenopathy as one of the systemic manifestations rather than regional lymphadenopathy secondary to drainage from the affected joints. Subsequently, the importance of the immunological events occurring in draining lymph nodes in the development of arthritis was documented. OBJECTIVE: To identify the relationships of local disease activity and background characteristics, including systemic disease activity, systemic disease activity, with axillary lymphadenopathy (AL) in RA using CT. METHODS: RA patients who had undergone chest CT were retrospectively analyzed. The maximum short axis of the ALNs was measured, and the number of positive ALNs ≥ 5 mm was counted. Tender and swollen joints in the upper limbs were counted as indicators of local disease activity. Background characteristics and systemic disease activity were assessed based on the selected RA indicators. Correlations between AL and both local disease activity and background characteristics including systemic disease activity were analyzed. RESULTS: Of 135 patients, 58 had positive ALNs (average size 7.97 mm, range up to 15 mm). The presence of positive unilateral ALNs was correlated with the severity of ipsilateral upper limb arthritis. Multivariate analysis showed correlations between AL and both local disease activity and serological findings such as serum C-reactive protein (CRP) and immunoglobulin (Ig) G. CONCLUSION: AL in patients with RA was correlated with local arthritis activity, as well as background characteristics and systemic disease activity.

The efficacy of transbronchial needle aspiration with endobronchial ultrasonography using a guide sheath for peripheral pulmonary lesions suspected to be lung cancer.

BACKGROUND: The efficacy of transbronchial needle aspiration (TBNA) with endobronchial ultrasonography using a guide sheath (EBUS-GS) for cases of peripheral pulmonary lesions (PPLs) has not been well established. The purpose of this study was to evaluate the efficacy of TBNA with EBUS-GS for PPLs. METHODS: We evaluated 130 patients suspected to have lung cancer who underwent transbronchial brushing (brushing), transbronchial biopsy (TBB), and TBNA with EBUS-GS. The pathological diagnostic yields of TBNA were compared to that of TBB and brushing. The histological diagnosis of TBNA was compared to that of surgical specimens. The results of epidermal growth factor receptor (EGFR) gene mutation in TBNA samples were compared to that in TBB or surgical specimens. RESULTS: The diagnostic yields of this study were 62.9% for brushing, 80.0% for TBB, and 77.1% for TBNA. Histological diagnosis was 84.8% for TBB and/or TBNA and pathological diagnosis was 86.7% for all the procedures. TBB and TBNA had significance higher than brushing (p < 0.05). TBB and TBNA had a tendency of higher diagnostic yields than brushing if EBUS probe was adjacent to PPLs (p = 0.058). Histological evaluations were obtained from TBNA specimens from 50 of 105 patients (47.6%) and these were identical to those of surgical specimens from 29 of 32 patients (90.6%). The results of EGFR gene mutation in TBNA specimens were identical to the same tissue obtained by surgery or TBB. CONCLUSIONS: TBNA with EBUS-GS for PPLs was a useful tool for accurate diagnosis and EGFR gene mutation analysis. This method may improve diagnostic accuracy and be useful for molecular testing. This study was approved by the institutional review board (Date of approval: May 27, 2013, approval number: 2816) of Tokyo Women's Medical University Hospital.

Intravenous Immunoglobulin Monotherapy for Granulomatous Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) is a heterogeneous subset of immunodeficiency disorders. Recurrent bacterial infection is the main feature of CVID, but various non-infectious complications can occur. A 42-year-old woman presented with cough and abnormal chest X-ray shadows. Laboratory tests showed remarkable hypogammaglobulinemia. Computed tomography revealed multiple consolidation and nodules on the bilateral lung fields, systemic lymphadenopathy, and splenomegaly. A surgical lung biopsy specimen provided the final diagnosis of lymphoproliferative disease in CVID, which was grouped under the term granulomatous lymphocytic interstitial lung disease. Interestingly, the lung lesions of this case resolved immediately after the initiation of intravenous immunoglobulin monotherapy.

Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan.

OBJECTIVE: Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. METHODS: We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. RESULTS: A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. CONCLUSIONS: The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.

A case of respiratory infection possibly caused by Mycobacterium triviale: Current problems on diagnostic and therapeutic strategies.

Mycobacterium triviale is a subspecies of the Mycobacterium terrae complex, which rarely causes disease in humans. We encountered a case of respiratory infection, possibly caused by M. triviale, which was successfully treated by levofloxacin and clarithromycin. Although DNA-DNA hybridization identified M. triviale in one of three samples, clinical validations convinced us that it was the pathogen. 16s ribosomal RNA sequencing would have been reliable and ideal to perform in this case, although it is not covered by the insurance system in Japan. Nevertheless, this experience remains to be instructive because the clinical course, guidelines on the diagnosis, and therapeutic strategies for respiratory infections caused by M. triviale are not well-known or have not been established. Awareness of the possibility of respiratory infections caused by M. triviale and further collection and analysis of its predisposing conditions are essential.

Rosai-Dorfman Disease of the Lung Overlapping with IgG4-related Disease: The Difficulty in Its Differential Diagnosis.

We herein report a case of Rosai-Dorfman disease (RDD) overlapping with IgG4-related disease (IgG4-RD), which presented as diffuse interstitial lung disease with a perilymphatic pattern, followed by submandibular gland and eyelid swelling. The pathological findings of the submandibular gland biopsy specimen were indicative of IgG4-RD alone. We diagnosed the patient with RDD with overlapping IgG4-RD. However, the optimal method for differentiating between these two entities is still controversial. It is important that clinicians are aware that RDD should be included in the differential diagnoses of diffuse interstitial lung disease with a perilymphatic pattern and that RDD can overlap with IgG4-RD.

Pulmonary ground-glass opacity: computed tomography features, histopathology and molecular pathology.

The incidence of pulmonary ground-glass opacity (GGO) lesions is increasing as a result of the widespread use of multislice spiral computed tomography (CT) and the low-dose CT screening for lung cancer detection. Besides benign lesions, GGOs can be a specific type of lung adenocarcinomas or their preinvasive lesions. Evaluation of pulmonary GGO and investigation of the correlation between CT imaging features and lung adenocarcinoma subtypes or driver genes can be helpful in confirming the diagnosis and in guiding the clinical management. Our review focuses on the pathologic characteristics of GGO detected at CT, involving histopathology and molecular pathology.

Effectiveness of Combined Therapy with Pirfenidone and Erythromycin for Unclassifiable Interstitial Pneumonia Induced by HTLV-1-associated Bronchioloalveolar Disorder (HABA).

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus involved in the pathogenesis of adult T-cell leukemia (ATL) and HTVL-1-associated bronchioloalveolar disorder (HABA). The clinical and pathological findings of HABA have been characterized as either a diffuse panbronchiolitis (DPB) pattern or idiopathic interstitial pneumonia (IIP) pattern. Treatments for HABA include corticosteroids for the IIP pattern and erythromycin for the DPB pattern. We herein report a case of HABA-associated unclassifiable interstitial pneumonia that improved with combined therapy with pirfenidone and erythromycin. This is the first report on the effectiveness of combined therapy with pirfenidone and erythromycin for HABA.

Cytologic Differential Diagnosis of Malignant Mesothelioma and Reactive Mesothelial Cells With FISH Analysis of p16.

BACKGROUND: Mesothelioma patients often present with serosal effusions, which are ideal for cytopathological diagnoses. However, the morphological overlap between malignant and benign mesothelial proliferation can make a conclusive cytological diagnosis of mesothelioma elusive because immunohistochemical staining does not discriminate definitively between the two in this setting. p16 is deleted in up to 80% of pleural mesotheliomas. The aim of this study was to establish the correlation between the p16 deletion status of the cell block with that of its corresponding tumor using fluorescence in situ hybridization (FISH) analysis for individual patient tumors. METHODS: Twenty-two biopsies and 24 corresponding cell blocks, containing serosal effusions with atypical mesothelial cells from 22 patients with histologically confirmed pleural mesotheliomas, were analyzed with p16 FISH. Seventeen cell blocks consisting of serosal effusions with reactive mesothelial cells from nonmesothelioma cases were also analyzed. Combined immunofluorescence and FISH were also performed. RESULTS: Seventeen of the 22 mesothelioma patients (77.3%) showed homozygous deletions of p16 in the tumor tissue and in the atypical mesothelial cells from the cell blocks. p16 FISH followed by immunofluorescence with EMA was helpful towards identifying the mesothelioma cells in the cell blocks. CONCLUSION: We confirmed that the p16 FISH results obtained from the cell blocks are as reliable as those from the tissue sections. Cell block analysis is recommended for patients with serosal effusions of unknown origins with the following methods: immunohistochemistry should be performed to validate the mesothelial origin, and p16 FISH should be performed to confirm malignancy. Diagn. Cytopathol. 2016;44:591-598. © 2016 Wiley Periodicals, Inc.

CT Features of Epidermal Growth Factor Receptor-Mutated Adenocarcinoma of the Lung: Comparison with Nonmutated Adenocarcinoma.

INTRODUCTION: The purpose of this study was to analyze the high-resolution computed tomography (HRCT) features of lung carcinoma on the basis of epidermal growth factor receptor gene (EGFR) mutation status. METHODS: A total of 263 consecutive patients in whom lung adenocarcinoma was diagnosed at our institution between January 2010 and December 2011 were enrolled in the study. All patients underwent HRCT and analysis of EGFR mutation status. The HRCT findings were retrospectively analyzed for tumor size, multiple bilateral lung metastases, convergence of surrounding structures, surrounding ground-glass opacity, prominent peribronchovascular extension, air bronchogram, notch, pleural indentation, spiculation, cavity, and pleural effusions. RESULTS: EGFR mutations were demonstrated in 103 patients (39.2%); the remaining 160 patients (60.8%) had the nonmutated type of adenocarcinoma. Compared with the nonmutated group, the mutated group had significantly higher frequencies of multiple bilateral lung metastases (p = 0.0152), convergence of surrounding structures (p < 0.0001), ground-glass opacity (p = 0.0011), and notch (p = 0.0428), but significantly lower frequencies of cavitation (p = 0.0004) and pleural effusions (p = 0.0064). The frequencies of the other CT findings were similar between the two groups. The devised prediction HRCT score for EGFR mutation was 78.4% sensitive and 70.4% specific. CONCLUSIONS: EGFR-mutated adenocarcinoma showed significantly higher frequencies of multiple bilateral lung metastases, convergence of surrounding structures, surrounding ground glass opacity, and notch at HRCT compared with the non-EGFR-mutated type. Conversely, EGFR-mutated adenocarcinoma showed cavity and pleural effusions less frequently than the nonmutated type did.

FISH analysis of intrapulmonary malignant mesothelioma without a clinically detectable primary pleural lesion: an autopsy case.

Patients with malignant mesothelioma typically present with a pleural effusion or pleural thickening and masses. A rare autopsy case of mesothelioma presenting with multiple bilateral lung nodules without clinically detectable pleural lesions is presented. A definitive diagnosis of the video-assisted thoracic surgery specimen could not be made, though a pattern of fibrosis mimicking organizing pneumonia was identified. Despite corticosteroid therapy, follow-up chest computed tomography showed enlargement of multiple nodules accompanied by the appearance of pleural thickening and effusions. The patient died of respiratory failure 11 months after initial presentation. Autopsy and retrospective analysis of the video-assisted thoracic surgery specimen using a p16 fluorescence in situ hybridization assay showed p16 homozygous deletion. The final diagnosis was sarcomatoid mesothelioma, and the lung nodules were intrapulmonary metastases from a clinically undetectable pleural sarcomatoid mesothelioma. It is important both to consider the possibility of mesothelioma with unusual clinical, radiological and pathological presentations and to remember that p16 fluorescence in situ hybridization analysis can play an important role in the diagnosis of mesothelioma.

Utility of continuous positive airway pressure therapy for treating chronic coughs in patients with obstructive sleep apnea.

We experienced two patients with chronic coughs whose symptoms persisted after initial treatment under a diagnosis of suspected upper airway cough syndrome or cough variant asthma. Neither patient exhibited daytime somnolence, although both were subsequently found to have severe obstructive sleep apnea. Following the administration of nocturnal continuous positive airway pressure therapy, the cough symptoms rapidly improved in both cases. These cases represent the first reports of obstructive sleep apnea-induced chronic cough in Japan.

EGFR mutation of adenocarcinoma in congenital cystic adenomatoid malformation/congenital pulmonary airway malformation: a case report.

An 80-year-old man underwent right upper lobectomy for the resection of multiple cysts accompanied by a nodule. The pathological diagnosis was adenocarcinoma with surrounding atypical epithelial cell proliferation in a Type 1 congenital cystic adenomatoid malformation/congenital pulmonary airway malformation. There was epidermal growth factor receptor mutation in the adenocarcinoma and surrounding atypical epithelial cells that had proliferated. Malignant transformation of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation may be related to the epidermal growth factor receptor pathway in this case, with atypical epithelial cell proliferation as a precursor. We emphasize the importance of complete resection of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation and the possibility of treatment with epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor-mutated cases.

[Sustainable efficacy of oral varenicline for smoking cessation].

Varenicline (Champix) is an alpha4beta2 nicotinic receptor antagonist that is used orally for treatment of nicotine dependence. We conducted a study to examine the sustainable efficacy of varenicline in smoking cessation. The subjects were 148 outpatients (113 men, 35 women; average age; 54.4 +/- 14.0 years) at 6 different hospitals, and their adverse events were monitored in each hospital. The 4-week continuous abstinence rates of smoking cessation were 17.6%, 75.0%, and 84.6% in groups treated for 4 or fewer weeks, 5 to 8 weeks, and 9 to 12 weeks, respectively, with the rate showing a significant increase according to treatment period. Among 83 patients who had adverse events, the abstinence rates were 76.9%, 92.3%, 54.5%, and 55.6% in an observed (OB) group, a nosotropic medication (NM) group, a dose-reduction (RD) group, and a drug-discontinuation (DC) group, respectively. Among 56 patients with nausea, the respective rates were 80.8%, 100.0%, 61.1%, and 50.0%, respectively, with a significantly higher success rate in the NM group than in the RD or DC groups (each p < 0.05). To sustain the efficacy of varenicline in patients with adverse events, we recommend a therapeutic strategy in which the active nosotropic medicine is administered over 12 weeks at the regular dosage.

Size of noncancerous hilomediastinal lymph nodes measured on coronal and sagittal reconstruction CT images.

PURPOSE: To determine the sizes of hilomediastinal lymph nodes on coronal and sagittal reconstruction computed tomographic images of subjects without known malignancies. MATERIALS AND METHODS: We evaluated 560 lymph nodes of 246 consecutive patients who underwent multidetector-row computed tomography (MDCT) of the chest, then reconstructed coronal and sagittal images on a viewer and measured short-axis diameters of lymph nodes in each station according to the American Thoracic Society (ATS) map for axial, coronal, and sagittal images. RESULTS: On coronal images, short-axis diameters were significantly larger than on axial images in station #4R (P < 0.01). On sagittal images, short-axis diameters were significantly smaller than on axial images in stations #4L (P < 0.01), #10R (P < 0.001), and #10L (P < 0.05). On coronal and sagittal images, short-axis diameters were significantly smaller than on axial images in stations #11R (P < 0.001). In #7, diameters were significantly larger on coronal images than on axial and sagittal images (P < 0.001), and diameters were significantly smaller on sagittal images than on axial images (P < 0.01). CONCLUSION: In stations #4R, #4L, #7, #10R, #10L, and #11R, measurements of short-axis diameters of hilomediastinal lymph nodes differed on coronal and sagittal images. On coronal and sagittal images, evaluation of hilomediastinal lymph nodes requires unique size criteria for every station.