Medical management of post-sublobar resection pulmonary granulomatous lesion: a report of two cases.

BACKGROUND: Automatic stapling devices are commonly utilized in pulmonary resections, including sublobar segmentectomy. Large tumors can develop around the staple line, posing challenges in distinguishing them from cancer recurrence or inflammatory changes. In this report, we present two cases of symptomatic staple granulomatous lesion effectively managed with medications. CASE PRESENTATION: A 74-year-old man presented with a persistent cough and sputum production six years post-segmentectomy for a hamartoma in the left upper lobe. Chest computed tomography (CT) revealed a large tumor around the staple line. Laboratory investigations and bronchoscopic examination revealed no malignancy. The patient received corticosteroids and a cyclooxygenase-2 inhibitor; despite experiencing adverse reactions to steroids, both tumor size and respiratory symptoms were significantly reduced. The second case involved a 78-year-old woman who underwent pulmonary resection for suspected lung cancer. Despite a non-malignant tumor diagnosis, she reported a cough six months post-surgery. Chest CT revealed extensive shadow around the surgical staple, which was diagnosed as mycobacterium granuloma. Low-dose erythromycin induced inflammatory changes but effectively reduced the lesion. CONCLUSIONS: Granulomatous lesions around the staple can be effectively managed with medication, and monitoring the treatment response proves valuable in distinguishing them from tumor recurrence post-pulmonary resection.

Validation of a diagnostic flowchart for tuberculous pleurisy in pleural fluid with high levels of adenosine deaminase.

INTRODUCTION: Adenosine deaminase (ADA) in pleural fluid is a useful marker for diagnosing tuberculous pleurisy. However, recent studies have reported a lower specificity of pleural fluid ADA levels. We previously developed a diagnostic flowchart for patients with pleural fluid ADA ≥40 U/L, incorporating variables such as pleural fluid lactate dehydrogenase <825 U/L, predominant pleural fluid neutrophils or cell degeneration, and a pleural fluid ADA/total protein ratio <14. This flowchart was effective in distinguishing between tuberculous pleurisy and other diseases. Here, we conducted a validation analysis of this flowchart. MATERIALS AND METHODS: We retrospectively collected data from 458 patients with pleural fluid ADA concentrations ≥40 U/L across eight institutions from January 2019 to December 2023. The diagnostic accuracy rate, sensitivity, and specificity of the diagnostic flowchart were analysed and compared to those in the original study. RESULTS: Eighty-seven patients were diagnosed with tuberculous pleurisy, and 371 patients were diagnosed with other diseases. The diagnostic accuracy, sensitivity, and specificity for diagnosing tuberculous pleurisy were 77.7%, 86.2%, and 75.7%, respectively. Compared with that in the original study, the rate of tuberculous pleurisy was lower (19.0% vs. 44.5%, p < 0.001), but the diagnostic accuracy rates were not significantly different (p = 0.253). On the basis of the findings from this validation study, we have revised the flowchart to enhance its utility. CONCLUSION: The diagnostic flowchart exhibited high diagnostic accuracy in this validation study, comparable to that in the original study. This validation confirms the effectiveness of the flowchart, even in settings with a low incidence of tuberculosis.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

A retrospective study of the efficacy of combined EGFR­TKI plus VEGF inhibitor/cytotoxic therapy vs. EGFR­TKI monotherapy for PD­L1­positive EGFR­mutant non­small cell lung cancer: North Japan Lung Cancer Study Group 2202.

The present multicenter study was performed to compare the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy with that of combined EGFR-TKI plus vascular endothelial growth factor receptor (VEGF) inhibitor/cytotoxic therapy in patients with programmed death-ligand 1 (PD-L1)-positive EGFR-mutant non-small cell lung cancer (NSCLC). Data from patients with PD-L1-positive EGFR-mutant NSCLC were collected from 12 institutes. Survival in patients treated with first- and second-generation EGFR-TKIs, osimertinib (third-generation EGFR-TKI), and combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy was analyzed by multiple regression analysis with adjustments for sex, performance status, EGFR mutation status, PD-L1 expression level, and the presence or absence of brain metastasis using a Cox proportional hazards model. Data from a total of 263 patients were analyzed, including 111 (42.2%) patients who had received monotherapy with a first- or second-generation EGFR-TKI, 132 (50.2%) patients who had received osimertinib monotherapy, and 20 (7.6%) patients who had received combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy (hereafter referred to as combined therapy). Multiple regression analysis using the Cox proportional hazards model showed that the hazard ratio (95% confidence interval) for progression-free survival was 0.73 (0.54-1.00) in the patients who had received osimertinib monotherapy and 0.47 (0.25-0.90) in patients who had received combined therapy. The hazard ratio for overall survival was 0.98 (0.65-1.48) in the patients who had received osimertinib monotherapy and 0.52 (0.21-1.31) in patients who had received combined therapy. In conclusion, combined therapy was associated with a significant reduction in the risk of progression compared with first- and second-generation EGFR-TKI monotherapy, and therefore, may be promising for the treatment of patients of NSCLC.

Serum Carcinoembryonic Antigen Levels Before the First Curative Hepatectomy for Metastatic Colorectal Cancer Is a Predictor of Recurrence.

BACKGROUND/AIM: The aim of this study was to evaluate the usefulness of serum carcinoembryonic antigen (CEA) levels before the first curative hepatectomy for metastatic colorectal cancer as a predictor of recurrence. PATIENTS AND METHODS: Between 2003 and 2010, 66 patients (45 male and 21 female) who underwent a first curative hepatectomy for metastatic colorectal cancer in our hospital were evaluated retrospectively. The mean patient age was 65.2 years (range=31-80 years). A total of 28 patients had synchronous liver metastasis, and the other 38 patients developed metachronous liver metastasis. RESULTS: The 5-year relapse-free survival rate after the first hepatectomy of the 16 patients with normal serum CEA level was 61.1%, whereas that of the 50 patients with abnormal serum CEA level was 34.3% (p<0.001). Among patients whose serum CEA levels were abnormal, the 5-year relapse-free survival rate after the first hepatectomy of the 34 patients with serum CEA levels less than 50 ng/ml was 48.1%, whereas that of the 16 patients with serum CEA level equal to or greater than 50 ng/ml was 6.3% (p<0.001). All eleven patients whose serum CEA levels were at least 100 ng/ml developed recurrence within one year after hepatectomy. CONCLUSION: Serum CEA levels before the first curative hepatectomy for metastatic colorectal cancer seem to be a predictor of recurrence.

Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.

BACKGROUND: Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection. METHODS: The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H2O2), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N-acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients. RESULTS: Treatment with H2O2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H2O2-potentiated IL-33 expression. In addition, H2O2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H2O2-potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H2O2-stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects. CONCLUSIONS: These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.

The dynamic shuttling of SIRT1 between cytoplasm and nuclei in bronchial epithelial cells by single and repeated cigarette smoke exposure.

SIRT1 (silent information regulator 2 homolog 1) is a crucial cellular survival protein especially in oxidative stress environments, and has been thought to locate within the nuclei, but also known to shuttle between cytoplasm and nuclei in some cell types. Here, we show for the first time the dynamics of SIRT1 in the presence of single or concurrent cigarette smoke extract (CSE) exposure in human bronchial epithelial cells (HBEC). In BEAS-2B HBEC or primary HBEC, SIRT1 was localized predominantly in cytoplasm, and the CSE (3%) induced nuclear translocation of SIRT1 from cytoplasm in the presence of L-buthionine sulfoximine (an irreversible inhibitor of γ-glutamylcystein synthetase), mainly through the activation of phosphatidylinositol 3-kinase (PI3K) α subunit. This SIRT1 nuclear shuttling was associated with FOXO3a nuclear translocation and the strong induction of several anti-oxidant genes including superoxide dismutase (SOD) 2 and 3; therefore seemed to be an adaptive response. When BEAS-2B cells were pretreated with repeated exposure to a lower concentration of CSE (0.3%), the CSE-induced SIRT1 shuttling and resultant SOD2/3 mRNA induction were significantly impaired. Thus, this result offers a useful cell model to mimic the impaired anti-oxidant capacity in cigarette smoking-associated lung disease such as chronic obstructive pulmonary disease.

Definition and diagnosis of asthma-COPD overlap (ACO).

It is now widely recognized that asthma and COPD can coexist as asthma-COPD overlap (ACO), but the preliminary attempts at providing universal guidelines for the diagnosis of ACO still need to be improved. We believe that a case can be made for devising guidelines for the diagnosis of this increasingly common disease that are specific to Japan. In this paper, we present our consensus-based description of ACO which we believe is realistic for use in our country. In addition, we cite the scientific evidence for our own "objective" features used to develop the criteria for COPD and asthma diagnosis. We acknowledge that they will need to be validated and updated over time, but hope the results will encourage further research on the characteristics and treatment of this commonly encountered clinical problem.

Relapsed Myasthenia Gravis after Nivolumab Treatment.

Nivolumab is a newly introduced promising therapy for treating lung cancer that restores the anti-tumor immunity by disrupting programmed cell death-1-mediated immuno-suppressive signaling. Although "new-onset" autoimmune diseases are well-known immune-related adverse events, whether or not nivolumab exacerbates "pre-existing" autoimmune disease remains unclear. We herein report a patient with "pre-existing" myasthenia gravis in whom nivolumab was administered that flared up after the treatment with nivolumab. Regardless of the disease stability, nivolumab has the potential to exacerbate an autoimmune disease, and we must pay close attention to each patient's medical history before administering this agent.

Production of reactive persulfide species in chronic obstructive pulmonary disease.

BACKGROUND: Oxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine ß-synthase and cystathionine γ-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown. OBJECTIVES: The aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD. METHODS: Lung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography-tandem mass spectrometry with ß-(4-hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified. RESULTS: The amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD. CONCLUSIONS: We have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD.

Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD.

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.

Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease.

RATIONALE: Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor ß superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence. METHODS: The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated. RESULTS: The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema. CONCLUSIONS: The decrease in GDF11 may be involved in the cellular senescence observed in COPD.

Blood flow evaluation using PINPOINT® in a case of incarcerated inguinal hernia: A case report.

Indocyanine green (ICG) fluorescence for intestinal blood flow has been reported, but application during laparoscopic surgery for incarcerated inguinal hernia has not been reported. Here, we report the case of a patient with an incarcerated inguinal hernia in whom the bowel was preserved after evaluation of intestinal blood flow with ICG fluorescence using PINPOINT®, a brightfield full-color, near-infrared fluorescence camera. A man in his 80s was diagnosed with incarcerated inguinal hernia and underwent laparoscopic surgery. The ascending colon and mesentery showed deep red discoloration on gross evaluation. However, intravenous injection of ICG revealed uniform fluorescence of the mesentery and bowel wall, indicating the absence of irreversible ischemic changes of the bowel. As such, no resection was performed, and transabdominal preperitoneal patch plasty was completed. The patient had a good postoperative course. In this case, ICG fluorescence with the PINPOINT was useful to avoid bowel resection during laparoscopic surgery.

A case of incarcerated femoral hernia with intestinal blood flow assessment by brightfield full-color near-infrared fluorescence camera: Report of a case.

INTRODUCTION: Indocyanine green (ICG) fluorescence has been reported for examining intestinal blood flow (IBF), but not in the case of bowel released from entrapment in a femoral hernia. We report the case of a patient with incarcerated obturator femoral hernia in whom the bowel was preserved after evaluation of IBF with ICG fluorescence using a brightfield full-color near-infrared fluorescence camera. PRESENTATION OF CASE: A woman in her 60s was diagnosed with incarcerated femoral hernia and underwent surgery. Laparotomy was performed to reduce bowel incarceration via an anterior approach. The small bowel showed deep-red discoloration on gross evaluation, but intravenous injection of ICG revealed uniform fluorescence of the mesentery and bowel wall. This indicated an absence of irreversible ischemic changes to the bowel, so resection was not performed and a modified Kugel herniorrhaphy was performed. The patient showed a good postoperative course. CONCLUSION: In herniorrhaphy with mesh, minimization of bowel resection is important for preventing postoperative infection of the mesh. In this case, ICG fluorescence with a near-infrared fluorescence camera was central to reducing bowel resection. ICG fluorescence may be useful for evaluating IBF in surgery for incarcerated femoral hernias.