Clinical and Prognostic Significance of Glutathione Peroxidase 2 in Lung Adenocarcinoma.

BACKGROUND: Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme with an important role in tumor progression in various cancers. However, the clinical significance of GPX2 in lung adenocarcinoma has not been clarified. METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze GPX2 mRNA expression. Then, we conducted immunohistochemistry (IHC) to assess GPX2 expression in specimens acquired from 351 patients with lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We investigated the association between GPX2 expression and clinicopathological characteristics and further analyzed the prognostic relevance. RESULTS: qRT-PCR revealed that GPX2 mRNA expression was notably higher in tumor cells than in normal tissues. IHC revealed that high GPX2 expression (n = 175, 49.9%) was significantly correlated with male sex, smoking, advanced pathological stage, and the presence of pleural, lymphatic, and vascular invasion. Patients with high GPX2 expression exhibited significantly shorter recurrence-free survival (RFS) and overall survival. Multivariate analysis identified high GPX2 expression as an independent prognostic factor of RFS. CONCLUSIONS: GPX2 expression was significantly associated with pathological malignancy. It is conceivable that high GPX2 expression reflects tumor malignancy. Therefore, high GPX2 expression is a significant prognostic factor of poor prognosis for completely resected lung adenocarcinoma.

Maximum resistance pressure at the time of lung tissue rupture after porcine lung transection using automatic linear staplers with different reinforcement methods.

PURPOSES: Polyglycolic acid (PGA) sheets, fibrin glue, and staple line reinforcement are frequently used to prevent air leakage during lung resection. However, the optimal staple-line reinforcement method remains unclear. METHODS: Cranial lung lobes of pigs were used to evaluate different staple line reinforcement methods (n = 6). Ventilator-assisted manometry was used to measure the maximum resistance pressure at the time of rupture of the lung tissue after stapling. RESULTS: The mean maximum resistance pressures at the time of lung tissue rupture after using the stapler alone, stapler with PGA sheet and fibrin glue, and stapler with reinforcement were 38.0 cmH2O, 51.3 cmH2O, and 62.7 cmH2O, respectively. A significant increase in the maximum resistance pressure was observed with stapler reinforcement (P < 0.001), while the differences between the other groups were not statistically significant (P = 0.055, P = 0.111). A histological assessment revealed disruption of alveolar structures near the needle-stitching site in the stapler alone, and in the stapler with PGA sheet and fibrin glue groups. Pleural rupture near the staple line was observed in the stapler with reinforcement group. CONCLUSIONS: The maximum resistance pressure before air leakage was significantly higher when using a stapler with reinforcement than when using a stapler alone.

Prognostic Impact of C-Reactive Protein-to-Lymphocyte Ratio in Non-small Cell Lung Cancer: A Propensity Score-Matching Analysis.

BACKGROUND: Many inflammatory and nutritional markers have been used to predict prognosis in lung cancer. The C-reactive protein (CRP)-to-lymphocyte ratio (CLR) is a useful prognostic factor in various cancers. However, the prognostic value of preoperative CLR in patients with non-small cell lung cancer (NSCLC) remains to be established. We examined the significance of the CLR compared with known markers. METHODS: A total of 1380 surgically resected NSCLC patients treated at two centers were recruited and divided into derivation and validation cohorts. After CLRs were calculated, patients were classified into high and low CLR groups based on the cutoff value determined by receiver operating characteristics curve analysis. Subsequently, we determined the statistical associations of the CLR with clinicopathological factors and prognosis and further analyzed its prognostic impact by propensity-score matching. RESULTS: Of all the inflammatory markers examined, CLR yielded the highest area-under-the-curve value. The prognostic impact of CLR remained significant after propensity-score matching. Prognosis was significantly worse in the high-CLR group than in the low-CLR group (5-year, disease-free survival [DFS]: 58.1% vs. 81.9%, P < 0.001; 5-year overall survival [OS]: 72.1% vs. 91.2%, P < 0.001). The results were confirmed in the validation cohorts. Multivariable analysis also showed high CLR as an independent factor for both DFS and OS (DFS: hazard ratio [HR] 1.42, P = 0.027; OS: HR 1.95, P = 0.0037). CONCLUSIONS: Preoperative CLR is a useful marker for predicting the prognosis of NSCLC patients who have undergone surgery.

Granzyme B (GZMB)-Positive Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma: Significance as a Prognostic Factor and Association with Immunosuppressive Proteins.

BACKGROUND: Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood. METHODS: We analyzed 273 patients with pathological stage (pStage) I-IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed. RESULTS: GZMB-Low was significantly associated with pStage II-III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis. CONCLUSIONS: We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient's immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma.

The Clinical Role of Adjuvant Chemotherapy after Sublobar Resection for Non-Small-Cell Lung Cancer ≤ 20 mm with Lymph Node Metastases: A Propensity-Matched Analysis of the National Cancer Database.

Sublobar resection is a standard surgical procedure for small-sized non-small-cell lung cancer (NSCLC). However, the clinical role of adjuvant chemotherapy for small-sized NSCLC with pathological lymph node (LN) metastasis after sublobar resection is unknown. The National Cancer Database was queried for NSCLC patients between 2004 and 2018. Eligibility included sublobar resection with pathological LN metastasis, R0 resection, Charlson comorbidity score = 0, clinical stage T1a-b, and tumor size ≤ 20 mm. The Kaplan-Meier method with a log-rank test and multivariable Cox proportional hazards analyses were used for assessing survival. The samples were evaluated before and after propensity score matching (PSM) with respect to age, sex, histologic type, and pathological LN status. Of 810 patients who met the eligibility criteria, 567 (70.0%) underwent adjuvant chemotherapy. After PSM, patients with adjuvant chemotherapy had a significantly longer survival than those without (median survival: 64.3 vs. 34.0 months, hazard ratio for death: 0.61, p < 0.0001). Multivariate analyses after PSM showed that younger age (p = 0.0206), female (p = 0.0005), and adjuvant chemotherapy (p < 0.0001) were independent prognostic factors for longer survival. Adjuvant chemotherapy has a prognostic impact in patients with small-sized NSCLC and pathological lymph node metastasis who undergo sublobar resection.

CD155 Expression in Early-stage Lung Adenocarcinoma.

BACKGROUND: CD155 is a transmembrane protein that belongs to the nectin-like molecule family that is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathological stage I lung adenocarcinoma remains poorly understood. METHODS: We analyzed 320 patients diagnosed with pathological stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinicopathological characteristics and clinical outcomes between these groups. RESULTS: EGFR mutation status was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, while 131 patients (40.9%) were EGFR mutant-type. Regarding CD155 expression, 77 patients (24.1%) were classified as high and 243 (75.9%) as low. The multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. In multivariate analysis, high CD155 expression was an independent poor prognostic factor for both recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type. CONCLUSIONS: Our findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathological stage I lung adenocarcinoma, particularly in cases without EGFR mutation.

MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC.

INTRODUCTION: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance. METHODS: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity. RESULTS: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs. CONCLUSIONS: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.

Hypothyroidism With ACTH Deficiency During Pembrolizumab Therapy for Lung Cancer: Case Report and Literature Review.

BACKGROUND/AIM: Immune-checkpoint inhibitors have recently shown great promise in treating various cancers, but often cause immune-related adverse events (irAEs). Simultaneous drug-induced hypothyroidism and isolated adrenocorticotropic hormone (ACTH) deficiency are rare irAEs. This combination of irAEs is associated with paradoxical endocrine dysfunction characterized by large amounts of thyroid-stimulating hormone (TSH) and small amounts of ACTH in the anterior lobe of the pituitary. We herein report a case of hypothyroidism with isolated ACTH deficiency during pembrolizumab therapy for recurrent lung cancer. CASE REPORT: Our patient was a 66-year-old man with recurrence of squamous cell lung carcinoma. Four months after chemotherapy that included pembrolizumab, the patient presented with general fatigue and laboratory tests showed high concentrations of TSH with low concentrations of free-T4. He was diagnosed with hypothyroidism and levothyroxine was prescribed. His ACTH concentration was found to be low 1 week later when he developed an acute adrenal crisis with associated hyponatraemia. We then changed his diagnosis to concurrent hypothyroidism with isolated ACTH deficiency. His condition improved after 3 weeks of administration of cortisol. CONCLUSION: It is difficult to diagnose a concurrent paradoxical endocrine disorder, such as hypothyroidism with isolated ACTH deficiency, as in the present case. Physicians should pay attention to symptoms and laboratory data to identify various types of endocrine disorders as irAEs.

Comparison of radiological and pathological tumor sizes in resected non-small cell lung cancer.

OBJECTIVES: In non-small cell lung cancer (NSCLC), T factor plays an important role in determining staging. The present study aimed to determine the validity of preoperative evaluation of clinical T (cT) factor by comparing radiological and pathological tumor sizes. METHODS: Data for 1,799 patients with primary NSCLC who underwent curative surgery were investigated. The concordance between cT and pathological T (pT) factors was analyzed. Furthermore, we compared groups with an increase or decrease of ≥ 20% and groups with an increase or decrease of < 20% in the size change between preoperative radiological and pathological diameters. RESULTS: The mean sizes of the radiological solid components and the pathological invasive tumors were 1.90 cm and 1.99 cm, respectively, correlation degree = 0.782. The group with increased pathological invasive tumor size (≥ 20%) compared with the radiologic solid component was significantly more likely female, consolidation tumor ratio (CTR) ≤ 0.5, and within cT1. Multivariate logistic analysis identified CTR < 1, cT ≤ T1, and adenocarcinoma as independent risk factors for increased pT factor. CONCLUSION: The radiological invasive area of tumors with cT1, CTR < 1, or adenocarcinoma on preoperative CT may be underestimated compared with pathological invasive diameter.

Conservative treatment for residual lung congestion after left upper trisegmentectomy: a case report.

Background: Currently, segmentectomy is the procedure of choice in approximately 10% of lung cancer surgeries in Japan. However, complications are often observed in that procedure. In particular, residual pulmonary congestion after segmentectomy often leads to surgical intervention. Case Description: We report a case of improved congestion in the residual lung after left upper trisegmentectomy (LUTS) with conservative treatment under careful observation. A 65-year-old man was diagnosed with bilateral lung cancer and initially underwent LUTS. On the next day after surgery, blood sputum was observed. Computed tomography (CT) showed consolidation in the lingual region of the left lung and stenosis of V4+5 in the left lung. The cause of the congestion was thought to be an isolated segment with part of the remaining S3 and a thin V4+5 with poor flow. Because pulmonary torsion or necrosis of the residual lung was not observed, conservative treatment with antibiotics under careful follow-up by CT was chosen. The pulmonary congestion and inflammatory reaction gradually improved, and the patient was discharged home on the 26th day after surgery. Conclusions: We experienced a case of residual pulmonary congestion after LUTS that resolved with conservative treatment. Careful follow-up of the patient's general condition and imaging studies are considered to be important.

Impact of Chronic Obstructive Pulmonary Disease on the Long-term Prognosis of Patients Undergoing Lobectomy for Non-small-cell Lung Cancer: A Propensity Score-matched Analysis.

BACKGROUND/AIM: Recent advances in surgery, such as thoracoscopic surgery, have made it possible to treat patients with chronic obstructive pulmonary disease (COPD) more safely than before. This study evaluated the short- and long-term prognosis of lobectomy in non-small cell lung cancer (NSCLC) patients with COPD. PATIENTS AND METHODS: This retrospective, propensity-matched, cohort analysis was conducted from January 2014 to December 2018. Among 441 patients who underwent lobectomy for NSCLC, 158 (35.8%) had a preoperative diagnosis of COPD. Propensity-matched analysis, incorporating preoperative variables, was used to compare postoperative hospital stay and complications, and long-term prognosis between the groups. RESULTS: Propensity matching estimated 145 patients in each group. There was no difference between the two groups for length of postoperative hospital stay (12 vs. 11 days, p=0.306). Postoperative complications were more frequent in the COPD group (24.1%) than in the non-COPD group (16.6%), but the difference was not significant (p=0.108). The 5-year overall survival rate was 86.2% in the COPD group and 82.1% in the non-COPD group after matching (p=0.580). The corresponding 5-year recurrence-free survival rate was 72.8% in the COPD group and 67.2% in the non-COPD group after matching (p=0.601). CONCLUSION: In case of Global Initiative for Chronic Obstructive Lung Disease (GOLD) I/II classification, COPD did not significantly worsen the prognosis of patients with NSCLC after lobectomy.

Surgical resection of a tuberculoma in the diaphragm: a case report.

BACKGROUND: Extrapulmonary tuberculosis commonly affects the lymphatic system, nervous system, and gastrointestinal system. Tuberculous infection in the muscle is very rare. Moreover, tuberculous infection in the diaphragm is extremely rare. We herein report a case of tuberculomas in the diaphragm and posterior mediastinum that were successfully diagnosed and treated. CASE PRESENTATION: We encountered a 62-year-old woman with a tuberculoma in the diaphragm. The patient presented with mild dyspnea. Computed tomography showed a mass in the left diaphragm, focal thickening of the posterior mediastinum, and multiple nodules in the lungs. Positron emission tomography-computed tomography showed increased uptake in the left diaphragm mass and thickening of the posterior mediastinum; therefore, we considered the masses to be malignant and planned surgical resection. However, the patient was diagnosed with tuberculosis from a sputum culture, and she was treated with anti-tuberculous therapy. The masses in the diaphragm and posterior mediastinum had become enlarged after 6 months of anti-tuberculous therapy; therefore, the patient underwent resection of both masses. Tuberculous infection was histologically confirmed in each lesion. She was pathologically diagnosed with tuberculous abscesses in the diaphragm and posterior mediastinum and began treatment with anti-tuberculosis drugs. CONCLUSIONS: Preoperative diagnosis of a tuberculoma in the diaphragm is usually difficult, and surgical intervention is important for both diagnosis and treatment.

Clinical significance of the combination of preoperative SUVmax and CEA in patients with clinical stage IA lung adenocarcinoma.

BACKGROUND: Preoperative maximum standardized uptake value (SUVmax) of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography and serum carcinoembryonic antigen (CEA) have been reported as prognostic factors for lung adenocarcinoma. However, the significance of combined SUVmax and CEA in early-stage lung adenocarcinoma is not well known. METHODS: We retrospectively evaluated the relationship between the combination of SUVmax and CEA and the prognosis of 410 patients with clinical stage IA lung adenocarcinoma who underwent resection. The cutoff values for SUVmax and CEA were determined by receiver operating characteristic curve analysis, and patients were categorized into high SC (SUVmax and CEA) group (SUVmax ≥2.96 and CEA ≥5.3), moderate SC group (either SUVmax <2.96 and CEA ≥5.3 or SUVmax ≥2.96 and CEA <5.3) and low SC group (SUVmax <2.96 and CEA <5.3). RESULTS: Kaplan-Meier curve analysis showed that patients with clinical stage IA lung adenocarcinoma in the high SC group had significantly shorter overall survival (OS) and recurrence-free survival (RFS) than the other groups (p = 0.011 and p < 0.0001, respectively). Multivariate analysis showed that high SC was an independent prognostic factor of OS (p = 0.029) and RFS (p < 0.0001). CONCLUSIONS: High values of SUVmax and CEA were associated with poor OS and RFS in patients with stage IA lung adenocarcinoma. Simultaneous evaluation of SUVmax and CEA may be an effective prognostic marker to determine the optimal treatment strategy of early-stage lung adenocarcinoma.

Spontaneous pneumothorax associated with cavitating pulmonary metastasis from breast cancer: a case report and literature review.

We report a 69-year-old woman with spontaneous pneumothorax associated with cavitating pulmonary metastasis from breast cancer. She was treated for right breast cancer (invasive ductal carcinoma, ypT4bN1M0, stage IIIB) 2 years earlier, and was admitted for right pneumothorax and chest computed tomography, which showed multiple small cavitating lesions in bilateral lungs. The pneumothorax was treated conservatively with chest drainage, but subsequently recurred ipsilaterally. During video-assisted thoracic surgery, we detected small white nodules with visceral pleural rupture; therefore, we performed partial lung resection. The pathological findings revealed metastatic breast cancer with pleural invasion. Forty days later, ipsilateral pneumothorax recurred, and chemical pleurodesis was performed, which resolved the pneumothorax and prevented subsequent recurrence. Early diagnosis and definitive treatment, including pleurodesis, should be considered to prevent recurrence of spontaneous pneumothorax and improve patients' quality of life, even in patients with advanced malignancy.

Assessment of Intraoperative Microbiological Culture in Patients with Empyema: Comparison with Preoperative Microbiological Culture.

PURPOSE: Assessing microbiological culture results is essential in the diagnosis of empyema and appropriate antibiotic selection; however, the guidelines for the management of empyema do not mention assessing microbiological culture intraoperatively. Therefore, we tested the hypothesis that intraoperative microbiological culture may improve the management of empyema. METHODS: We performed a retrospective analysis of 47 patients who underwent surgery for stage II/III empyema from January 2011 to May 2019. We compared the positivity of microbiological culture assessed preoperatively at empyema diagnosis versus intraoperatively. We further investigated the clinical characteristics and postoperative outcomes of patients whose intraoperative microbiological culture results were positive. RESULTS: The positive rates of preoperative and intraoperative microbiological cultures were 27.7% (13/47) and 36.2% (17/47), respectively. Among 34 patients who were culture-negative preoperatively, eight patients (23.5%) were culture-positive intraoperatively. Intraoperative positive culture was significantly associated with a shorter duration of preoperative antibiotic treatment (p = 0.002). There was no significant difference between intraoperative culture-positive and -negative results regarding postoperative complications. CONCLUSIONS: Intraoperative microbiological culture may help detect bacteria in patients whose microbiological culture results were negative at empyema diagnosis. Assessing microbiological culture should be recommended intraoperatively as well as preoperatively, for the appropriate management of empyema.

Interpleural distance predicts persistent air leak after initial primary spontaneous pneumothorax.

BACKGROUND: Initial surgical intervention for a first episode of primary spontaneous pneumothorax (PSP) is controversial. However, if air leak persists after initial drainage, surgical treatment is recommended. Therefore, we investigated risk factors for persistent air leak (PAL) in patients with a first episode of PSP. METHODS: We retrospectively analyzed 122 patients with a first episode of PSP between January 2011 and April 2019. PAL was defined as air leak lasting 72 hours or longer. Early admission was defined hospital admission within 24 hours of symptom onset. Three methods were used to estimate pneumothorax size on chest X-rays taken at admission: interpleural distance, apex-cupola distance, and Light index. RESULTS: Among 122 patients, 55 developed PAL (PAL group) and 67 did not (non-PAL group). The size of pneumothorax was significantly larger in the PAL group than in the non-PAL group in all three methods of assessment (P<0.001). Early hospital admission was significantly associated with PAL (P=0.026). Logistic regression analysis revealed that the odds ratio for PAL per unit increase in pneumothorax size evaluated with the interpleural distance was 1.304 (P<0.001). Multivariate logistic regression analysis showed that interpleural distance at the hilum and early admission (P<0.001, P=0.008, respectively) were independent predictors of PAL in patients with a first episode of PSP. CONCLUSIONS: In our study, we demonstrated that the interpleural distance at the hilum is a simple and effective predictor of PAL in patients with a first episode of PSP. Our data may help decision-making for initial surgical treatment in these patients.