Correlation analysis between driver gene mutation and clinicopathological features in lung adenocarcinoma based on real-world cumulative clinical data.

Background: Driver genes are essential predictors of targeted therapeutic efficacy. Detecting driver gene mutations in lung adenocarcinoma (LUAD) patients can help to screen for targeted drugs and improve patient survival benefits. This study aims to investigate the mutation characterization of driver genes and their correlation with clinicopathological features in LUAD. Methods: A total of 440 LUAD patients were selected from Sir Run Run Shaw Hospital between July 2019 and September 2022. Postoperative tissue specimens were analyzed for gene mutations using next-generation sequencing technology, focusing, including epidermal growth factor receptor EGFR, ALK, ROS1, RET, KRAS, MET, BRAF, HER2, PIK3CA and NRAS. At the same time, clinicopathological data were collected and organized for multidimensional correlation analysis. Results: Of 440 LUAD patients, driver gene mutations were not detected in 48 patients. The proportion of patients with driver gene mutations was as high as 89.09%. The top three driver genetic mutations were EGFR, KRAS, and MET. Sixty-nine types of EGFR mutations were detected and distributed in the protein tyrosine kinase catalytic domain (56, 81.16%), Furin-like cysteine-rich region (9, 13.04%), receptor binding domain (3, 4.35%), and EGFR transmembrane domain (1, 1.45%). Single gene locus mutation occurred in 343 LUAD patients, but the mutation gene types covered all tested genes. Our findings showed that EGFR mutations were more commonly observed in non-smoking and female patients (P<0.01), KRAS mutations were more prevalent in male patients and smokers (P<0.01), ROS1 mutations had larger tumor diameters (P<0.01) and RET mutations were more prevalent in smokers (P<0.05). Conclusions: LUAD patients exhibit diverse genetic mutations, which may co-occur simultaneously. Integrated analysis of multiple mutations is essential for accurate diagnosis and effective treatment of the disease. The use of NGS can significantly expand our understanding of gene mutations and facilitate integrated analysis of multiple gene mutations, providing critical evidence for targeted treatment methods.

A case report of cStage IIIB squamous cell lung carcinoma completely resected after downstaging with neoadjuvant therapy.

Background: The most effective method and length of time for administering adjuvant immunotherapy after surgery for non-small cell lung cancer (NSCLC) are still unknown. Various clinical trials have utilized diverse strategies for adjuvant treatment. In this case, we explore the potential benefits of neoadjuvant immunotherapy combined with chemotherapy in managing locally advanced lung squamous carcinoma, which often poses challenges for treatment. This multimodal approach aims to downstage tumors and optimize surgical outcomes. Case Description: Following a diagnosis of stage IIIB lung cancer, the patient underwent three cycles of neoadjuvant therapy using sintilimab, Abraxane, and Lobaplatin, resulting in a significant 45% reduction in tumor size. Subsequently, a right lower lobe lobectomy and systematic lymphadenectomy were performed using a uniportal video-assisted thoracic surgery (VATS) approach. Postoperative analysis revealed negative lymph nodes, with only a 5-mm residual tumor in the tumor bed, downstaging the cancer to IA1. Remarkably, the patient experienced a smooth recovery without any postoperative complications. One cycle of adjuvant therapy was administered following the operation to further support the patient's recovery and minimize the risk of disease recurrence. This comprehensive treatment approach underscores the importance of neoadjuvant therapy in optimizing surgical outcomes and improving long-term prognosis for patients with locally advanced lung cancer. Conclusions: For patients with stage III locally advanced lung squamous carcinoma, the combination of Sintilimab and Platinum-based drugs can be used as a neoadjuvant therapy which can reduce the difficulty of the operation.

Prognostic value of perioperative changes in the prognostic nutritional index in patients with surgically resected non-small cell lung cancer.

PURPOSE: This single-institution retrospective cohort study was conducted to assess the prognostic significance of perioperative changes in the prognostic nutritional index (PNI) in patients who underwent surgery for non-small cell lung cancer (NSCLC). METHODS: Clinicopathological data were collected from 441 patients who underwent lobectomy for NSCLC between 2010 and 2016.The PNI ratio (postoperative PNI/preoperative PNI) was used as an indicator of perioperative PNI changes. Prognostic differences were investigated based on PNI ratios. RESULTS: The optimal cut-off value of the PNI ratio for overall survival (OS) was set at 0.88 using a receiver operating characteristic curve. The PNI ratio was inversely related to a high smoking index, interstitial lung disease, and postoperative pulmonary complications. The 5-year OS rates for the high vs. low PNI ratio groups were 88.2% vs. 68.5%, respectively (hazard ratio [HR]: 3.04, 95% confidence interval [CI]: 1.90-4.86). Multivariable analysis revealed that a low PNI ratio was significantly associated with poor prognosis (HR: 2.94, 95% CI: 1.77-4.87). The PNI ratio was a more sensitive indicator than postoperative PNI status alone for identifying patients at high risk of mortality, particularly those with non-lung cancer causes. CONCLUSION: The perioperative PNI change is a significant prognostic factor for patients with NSCLC.

The CONUT score is associated with the pathologic grade in non-small cell lung cancer.

PURPOSE: Nutritional scores have been reported to be useful prognostic factors for various cancers. This study evaluated the usefulness of the preoperative controlling nutritional status (CONUT) score as a predictor of recurrence of non-small cell lung cancer (NSCLC). METHODS: The present study included 422 patients with stage I-IIIA NSCLC who underwent complete resection at Tohoku University Hospital between January 2010 and December 2016. The patients were divided into the low-CONUT and high-CONUT groups based on their CONUT scores. Overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rates in the low- and high-CONUT groups were evaluated retrospectively. RESULTS: One hundred forty-seven patients (34.8%) were assigned to the high-CONUT group. The high-CONUT group had a significantly worse performance status, pleural invasion, vascular invasion, and lung metastasis. In the whole cohort, the low-CONUT group showed better overall survival, recurrence-free survival, and a low cumulative recurrence rate in comparison to the high-CONUT group. There was no significant difference in prognosis or recurrence between the low- and high-CONUT groups after propensity score matching. CONCLUSION: Patients with a high CONUT score may be at high risk of recurrence because of the high frequency of pleural invasion, vascular invasion, and lung metastasis.

An indocyanine green fluorescence-guided operation for diagnosing and treating pleuroperitoneal communication.

Pleuroperitoneal communication occurs when ascites moves from the abdominal cavity to the pleural cavity via a diaphragmatic fistula. Managing large pleural fluid volumes is challenging, often requiring an operation. Identifying small diaphragmatic fistulas during the operation can be problematic, but ensuring their detection improves outcomes. This video tutorial presents a recent empirical case in which we successfully identified and closed a pleuroperitoneal contact using a thoracoscopic surgical procedure aided by indocyanine green fluorescence imaging. The patient, a 66-year-old woman, was hospitalized due to acute dyspnoea from a right thoracic pleural effusion during hepatic ascites treatment for cirrhosis. Because ascites decreased with pleural fluid drainage, surgical intervention was considered due to suspicion of a pleuroperitoneal connection. During the operation, indocyanine green was injected intraperitoneally, and near-infrared fluorescence-guided thoracoscopy pinpointed the location of the diaphragmatic fistula. The fistula was sutured and reinforced with a polyglycolic acid sheet and fibrin glue. Detecting the fistula intraoperatively is crucial to prevent recurrence, and the indocyanine green fluorescence method is a safe and effective technique for detecting small fistulas.

Long-term outcomes of 5-year survivors without recurrence after the complete resection of non-small cell lung cancer after lobectomy: a landmark analysis in consideration of competing risks.

PURPOSE: Among non-small cell lung cancers (NSCLC), 5 years is a benchmark in cancer control and treatment, but a certain percentage of cases recur after 5 years. The long-term post-recurrence outcomes remain controversial. To examine the accurate prognostic factors associated with survival and cancer recurrence among 5-year survivors, a landmark analysis that considered competing risks was performed. METHODS: Complete resection of NSCLC was performed in 2482 patients between January 2003 and December 2015. A total of 1431 patients were 5-year survivors without recurrence. A landmark time analysis was applied to the overall survival (OS) and recurrence-free survival (RFS) from 5 years after surgery, and the findings were calculated using the Kaplan-Meier method. The cumulative incidence of cause-specific death and recurrence was estimated using the cumulative incidence function, while carefully considering the competing risks. RESULTS: Postoperative recurrence was detected in 732 patients, of whom 68 (9.3%) had recurrence after 5 years. The median follow-up period was 8.2 years. In the competing risk analysis, the independent poor prognostic factors associated with cause-specific death were age ≥ 75 years, lymph node metastasis and pleural invasion. CONCLUSIONS: Patients requiring a follow-up for > 5 years were aged ≥ 75 years and had either lymph node metastasis or pleural invasion.

Evolution of Pleural Solitary Fibrous Tumors Causing Severe Hypoglycemia after Exceptionally Long Asymptomatic Periods: Report of Two Surgical Cases.

Non-islet cell tumor hypoglycemia (NICTH) is one of the paraneoplastic syndromes manifesting severe hypoglycemia caused by aberrant production of high-molecular-weight insulin-like growth factor 2 (big-IGF2). Two surgical cases of extremely large thoracic solitary fibrous tumors (SFT) with unusual history of NICTH are presented. One case manifested severe hypoglycemia after four years of the first complete surgical resection of the tumor with potential malignant transformation, and the other case showed severe hypoglycemia after ten years of the first detection of the tumor. Meticulous laboratory testing, including serum endocrinological tests and western immunoblotting before and after surgery was performed, and both cases were diagnosed as NICTH. Both patients underwent open thoracic surgery. The patients showed normal glucose and hormone levels immediately after the resection of responsible tumors with elevated blood insulin concentration. SFTs are generally considered benign; however, life-threatening hypoglycemia can happen regardless of treatment. Careful follow-up of the tumor growth is warranted.

Morphological Predictors of Primary Lung Cancer among Part-Solid Ground-Grass Nodules on High-Resolution CT.

Recent advancements in computed tomography (CT) scanning have improved the detection rates of peripheral pulmonary nodules, including those with ground-glass opacities (GGOs). This study focuses on part-solid pure ground-glass nodules (GGNs) and aims to identify imaging predictors that can reliably differentiate primary lung cancer from nodules with other diagnoses among part-solid GGNs on high-resolution CT (HRCT). A retrospective study was conducted on 609 patients who underwent surgical treatment or observation for lung nodules. Radiological findings from pre-operative HRCT scans were reviewed and several CT imaging features of part-solid GGNs were examined for their positive predictive value to identify primary lung cancer. The proportions of the nodules with a final diagnosis of primary lung cancer were significantly higher in part-solid GGNs (91.9%) compared with solid nodules (70.3%) or pure GGNs (66.7%). Among CT imaging features of part-solid GGNs that were evaluated, consolidation-to-tumor ratio (CTR) < 0.5 (98.1%), pleural indentation (96.4%), and clear tumor border (96.7%) had high positive predictive value to identify primary lung cancer. When two imaging features were combined, the combination of CTR < 0.5 and a clear tumor border was identified to have 100% positive predictive values with a sensitivity of 40.8%. Thus we conclude that part-solid GGNs with a CTR < 0.5 accompanied by a clear tumor border evaluated by HRCT are very likely to be primary lung cancers with an acceptable sensitivity. Preoperative diagnostic procedures to obtain a pathological diagnosis may potentially be omitted in patients harboring such part-solid GGNs.

A comparative study of surgical outcomes for secondary spontaneous pneumothorax and the postoperative survival prognostic factor: interstitial vs. non-interstitial pneumonia.

PURPOSE: To investigate the surgical outcomes and postoperative survival prognostic factors of intractable secondary spontaneous pneumothorax. METHODS: A total of 95 patients who underwent thoracoscopic surgery for intractable secondary spontaneous pneumothorax between April 2010 and March 2020 were included in this study. These patients were classified into interstitial pneumonia and non-interstitial pneumonia groups, and a comparative study was performed on surgical outcomes and postoperative survival prognostic factors. RESULTS: There was no difference in the 1-year overall survival rate between the two groups. However, the 3-year overall survival rate was significantly lower in the interstitial pneumonia group than in the non-interstitial pneumonia group. The differences in short-term surgical outcomes (persistent air leakage, postoperative complications, etc.) were not significant between the two groups. Univariate analysis revealed that the drainage period, the development of postoperative complications, and recurrence were significant independent postoperative survival prognostic factors for all cases. Postoperative complications were the only associated postoperative survival prognostic factor for interstitial pneumonia pneumothorax in the multivariate analysis. CONCLUSION: The development of postoperative complications can cause poor postoperative survival prognosis of intractable secondary spontaneous pneumothorax due to interstitial pneumonia.

An accurate prediction of negative lymph node metastasis with consideration of glucose metabolism in early-stage non-small cell lung cancer.

OBJECTIVE: We aimed to identify risk factors in lymph node metastasis in early-stage non-small cell lung cancer (NSCLC) and predict lymph node metastasis. METHODS: A total of 416 patients with clinical stage IA2-3 NSCLC who underwent lobectomy and lymph node dissection between July 2016 and December 2020 at National Cancer Center Hospital East were included. Multivariable logistic regression was performed to develop a model for predicting lymph node metastasis. Leave-one-out cross-validation was performed to evaluate the developing prediction model, and sensitivity, specificity, and concordance statistics were calculated to evaluate its diagnostic performance. RESULTS: The formula for calculating the probability of pathological lymph node metastasis included SUVmax of the primary tumor and serum CEA level. The concordance statistics was 0.7452. When the cutoff value associated with the risk of incorrectly predicting pathological lymph node metastasis was 7.2%, the diagnostic sensitivity and specificity for predicting metastasis were 96.4% and 38.6%, respectively. CONCLUSIONS: We created a prediction model for lymph node metastasis in NSCLC by combining the SUVmax of the primary tumor and serum CEA levels, which showed a particularly strong association. This model is clinically useful as it successfully predicts negative lymph node metastasis in patients with clinical stage IA2-3 NSCLC.

The significance of regular chest computed tomography in postoperative surveillance for surgically resected non-small cell lung cancer based on TNM 8th staging system.

OBJECTIVES: Although several societies recommend regular chest computed tomography (CT) scans for the surveillance of surgically resected non-small cell lung cancer (NSCLC), there is paucity of evidence to support these statements. This study aimed to clarify whether regular CT scans improved the prognosis of patients with surgically resected NSCLC based on TNM 8th classification. METHODS: Patients with pathologic Stage 0-III NSCLC who underwent complete surgical resection other than sublobar resection procedures were enrolled in the study. For these patients, clinicopathological data and postoperative surveillance data were collected by the retrospective review of medical records. Patients were categorized into the chest X-ray (CXR) group or the CT group according to whether they were followed-up with basic examinations including CXR or basic examinations plus regular chest CT. Postoperative overall survival was compared between the two groups. RESULTS: Six hundred sixty five patients were categorized into the CXR (n = 245) and CT (n = 420) groups. The clinicopathological backgrounds did not differ to a statistically significant extent. Recurrence was seen in 68 (27.3%) patients in the CXR group and 117 (27.8%) patients in the CT group. The 5-year overall survival rates of the two groups did not differ to a statistically significant extent (CXR, 76.5%; CT, 78.3%, P = 0.22). CONCLUSION: Regular chest CT scans may not improve the prognosis of surgically resected NSCLC. Further study is warranted to precisely evaluate the benefit of CT-based postoperative surveillance of NSCLC.

Systemic-to-pulmonary artery shunt treated with transcatheter arterial embolization and subsequent lung segmentectomy.

BACKGROUND: Systemic-to-pulmonary artery shunt (SPAS) is a rare condition that can occur as a result of congenital heart disease or chronic pulmonary inflammation, occasionally leading to life-threatening hemoptysis. Computed tomography (CT) imaging is crucial in the diagnosis of SPAS, and the optimal management approach for SPAS remains uncertain. This case report presents a novel approach to the treatment of SPAS, consisting of transcatheter arterial embolization of the systemic artery followed by lung segmentectomy. CASE PRESENTATION: A 42-year-old man with abnormal chest findings was referred to us and a diagnosis of SPAS was established based on the CT findings showing a blood flow regurgitation from the dilated left 4th intercostal artery to the Lt. A6. The patient was asymptomatic but we decided to treat him to prevent a risk of future hemoptysis. Transcatheter arterial embolization (TAE) of systemic arteries followed by S6 segmentectomy was successfully performed with minimal blood loss and complete removal of the dilated intra-pulmonary blood vessels. Histological analysis confirmed the diagnosis of SPAS. CONCLUSION: We reported a case of SPAS, who was successfully treated with the combination of TAE and subsequent segmentectomy. The blood loss during surgery was minimal and this strategy appeared to minimize future recanalization and hemoptysis. Further studies and long-term follow-up of SPAS patients are required to establish standardized management guidelines for this rare condition.

Comparison of various lung intersegmental plane identification methods.

Keeping a sufficient surgical margin free of tumor is important to prevent local recurrence in lung segmentectomy. Accurate identification of the intersegmental plane is essential to achieve adequate surgical margins. Traditionally, the inflation-deflation method was used to identify the intersegmental plane. However, in recent years, various intersegmental plane identification methods, including systemic indocyanine green injection, have been reported and shown to be useful. The purpose of this review was to evaluate the identification rates, advantages, and disadvantages of various intersegmental identification methods in lung segmentectomy. There are primarily six methods: inflation-deflation method, selective segmental inflation, endobronchial dye injection, virtual-assisted lung mapping, systemic indocyanine green injection, and pure oxygen method. These are broadly classified into those that use bronchi and pulmonary arteries anatomically and those that use air and dye technically. In this review, all methods showed relatively high identification rates. Moreover, high identification rates were expected, especially with systemic indocyanine green injection and the pure oxygen method. Each method has its advantages and disadvantages as varying situations entail different methods. It is necessary to select and apply them effectively; therefore, further improvement for each method will be required in the future.

Efficacy of platinum-based adjuvant chemotherapy for epidermal growth factor receptor-mutant lung adenocarcinoma.

Background: The ADAURA trial reported that osimertinib improved overall survival (OS) as an adjuvant chemotherapy for pathological stage IB-IIIA epidermal growth factor receptor (EGFR) mutant lung cancer compared with a placebo. Currently, platinum-based adjuvant chemotherapy is the standard treatment for patients with or without EGFR mutations. This study aimed to evaluate the efficacy of platinum-based adjuvant chemotherapy in patient with stage II-IIIA EGFR mutant lung adenocarcinoma. Methods: We collected the medical records of consecutive patients who underwent surgical resection for lung adenocarcinoma between 2005 and 2012 at the four participating institutions. The data of 173 patients with different EGFR mutation status were retrospectively evaluated to determine the efficacy of platinum-based adjuvant chemotherapy for OS and recurrence-free survival (RFS). We further analyzed OS using the inverse probability of treatment weighting method with propensity scores. Results: The median age was 69 years (range, 45-85 years); 95 (54.9%) were male and 74 (42.8%) had EGFR mutations. A total of 43 patients with EGFR mutants (58.1%) and 43 patients with wild-type EGFR tumors (43.4%) received platinum-based adjuvant chemotherapy. No differences in RFS and OS were observed between EGFR mutant and wild-type EGFR in lung adenocarcinoma without adjuvant therapy. However, wild-type EGFR showed an improvement in OS with platinum-based adjuvant chemotherapy in inverse probability of treatment weighting analysis, whereas those with EGFR mutations showed no significant difference in OS between the surgery-only group and the adjuvant group. The deletion of exon 19 and exon 21 L858R point mutation showed no significant differences in OS between the surgery-only group and the adjuvant group, respectively. The hazard ratio (HR) exceeded 1 for uncommon EGFR mutations. Conclusions: Platinum-based adjuvant chemotherapy may be less effective for EGFR-mutant lung adenocarcinoma, regardless of the mutation type.

[Iatrogenic Injury of the Bronchus Suspiciously Caused by Sengstaken-Blakemore Tube into the Airway].

BACKGROUND: Tracheobronchial injury is often operated urgently because of the risk of high mortality. However, small injuries can recover by conservative management. CASE: A 65-year-old man was treated for esophageal varix with transcatheter arterial embolization therapy. He vomited blood and endoscopic sclerotherapy was performed because a Sengstaken-Blake-more tube could not be inserted. Thereafter, computed tomography( CT) detected mediastinal emphysema and an injury to his left main bronchus. The patient consulted our department and bronchoscopy detected a laceration of the left main bronchus. Conservative management was chosen because the laceration was limited to the membranous portion, with the improvement of inflammatory reaction. Several weeks later, CT and bronchoscopy confirmed recovery from the injury of the left main bronchus without stricture. CONCLUSION: An operation is indicated for many tracheobronchial injuries. However, some injuries can recover with conservative management. It is important that indication for surgery should be considered based on bronchoscopic findings and the progress of inflammatory reaction.

Clinicopathological features of intraoperative pleural lavage cytology for non-small cell lung cancer.

OBJECTIVE: The significance of clinicopathological features of pre- and post-resection pleural lavage cytology (PLC) for non-small cell lung carcinoma (NSCLC) currently remains unknown. METHODS: Between January 2010 and December 2012, pre- and post-resection PLC were performed for NSCLC in 565 patients at Tohoku University, Miyagi Cancer Center, or Sendai Medical Center. The relationship between the clinicopathological features and patient outcomes was analyzed. RESULTS: Twenty-two patients (3.9%) had positive findings from pre- or post-resection PLC. Both PLC were correlated with pT and pl factors, while only post-resection PLC was correlated with pN factor (p < 0.005). The 5-year disease-free survival (DFS) rate of the positive pre-resection PLC was significantly poorer than that of negative (26.7% vs. 76.9%, p < 0.0001). In addition, the 5-year DFS of the positive post-resection PLC was also poorer than that of negative (14.3% vs. 76.0%, p < 0.0001). Multivariate analyses revealed that both PLC were not independent prognostic factors in our study. CONCLUSIONS: A significant association of post-resection PLC with N factor is considered to be characteristics of post-resection PLC different from pre-resection PLC. A prognostic impact of post-resection PLC and its detailed difference from pre-resection PLC should be clarified by further investigations.

[A Pulmonary Mucoepidermoid Carcinoma with Anaplastic Lymphoma Kinase Fusion Responding to Alectinib Hydrochloride].

Few cases of lung mucoepidermoid carcinomas with anaplastic lymphoma kinase (ALK) fusion have been reported. A 35-year-old woman was found to have an abnormal chest X-ray. A tumor and obstructive pneumonitis in her left upper lobe was detected using computed tomography (CT). She was admitted to our hospital, and was diagnosed with mucoepidermoid carcinoma by transbronchial biopsy. Left pneumonectomy and lymphadenectomy were performed for lung mucoepidermoid carcinoma and a mediastinal lymph node metastasis (pT2aN2M0, stage ⅢA). Postoperative radiotherapy (50 Gy) to the mediastinum and chemotherapy were performed followed by several radiotherapies for cervical and mediastinal lymph node and right ischium metastases. Since then, further radiotherapy was impossible. However, we detected ALK fusion in the resected specimen and the cancer responded to alectinib hydrochloride.

Subacute Sensory Ataxic Neuronopathy With Thymoma Presenting Marked Improvement After Steroid Therapy.

Subacute sensory ataxic neuronopathy is a well-known form of paraneoplastic syndrome. Most sensory neuronopathies are associated with small cell lung cancer and anti-Hu antibodies, and usually show only slight improvement with immunotherapy. To date, there have been few reports of neuropathy associated with thymoma and no treatment strategy has been established for thymoma-related neuropathy. Here, we provide the first report of a case of sensory ataxic neuronopathy with thymoma that showed marked improvement after steroid therapy, even though preceding intravenous immunoglobulin treatments and tumor resection were less effective. A 57-year-old Japanese man was referred to our hospital with a 6-week history of distal paresthesia in his four limbs and an unsteady gait. He presented with left-dominant ataxia in his four limbs due to reduced sensation in his extremities. He also complained of constipation, difficulty urinating, and erectile dysfunction. Upon investigation, including electrodiagnostic studies, the patient was diagnosed as having sensory ataxic neuronopathy with invasive thymoma. A first round of intravenous immunoglobulin therapy, a following thymectomy, and a second round of intravenous immunoglobulin therapy after the surgery were not effective in treating his neurological symptoms. Subsequently, oral steroid therapy was started, which brought about a remarkable improvement; 6 weeks after the beginning of the steroid therapy, his neurological symptoms were resolved, except for slight distal paresthesia in his feet. Although rarely reported, thymoma can underlie sensory neuronopathy, and the response of thymoma-associated sensory neuronopathy to immunotherapy might be better than that of anti-Hu antibody-related neuropathies. Even if the first immunotherapy is not effective in treating neuropathy with thymoma, further immunomodulatory treatment should be tried after treating the tumor.

Attenuation of zinc-enhanced inflammatory M1 phenotype of microglia by peridinin protects against short-term spatial-memory impairment following cerebral ischemia in mice.

Activated microglia exhibit two opposite activation states, the inflammatory M1 and the anti-inflammatory M2 activation states. In the mammalian brain, ischemia elicits a massive release of zinc from hippocampal neurons, and the extracellular zinc primes M1 microglia-by inducing reactive oxygen species (ROS) generation-to enhance their production of proinflammatory cytokines, which ultimately results in short-term spatial memory impairment. Here, we examined how peridinin, a carotenoid in dinoflagellates, affects the zinc-enhanced inflammatory M1 phenotype of microglia. Treatment of microglia with 30-300 ng/mL peridinin caused a dose-dependent attenuation of zinc-enhanced interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNFα) secretion when M1 activation was induced by lipopolysaccharide exposure. Moreover, peridinin inhibited the increase in ROS levels in zinc-treated microglia without directly interacting with zinc. Notably, when mice were administrated peridinin (20-200 ng/animal) intracerebroventricularly 5 min before cerebral ischemia-reperfusion, the peridinin treatment not only suppressed the increase in expression of IL-1ß, IL-6, TNFα, and the microglial M1 surface marker CD16/32, but also protected the mice against ischemia-induced short-term spatial-memory impairment. Our findings suggest that peridinin prevents extracellular zinc-enhanced proinflammatory cytokine secretion from M1 microglia by inhibiting the increase in microglial ROS levels, and that this anti-inflammatory effect of peridinin might result in protection against deficits in short-term spatial memory.

Growth inhibition of KRAS­ and EGFR­mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis.

The need for effective treatment of KRAS­mutant lung cancer is an emerging issue. Rho GTPase­activating protein 35 (ARHGAP35) is reported to be a possible molecular target for lung adenocarcinoma. We investigated the effect of long­term ARHGAP35 suppression on the proliferation, migration and molecular dynamics of lung adenocarcinomas harboring KRAS and EGFR gene mutations. Lung adenocarcinoma cell lines A549 (KRAS­mutant) and PC9 and H1975 (EGFR­mutants) were used, and ARHGAP35 knockdown was carried out using puromycin. Cell viability, migration and molecular dynamics were assayed 1 month after introducing small hairpin RNA. The compensatory upregulated mechanism was screened by western blotting and confirmed by a specific inhibitor. Finally, we tested the effects of cosuppression of the SRC/ARHGAP35 axis and the identified pathway in vitro. ARHGAP35 suppression was attenuated by long­term knockdown of the target genes. Compensatory mechanisms by SRC and STAT3 caused attenuation in A549 cells. After long­term ARHGAP35 knockdown, both A549 and PC9 cells were more sensitive to treatment with a STAT3 inhibitor. The suppressive effect of ARHGAP35 knockdown on migration was sustained, but only modest, in all cell lines. Synergistic and strong growth inhibition was observed with concomitant use of an SRC inhibitor and a STAT3 inhibitor in A549 cells. STAT3 activation compensated for ARHGAP35 knockdown in lung adenocarcinoma with the KRAS mutation. Moreover, cosuppression of the STAT3 pathway and SRC/ARHGAP35 axis may be an effective strategy for treating lung adenocarcinoma, especially in the presence of a KRAS mutation.