Impact of interstitial lung disease gender-age-physiology index in surgically treated lung cancer.

BACKGROUND: The postoperative prognosis of patients with interstitial lung disease (ILD) and lung cancer is poor. Recently, the ILD-gender-age-physiology (GAP) index was identified as a clinical prognostic factor for patients with ILD. This study investigated the ILD-GAP index and oncological factors regarding postoperative outcomes. METHODS: We retrospectively reviewed 87 lung cancer patients with comorbid ILD who underwent curative resection at our institution between April 2005 and December 2019. Short-term postoperative outcomes and overall survival (OS) based on the ILD-GAP index were examined. OS rates after surgery were calculated using the Kaplan-Meier method, and group differences were analyzed using the Log-Rank test. Univariate and multivariate analyses for OS were performed using the Cox regression model. RESULTS: Multivariate analyses revealed ILD-GAP index ≥ 4 [Hazard ratio, 3.349; 95% confidence interval 1.375-8.155; P = 0.008] as a factor associated with OS. In the ILD-GAP index ≥ 4 group, no deaths occurred from primary lung cancer, with respiratory-related deaths being the most common, and exacerbation of ILD was more frequent (P = 0.007). Regarding perioperative results, a significant difference was observed in 90-day mortality (2.7% vs. 23.0% [P = 0.022]), and more patients required home oxygen therapy (14.9% vs. 69.2% [P < 0.001]) in the ILD-GAP index ≥ 4 group. CONCLUSIONS: An ILD-GAP index ≥ 4 indicated a poor prognostic factor for patients with surgically treated lung cancer. Careful consideration of surgical indications is essential for patients with an ILD-GAP index ≥ 4.

DNA methylation and mRNA expression of ZNF577 as biomarkers for the detection and prognosis of lung adenocarcinoma.

Despite advances in science and technology, lung cancer remains a major public health issue. The discovery of early diagnostic and prognostic markers is still needed to reduce the mortality rate of lung cancer, which is the highest among all cancer types. Aberrations in the DNA methylation system have an important role in human cancer and are promising for the development of early diagnostic and prognostic markers. The present study focused on zinc finger protein (ZNF)577, whose encoding gene was indicated to exhibit promoter hypermethylation together with 9 other genes in lung adenocarcinoma (LADC) in a previous study by our group. ZN577 is a member of the ZNG family and its functional role has so far remained elusive. LADC tissue samples surgically resected at Tokushima University Hospital (Tokushima, Japan) between April 1999 and November 2013 were collected. A total of 73 tumors and 27 paired tumor-adjacent normal tissues were examined for DNA methylation and mRNA expression of ZNF577. A total of 149 LADC tissue samples were collected and evaluated by immunohistochemistry (IHC) for the tissue expression of ZNF577. High methylation (n=27, P<0.0001) and low mRNA expression levels (n=27, P<0.031) of ZNF577 were identified in LADC tissues, and it was demonstrated that methylation levels were inversely correlated with mRNA expression levels (P=0.0116, ρ=-0.2515). Among the LADC tissues, lepidic-patterned samples had lower methylation levels of ZNF577 than other pathological types. In addition, mRNA expression levels of ZNF577 were significantly higher in females, non-smokers and stage I samples. Overall survival [P<0.0001; area under curve (AUC)=0.8658] and disease-free survival (DFS; P<0.0004; AUC=0.7232) rates were significantly higher in the ZNF577 high mRNA expression group than in the ZNF577 low mRNA expression group. Among the 149 LADC samples examined by IHC, 105 were negative and 44 were positive for the tissue expression of ZNF577. Cox regression analysis showed poorer DFS (hazard ratio: 3.917; P=0.023) in patients with lower expression of ZNF577. In conclusion, higher methylation levels of ZNF577 were observed in LADC tissues than in normal lung tissue and low mRNA expression of ZNF577 was associated with unfavorable prognosis.

Symptomatic adverse events of chemotherapy in breast cancer patients:Using CTCAE, PRO-CTCAE, and EORTC QLQ-C30.

BACKGROUND: The Common Terminology Criteria for Adverse Events (CTCAE) is used as a tool to evaluate the adverse events (AE) of chemotherapy in cancer patients. Since CTCAE by medical providers underestimates AE more than patient-reported outcomes (PRO), the National Cancer Institute developed PRO-CTCAE. The present study investigated differences between symptoms detected using CTCAE by medical providers and PRO-CTCAE by breast cancer patients. METHODS: Patients received chemotherapy comprising epirubicin and cyclophosphamide pre- or postoperatively. AE were evaluated using 4 questionnaires:PRO-CTCAE, CTCAE, the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ-30), and Hospital Anxiety and Depression Scale (HADS) after 1, 2, and 3 courses of chemotherapy. RESULTS: Forty-two patients were registered. Regarding the recognition of psychological symptoms, such as fatigue, anxiety, and discouragement, and subjective symptoms, including heart palpitations and shortness of breath, PRO using PRO-CTCAE was significantly higher than medical provider-recognized outcomes using CTCAE. Concerning the recognition of regimen-specific symptoms, such as vomiting, nausea, and decreased appetite, medical provider- recognized outcomes were the same or higher than PRO. In QLQ-C30, the physical and role functions, fatigue and dyspnea significantly worsened after 2 and 3 courses of chemotherapy. J. Med. Invest. 71 : 82-91, February, 2024.

Hexavalent chromium exposure activates the non-canonical nuclear factor kappa B pathway to promote immune checkpoint protein programmed death-ligand 1 expression and lung carcinogenesis.

Lung cancer is the leading cause of cancer-related death worldwide; however, the mechanism of lung carcinogenesis has not been clearly defined. Chronic exposure to hexavalent chromium [Cr(VI)], a common environmental and occupational pollutant, causes lung cancer, representing an important lung cancer etiology factor. The mechanism of how chronic Cr(VI) exposure causes lung cancer remains largely unknown. By using cell culture and mouse models and bioinformatics analyses of human lung cancer gene expression profiles, this study investigated the mechanism of Cr(VI)-induced lung carcinogenesis. A new mouse model of Cr(VI)-induced lung carcinogenesis was developed as evidenced by the findings showing that a 16-week Cr(VI) exposure (CaCrO4, 100 µg per mouse once per week) via oropharyngeal aspiration induced lung adenocarcinomas in male and female A/J mice, whereas none of the sham-exposed control mice had lung tumors. Mechanistic studies revealed that chronic Cr(VI) exposure activated the non-canonical NFκB pathway through the long non-coding RNA (lncRNA) ABHD11-AS1/deubiquitinase USP15-mediated tumor necrosis factor receptor-associated factor 3 (TRAF3) down-regulation. The non-canonical NFκB pathway activation increased the interleukin 6 (IL-6)/Janus kinase (Jak)/signal transducer and activator of transcription 3 (Stat3) signaling. The activation of the IL-6/Jak signaling axis by Cr(VI) exposure not only promoted inflammation but also stabilized the immune checkpoint molecule programmed death-ligand 1 (PD-L1) protein in the lungs, reducing T lymphocyte infiltration to the lungs. Given the well-recognized critical role of PD-L1 in inhibiting anti-tumor immunity, these findings suggested that the lncRNA ABHD11-AS1-mediated non-canonical NFκB pathway activation and PD-L1 up-regulation may play important roles in Cr(VI)-induced lung carcinogenesis.

Aberrant DNA Methylation of NPTX2 as an Indicator of Malignant Behavior in Thymic Epithelial Tumors.

Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT.

Epigenetic downregulation of O6-methylguanine-DNA methyltransferase contributes to chronic hexavalent chromium exposure-caused genotoxic effect and cell transformation.

Hexavalent chromium [Cr(VI)] is a common environmental pollutant and chronic exposure to Cr(VI) causes lung cancer and other types of cancer in humans, although the mechanism of Cr(VI) carcinogenesis remains elusive. Cr(VI) has been considered as a genotoxic carcinogen, but accumulating evidence indicates that Cr(VI) also causes various epigenetic toxic effects that play important roles in Cr(VI) carcinogenesis. However, it is not clear how Cr(VI)-caused epigenetic dysregulations contributes to Cr(VI) carcinogenesis. This study investigates whether Cr(VI) epigenetic toxic effect has an impact on its genotoxic effect. It was found that chronic low dose of Cr(VI) exposure time-dependently down-regulates the expression of a critical DNA damage repair protein O6-methylguanine-DNA methyltransferase (MGMT), leading to the increases of the levels of the highly mutagenic and carcinogenic DNA lesion O6-methylguanine (O6-MeG) in human bronchial epithelial BEAS-2B cells. Moreover, the levels of MGMT and O6-MeG in chronic Cr(VI) exposure-caused human lung cancer tissues are also significantly lower and higher than that in the adjacent normal lung tissues, respectively. It was further determined that chronic low dose of Cr(VI) exposure-transformed BEAS-2B cells display impaired DNA damage repair capacity and a high sensitivity to the toxicity of the alkylating chemotherapeutic drug Temozolomide. In contrast, stably overexpressing MGMT in parental BEAS-2B cells reverses chronic low dose of Cr(VI) exposure-caused DNA damage repair deficiency and significantly reduces cell transformation by Cr(VI). Further mechanistical studies revealed that chronic low dose of Cr(VI) exposure down-regulates MGMT expression through epigenetic mechanisms by increasing DNA methylation and histone H3 repressive modifications. Taken together, these findings suggest that epigenetic down-regulation of a crucial DNA damage repair protein MGMT contributes significantly to the genotoxic effect and cell transformation caused by chronic low dose of Cr(VI) exposure.

Increased Lipogenesis Is Important for Hexavalent Chromium-Transformed Lung Cells and Xenograft Tumor Growth.

Hexavalent chromium, Cr(VI), is a known carcinogen and environmental health concern. It has been established that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to the Cr(VI)-induced carcinogenesis mechanism. However, some hallmarks of cancer remain under-researched regarding the mechanism behind Cr(VI)-induced carcinogenesis. Increased lipogenesis is important to carcinogenesis and tumorigenesis in multiple types of cancers, yet the role increased lipogenesis has in Cr(VI) carcinogenesis is unclear. We report here that Cr(VI)-induced transformation of three human lung cell lines (BEAS-2B, BEP2D, and WTHBF-6) resulted in increased lipogenesis (palmitic acid levels), and Cr(VI)-transformed cells had an increased expression of key lipogenesis proteins (ATP citrate lyase [ACLY], acetyl-CoA carboxylase [ACC1], and fatty acid synthase [FASN]). We also determined that the Cr(VI)-transformed cells did not exhibit an increase in fatty acid oxidation or lipid droplets compared to their passage-matched control cells. Additionally, we observed increases in ACLY, ACC1, and FASN in lung tumor tissue compared with normal-adjacent lung tissue (in chromate workers that died of chromate-induced tumors). Next, using a known FASN inhibitor (C75), we treated Cr(VI)-transformed BEAS-2B with this inhibitor and measured cell growth, FASN protein expression, and growth in soft agar. We observed that FASN inhibition results in a decreased protein expression, decreased cell growth, and the inhibition of colony growth in soft agar. Next, using shRNA to knock down the FASN protein in Cr(VI)-transformed BEAS-2B cells, we saw a decrease in FASN protein expression and a loss of the xenograft tumor development of Cr(VI)-transformed BEAS-2B cells. These results demonstrate that FASN is important for Cr(VI)-transformed cell growth and cancer properties. In conclusion, these data show that Cr(VI)-transformation in vitro caused an increase in lipogenesis, and that this increase is vital for Cr(VI)-transformed cells.

Early Prediction of Radiotherapeutic Efficacy in a Mouse Model of Non-Small Cell Lung Carcinoma Using 18F-FLT and 18F-FDG PET/CT.

This study investigated the usefulness of [18F]-3'-deoxy-3'-fluorothymidine (18F-FLT) and [18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging for predicting the therapeutic efficacy of non-small cell lung cancer (NSCLC) irradiation at an early stage after radiation treatment. Mice were xenografted with the human lung adenocarcinoma line A549 or large cell lung cancer line FT821. Tumour uptake of 18F-FLT and 18F-FDG was imaged using PET/CT before and 1 week after irradiation. In A549 tumours, 18F-FLT uptake was significantly decreased, and 18F-FDG uptake was unchanged post-irradiation compared with pre-irradiation. In FT821 tumours, uptake of both 18F-FLT and 18F-FDG uptake was substantially decreased post-irradiation compared with pre-irradiation. In both xenografts, tumour volumes in the irradiated groups were significantly decreased compared with those in the control group. 18F-FLT is expected to contribute to individual NSCLC therapy because it accurately evaluates the decrease in tumour activity that cannot be captured by 18F-FDG. 18F-FDG may be useful for evaluating surviving cells without being affected by the inflammatory reaction at an extremely early stage, approximately 1 week after irradiation. Combined use of 18F-FLT and 18F-FDG PET/CT imaging may increase the accurate prediction of radiotherapy efficacy, which may lead to improved patient outcomes and minimally invasive personalised therapy. J. Med. Invest. 70 : 361-368, August, 2023.

Assessment of dyspnea, ADL, and QOL in the perioperative period in lung cancer patients treated with minimally invasive surgery.

OBJECTIVE: Patients with lung cancer generally undergo minimally invasive surgery, such as video-assisted thoracoscopic surgery (VATS). This study examined the changes in health conditions and symptoms of patients with lung cancer using the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ) C-30 questionnaires after surgery. METHODS: This was a longitudinal descriptive study. One hundred and three patients with lung cancer who underwent lung resection at Tokushima University Hospital between 2012 and 2021 were eligible. They completed EORTC QLQ-C30, QLQ-LC13, the Cancer Dyspnea scale (CDS), and pulmonary-ADL (P-ADL) before and 1, 3, and 6 months after surgery. RESULTS: Regarding functional scale scores, impairments in physical and role functions persisted for 6 months after surgery. In symptom scale scores, fatigue, pain, dyspnea, and appetite loss continued for 6 months after surgery. In CDS, sense of effort, discomfort, and total dyspnea scale scores were elevated for 6 months after surgery. In P-ADL, most ADL were impaired 1 month after surgery, but recovered by 3 months. The dyspnea index of ADL was lower for 6 months after surgery. CONCLUSIONS: Impairments in health conditions and symptoms persisted for 6 months after surgery despite its minimally invasive nature. J. Med. Invest. 70 : 388-402, August, 2023.

Resilience in cancer care : What should nurses do?

Cancer is a serious threat to human health worldwide. Attention to the quality of life (QoL) of cancer patients is increasingly recognized as an important component of and a fundamental task in cancer care. Recent studies illustrate that resilience is a key biological factor affecting cancer patients' health status and QoL. However, few studies have focused on resilience during medical procedures of cancer patients from the perspective of nursing. In this study, we summarize recent literature exploring the clinical significance of resilience in oncology nursing, propose strategies for cancer care to improve the QoL of patients through interventions on resilience, and focus on emerging theories in oncology nursing. In summary, this will emphasize the importance of resilience in oncology nursing and benefit the clinical practices that improve patients' QoL and reduce the social burden caused by cancer. J. Med. Invest. 70 : 1-6, February, 2023.

Aberrant methylation of dipeptidyl peptidase­like 6 as a potential prognostic biomarker for lung adenocarcinoma.

We previously performed the genome-wide screening of aberrantly methylated CpG islands (CGIs) using the paired tumorous and non-tumorous tissues of 12 lung adenocarcinomas (LADC). In comparisons with paired normal lung tissues, dipeptidyl peptidase-like 6 (DPP6) has been identified as the most significantly hypermethylated CGI in LADC. DPP6 is a protein that modulates A-type potassium channels in the somatodendritic compartments of neurons, which play a role in synaptic plasticity. Previous studies have showed that DPP6 is downregulated in cancers, such as acute myeloid leukemia and melanoma, but upregulated in colon cancer, which is attributed to hyper- and hypomethylation, respectively. The present study investigated the methylation and expression levels of DPP6 and its prognostic value in patients with LADC. The DNA methylation and mRNA expression levels of DPP6 in surgically resected LADC tissues were examined by bisulfite pyrosequencing and reverse transcription-quantitative PCR, respectively. The DNA methylation and mRNA expression levels of DPP6 were both significantly higher in LADC tissues compared with in normal lung tissues (n=25; P<0.0001). Overall and disease-free survival rates were significantly higher in LADC with high mRNA expression levels compared with those with low levels. In conclusion, epigenetic alterations in DPP6 were significantly higher in LADC tissues compared with in normal lung tissues, which may contribute to the malignant features and worse prognosis of these patients.

Psychological Adjustment and Related Factors in Patients with Recurrence/Metastatic Lung Cancer after Curative Surgery.

The purpose of study was to clarify the psychological adjustment and related factors in lung cancer patients with recurrence/metastasis after curative surgery. Forty-one with lung cancer who were informed of a recurrence/metastasis after curative surgery completed a questionnaire comprised of the Mental Adjustment to Cancer Scale (MAC), Psychological Adjustment scale for Cancer Survivors (PACS), and information pertaining to demographic variables. When healthcare providers intervene in patients with lung cancer that has recurred/metastasized after curative surgery, it is necessary to assess patients' psychological adjustment based on demographic information, such as age, sex, marital status, and employment status, and to provide effective support promptly. Factors associated with psychological adjustment with recurrent/metastatic lung cancer after curative surgery were 1) female, 2) having a job, 3) over 65 years of age, 4) having a spouse, and 5) advanced-stage cancer. There was no difference in psychological adjustment between treatment and the period from cancer incidence to recurrence/metastatic. J. Med. Invest. 70 : 200-207, February, 2023.

Cone-beam computed tomography-guided endobronchial ultrasound using an ultrathin bronchoscope for diagnosis of peripheral pulmonary lesions: a prospective pilot study.

Background: Multimodal transbronchial biopsy (TBB) may have improved diagnostic yield for peripheral pulmonary lesions suspected as lung cancer. Radial endobronchial ultrasound (R-EBUS) provides real-time imaging and confirmation of the location of the lesions. Cone-beam computed tomography (CBCT) can confirm that the forceps tip has reached the lesion before biopsy. Methods: Patients with peripheral pulmonary lesions and a positive computed tomography (CT) bronchus sign (based on slice thickness of 1 mm) were prospectively enrolled. An ultrathin bronchoscope (UTB) and R-EBUS probe were advanced to the target bronchus. Thereafter, forceps were advanced, and CBCT was performed. R-EBUS was performed for re-navigation, if possible. The obtained EBUS and CBCT images were classified into "within" (type 1), "adjacent to" (type 2), or "far from" (type 3), based on the probe or forceps tip. Results: For 20 lesions, the diagnostic yield was 85%. The primary EBUS images were of types 1, 2, and 3 in 12, 6, and 2 cases, respectively. The primary CBCT images were of types 1, 2, and 3 in 12, 6, and 2 cases, respectively. Primary EBUS and CBCT image types were equivalent in 14 cases. Of the 12 cases with type 1 primary EBUS image, 9 cases had a type 1 primary CBCT image, while 3 cases exhibited positional misalignment of the forceps tip. Re-navigation was required in 8 cases with types 2 and 3 primary CBCT images. Conclusions: CBCT-guided TBB using an UTB and EBUS may enable real-time positioning guidance and better re-navigation in the diagnosis of peripheral pulmonary lesions.

Sodium-glucose cotransporter 2 inhibitor-associated perioperative ketoacidosis: a systematic review of case reports.

Although the recommended preoperative cessation period for sodium-glucose cotransporter 2 inhibitors (SGLT2is) changed in 2020 (from 24 h to 3-4 days preoperatively) to reduce the risk of SGLT2i-associated perioperative ketoacidosis (SAPKA), the validity of the new recommendation has not been verified. Using case reports, we assessed the new recommendation effectiveness and extrapolated precipitating factors for SAPKA. We searched electronic databases up to June 1, 2022 to assess SAPKA (blood pH < 7.3 and blood or urine ketone positivity within 30 days postoperatively in patients taking SGLT2i). We included 76 publications with 99 cases. The preoperative SGLT2i cessation duration was reported for 59 patients (59.6%). In all cases with available cessation periods, the SGLT2is were interrupted < 3 days preoperatively. No SAPKA cases with > 2-day preoperative cessation periods were found. Many case reports lack important information for estimating precipitating factors, including preoperative SGLT2i cessation period, body mass index, baseline hemoglobin A1c level, details of perioperative fluid management, and type of anesthesia. Our study suggested that preoperative SGLT2i cessation for at least 3 days could prevent SAPKA. Large prospective epidemiologic studies are needed to identify risk factors for SAPKA.

Chronic Hexavalent Chromium Exposure Upregulates the RNA Methyltransferase METTL3 Expression to Promote Cell Transformation, Cancer Stem Cell-Like Property, and Tumorigenesis.

Hexavalent chromium [Cr(VI)] is a common environmental carcinogen causing lung cancer in humans. This study investigates the mechanism of Cr(VI) carcinogenesis focusing on the role of the epitranscriptomic dysregulation. The epitranscriptomic effect of Cr(VI) was determined in Cr(VI)-transformed human bronchial epithelial cells, chromate-exposed mouse and human lungs. The epitranscriptomic effect and its role in Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property, and tumorigenesis were determined by microarray analysis, soft agar colony formation, suspension spheroid formation, and mouse xenograft tumorigenesis assays. It was found that chronic Cr(VI) exposure causes epitranscriptomic dysregulations as evidenced by the increased levels of total RNA N6-methyladenosine (m6A) modification and the RNA m6A methyltransferase like-3 (METTL3) in Cr(VI)-transformed cells and chromate exposure-caused mouse and human lung tumors. Knockdown of METTL3 expression in Cr(VI)-transformed cells significantly reduces their m6A levels and transformed phenotypes and tumorigenicity in mice. Moreover, knockdown of METTL3 expression in parental nontransformed cells significantly reduces the capability of chronic Cr(VI) exposure to induce cell transformation and CSC-like property. Together, this study reveals that chronic Cr(VI) exposure is capable of altering cellular epitranscriptome by increasing the m6A RNA modification via upregulating the RNA methyltransferase METTL3 expression, which plays an important role in Cr(VI)-induced cell transformation, CSC-like property, and tumorigenesis.

GHSR methylation-dependent expression of a variant ligand and receptor of the ghrelin system induces thymoma tumorigenesis.

Our previous study reported that the DNA methylation of growth hormone secretagogue receptor (GHSR) was significantly higher in thymoma or thymic carcinoma (TC) than in normal thymic tissue samples. Thymic epithelial tumors (TETs) with higher GHSR DNA methylation were associated with significantly worse prognosis than those with lower levels of DNA methylation. Diversified components of the ghrelin-GHSR axis may exert opposing effects in cancer progression, depending on the cancer type in question. However, the precise function of the axis remains unclear. In the present study, the mRNA expression of five key components of the ghrelin system [native ligand ghrelin, variant ligand In-1 ghrelin, native receptor GHSR1a, variant receptor GHSR1b and acylation enzyme ghrelin O-acyltransferase (GOAT)] were examined in 58 TET samples by reverse transcription-quantitative PCR, and protein expression of GHSR1a and GHSR1b was assessed in 20 TETs using immunohistochemistry. The results revealed that In-1 ghrelin, GHSR1b (variant forms) and GOAT were more strongly expressed in thymoma compared with thymic-adjacent tissue. By contrast, no significant differences were observed in the expression of ghrelin and GHSR1a (native forms) between thymoma and thymic tissue. The mRNA expression of In-1 ghrelin and GHSR1b (variant forms) was positively associated with GHSR methylation in thymoma tissue samples. However, a relationship was not found between ghrelin, GHSR1a or GOAT expression (native forms) and GHSR methylation in thymoma. Immunohistochemical analysis revealed that mRNA expression of GHSR1a and GHSR1b generally correlated with expression of the corresponding protein, and that the expression of GHSR1b was increased in advanced-stage TETs. These results indicate that the DNA methylation of GHSR is associated with a shift from native expression (ghrelin and GHSR1a) to variant expression (In-1 ghrelin and GHSR1b), which induces the tumorigenesis of thymoma, but not TC.

Intrathymic Plasmablasts Are Affected in Patients With Myasthenia Gravis With Active Disease.

BACKGROUND AND OBJECTIVES: To investigate intrathymic B lymphopoiesis in patients with myasthenia gravis (MG) and explore thymus pathology associated with clinical impact. METHODS: Thymic lymphocytes from 15 young patients without MG, 22 adult patients without MG, 14 patients with MG without thymoma, and 11 patients with MG with thymoma were subjected to flow cytometry analysis of T follicular helper (Tfh), naive B, memory B, plasmablasts, CD19+B220high thymic B cells, B-cell activating factor receptor, and C-X-C chemokine receptor 5 (CXCR5). Peripheral blood mononuclear cells of 16 healthy subjects and 21 untreated patients with MG were also analyzed. Immunologic values were compared, and correlations between relevant values and clinical parameters were evaluated. RESULTS: The frequencies of circulating and intrathymic plasmablasts were significantly higher in patients with MG than controls. On the other hand, the frequency of CD19+B220high thymic B cells was not increased in MG thymus. We observed a significant increase in CXCR5 expression on plasmablasts in MG thymus and an increased frequency of intrathymic plasmablasts that was correlated with preoperative disease activity. The frequency of intrathymic Tfh cells was significantly lower in patients who received immunosuppressive (IS) therapy than those without IS therapy. However, there was no significant difference in the frequency of intrathymic plasmablasts irrespective of IS therapy. DISCUSSION: Our findings confirmed a correlation between increased frequency of intrathymic plasmablasts and disease activity before thymectomy. We postulate that activated intrathymic plasmablasts endow pathogenic capacity in MG.

Hypervascularized bronchial arteries as a risk factor for intraoperative bleeding and prolonged surgery.

BACKGROUND: The present study investigated whether highly vascularized bronchial arteries affect the intraoperative blood loss and the operative time of video-assisted thoracic surgery (VATS) lobectomy for patients with non-small cell lung cancer.Methods: We retrospectively collected data on consecutive pathological stage I to IIIA non-small cell lung cancer patients who underwent VATS lobectomy with systematic lymph node dissection between January 2017 and December 2019. Patients were divided into the following two groups according to bronchial artery diameters on preoperative enhanced contrast computed tomography (CT) findings: ≤2 and >2 mm groups. RESULTS: Among the 175 patients enrolled, risk factors for intraoperative blood loss >50 mL were being male (P=0.005), a history of smoking (P=0.01), percent forced expiratory volume in 1 s (FEV1.0%) <70% (P=0.012), squamous cell carcinoma (P=0.049), and a bronchial artery diameter >2.0 mm (P<0.001) in the unadjusted analysis, and a bronchial artery diameter >2.0 mm (P<0.001) in the multivariable analysis. Risk factors for an operative time >200 min were being male (P<0.001), a history of smoking (P=0.007), FEV1.0% <70% (P=0.011), squamous cell carcinoma (P=0.046), a bronchial artery diameter >2.0 mm (P<0.001), and experience of surgeon <10 years (P=0.011) in the unadjusted analysis, and being male (P=0.047), a bronchial artery diameter >2.0 mm (P=0.024), and experience of surgeon <10 years (P=0.047) in the multivariable analysis. CONCLUSIONS: Bronchial artery diameter was the most important risk factor of intraoperative bleeding and prolonged operative time during VATS lobectomy.

Diagnosis of visceral pleural invasion using confocal laser endomicroscopy during lung cancer surgery.

BACKGROUND: Visceral pleural invasion (VPI) in lung cancer is a significant prognostic factor; however, it is difficult to diagnose preoperatively or intraoperatively. In this study, we examined the possibility of intraoperative diagnosis of VPI using confocal laser endomicroscopy (CLE). METHODS: Among patients with primary lung cancer who underwent surgery between April 2018 and August 2019, those in whom the tumor was in contact with the pleura on chest computed tomography and whose pleural changes were intraoperatively confirmed were enrolled in this study. In the 35 patients who underwent lung resection (6 cases with visceral pleural infiltration), the area where pleural change was noted was observed and a short video was recorded using CLE. Based on the video images, three evaluators determined the defect ratio (0%, 25%, 50%, 75%, and 100%) of the autofluorescence-positive structure. The area under the receiver operating characteristic curve was used to evaluate the diagnostic performance for VPI. In 15 cases (3 cases with VPI), a validation study was performed for intraoperative VPI according to the cutoff value of the defect ratio of the autofluorescence-positive structure. RESULTS: The areas under the receiver operating characteristic curve for the defect ratio of the autofluorescence-positive structure were 0.86-0.91 for the three readers. Using defect ratio of autofluorescence-positive structure cutoff of ≥50% as predictor of VPI, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 83.3-100.0%, 57.7-73.1%, 35.3-41.7%, 95.0-100.0%, and 75.0-78.1%, respectively, for the three readers. In the validation study, the sensitivity was 100%, the specificity was 83.3%, and the diagnostic accuracy rate was 86.7%. CONCLUSIONS: The diagnosis of VPI through CLE is simple, non-invasive, and has high diagnostic accuracy rates. This method may be applicable for determining surgical procedures.

The Development of the Arm Fixation Method to Prevent Ipsilateral Shoulder Pain in Patients Undergoing Lung Resection.

PURPOSE: The aim of the present study was to investigate the efficacy of a new upper limb fixation method-body pillow position for preventing postoperative ipsilateral shoulder pain (ISP) in patients undergoing lung resection. DESIGN: An experimental study design was used. METHODS: We conducted two comparisons (group A: the previous position using the arm fixation device; group B: the body pillow position) at random and examined an arm fixation method that is effective for ISP prophylaxis in patients undergoing surgery in the lateral decubitus position. FINDINGS: We approached 87 patients, two were excluded, and, thus, 85 were randomly assigned to group A (n = 43) or group B (n = 42). No significant differences were observed in the frequency of ISP between groups A and B (25.6% vs 26.2%). The intensity of ISP between both groups was analyzed by a repeated-measures analysis of variance and was shown to decrease over time in 22 patients (P = .010). The intensity of ISP on postoperative days 0 to 3 was slightly lower in group B than in group A (P = .158). Risk factors for ISP were the duration of surgery (odds ratio, 1.01; 95% confidence interval, 1.00 to 1.01) and pre-existing shoulder stiffness (odds ratio, 5.15; 95% confidence interval, 1.07 to 24.83). CONCLUSIONS: There was no significance in the frequency of ISP between group A and group B. The intensity of ISP on postoperative days 0 to 3 was lower in group B than in group A, although there was no significant difference. It is important perspective for perioperative care providers to prevent ISP for early postoperative recovery and improvement of postoperative quality of life. These results suggested that we must consider a better position for preventing postoperative ISP in patients undergoing lung resection.