Effectiveness of the 2019-2020 Influenza Vaccine and the Effect of Prior Influenza Infection and Vaccination in Children during the First Influenza Season Overlapping with the COVID-19 Epidemic.

BACKGROUND: Behavioral changes among Japanese, along with the coronavirus disease 2019 (COVID-19) epidemic, may affect the seasonal influenza epidemic in Japan and change influenza vaccine effectiveness (VE). METHODS: This single-center, test-negative case-control (TNCC) study estimated influenza VE in children for the first influenza season (2019/20) to overlap the COVID-19 epidemic in. Effects of prior influenza infection and vaccination in children were assessed for the 2019-2020 season. RESULTS: Among 386 children, adjusted VE was significant for influenza A/H1N1 (45.5%; 95% confidence interval [CI]: 2.0-69.7) and influenza B (66.7%; 95% CI: 35.9-82.7). Among patients aged 0-6 years, adjusted VE was significant for influenza A (total: A/H1N1+A/H3N2) (65.0%; 95% CI: 22.2-84.3), influenza A/H1N1 (64.8%; 95% CI: 16.9-85.1) and influenza B (87.4%; 95% CI: 50.5-96.8). No VE was observed in patients aged 7-15 years. Administration of two vaccine doses tended to decrease incidences of influenza A (total) and influenza A/H1N1 in patients aged 0-6 years. The adjusted odds ratios (ORs) of influenza B infection in patients, who had influenza during the previous season, were significantly lower among all participants (0.29; 95% CI: 0.11-0.78) and patients aged 7-15 years (0.34; 95% CI: 0.12-0.94). The adjusted ORs of influenza infections were not significant in patients vaccinated during the previous season. CONCLUSIONS: TNCC-based estimates of influenza VE were consistent despite the overlapping COVID-19 epidemic.

Estimation of the Effectiveness of Quadrivalent Influenza Vaccines by Distinguishing Between Influenza A (H1N1) pdm09 and Influenza A (H3N2) Using Rapid Influenza Diagnostic Tests During the 2018-2019 Season.

Objective To estimate the effectiveness of quadrivalent influenza vaccines during the 2018-2019 season for influenza A (H1N1) pdm09 and A (H3N2) in all age groups. Methods A test-negative case-control study was performed. Patients A total of 1,331 participants were divided into 4 groups (younger children: ≤6 years, older children: 7-15 years, younger adults: 16-64 years, and older adults: ≥65 years). Results For all children, the adjusted vaccine effectiveness (VE) was significant against any influenza [41.3% (95% confidence interval (CI): 19.7-57.2%)], total A [A (H1N1) pdm09 and (H3N2); 38.3% (95% CI: 15.1-55.1%)], and A [H3N2; 39.8% (95% CI: 13.8-57.9%)]. In younger children, the adjusted VE against any influenza was 44.8% (95% CI: 14.1-64.5%) and against total A was 43.8% (95% CI: 12.5-63.9%). For all adults, the adjusted VE was significant against any influenza was 42.3% (95% CI: 17.9-59.5%); total A, 39.3% (95% CI: 13.5-57.4%); A (H1N1) pdm09, 56.7% (95% CI: 19.1-76.8%); and A (H3N2), 33.2% (95% CI: 1.5-54.6%). In younger adults, the adjusted VE against any influenza was 43.4% (95% CI: 17.3-61.2%), total A, 41.7% (95% CI: 14.4-60.3%); A (H1N1) pdm09, 56.2% (95% CI: 14.9-77.5%); and A (H3N2), 34.5% (95% CI: 0.3-56.9%). In both older children and older adults, no significant VE was observed. Conclusion This study is the first to report on the VE against all types of influenza in all age groups using a rapid influenza diagnostic test. The VE varied with both age and influenza subtype.

Effectiveness of quadrivalent influenza vaccine based on the test-negative control study in children during the 2016-2017 season.

To estimate the vaccine effectiveness (VE) of quadrivalent influenza vaccine, I conducted a test-negative case control study in children, based on the rapid influenza diagnostic test (RIDT), during the 2016-2017 season. Overall, the adjusted VE was significant for any influenza (influenza A + B); VE: 30.2% (95% confidence interval [CI]: 5.4-48.4) and influenza B: 48.2% (95% CI: 11.3-69.7). The participants were divided into three age groups (group A: 0-4 years old, group B: 5-9 years old, and group C: 10-15 years old); in group A, the adjusted VE of quadrivalent influenza vaccine was significant for any influenza (A + B): 58.6% (95% CI: 28.8-76.0), influenza A: 53.9% (95% CI: 16.4-74.6), and influenza B: 78.6% (95% CI: 23.6-94.0). In both groups B and C, VE was not observed for any of the types of influenza. In only group A, two doses of vaccines provided significantly better VE against any influenza, as well as both influenzas A and B, than single-dose vaccines and cases in which vaccination was not administered. In conclusion, quadrivalent influenza vaccine showed significant VE and dose-dependent VE against any influenza and both influenzas A and B, in children aged 0-4 years during the 2016-2017 season. Both the VE and dose-dependent VE were almost not observed in older group. However, this may due to low rate of vaccination, particularly in children aged 10-15 years.

VEGF in patients with non-small cell lung cancer during combination chemotherapy of carboplatin and paclitaxel.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor related to tumor growth and metastasis. However, little is known about the clinical significance of circulating VEGF in cancer patients. PATIENTS AND METHODS: Eighteen patients with non-small cell lung cancer received chemotherapy using carboplatin and paclitaxel. Plasma levels of VEGF were analyzed at baseline and after 2 cycles of chemotherapy. RESULTS: Partial remission was observed in 3 patients (16.7%), stable disease in 10 patients (55.6%) and progressive disease in 5 patients (27.8%). Patients with partial remission or stable disease had significantly lower levels of plasma VEGF than did patients with progressive disease, both at baseline (p=0.0341) and after 2 cycles of chemotherapy (p=0.0265). There were no significant changes of plasma VEGF during chemotherapy. CONCLUSION: Pretreatment plasma levels of VEGF are a useful marker for predicting disease control by chemotherapy.

Indications for mediastinoscopy and comparison of lymph node dissections in candidates for lung cancer surgery.

A prospective phase II study of indications for surgery, using video-assisted mediastinoscopy (VAM) to detect mediastinal lymph node metastasis was conducted in patients with resectable primary lung cancer of clinical stages I-IIIA. According to the indication criteria for VAM, Group A patients had primary tumor resection and lymph node sampling without VAM. Patients without detected metastasis by VAM underwent thoracotomy and systematic lymph node dissection (Group B). Cases with mediastinal lymph node involvement confirmed by VAM were treated with chemotherapy followed by radiotherapy (Group D) or by thoracotomy (Group C) with extended dissection of mediastinal lymph nodes via median sternotomy. Of the 359 eligible patients, 209 underwent VAM (Group V) and 150 had thoracotomy without VAM (Group A). Of the VAM patients, 158 were negative for mediastinal involvement and underwent thoracotomy (Group B). Fifty-one patients had metastases and were given chemotherapy or chemo-radiotherapy. After two courses of chemotherapy, 22 patients with partial response (PR) or stable disease (SD) but reduced tumor markers received surgery with mediastinal lymph node dissection (Group C). The 2- and 5-year survival rates were 93.0 and 88.5% for Group A, and 89.5 and 61.5% for Group B, while the 2-year rate in Group C was 60.3%. In stage IA patients, Group A 2- and 5-year survival rates were 98.6 and 95.1%, the respective Group B rates being 96.3 and 89.9%. The more favorable Group A outcomes indicated both successful selection by these criteria of patients not requiring mediastinal examination, and the superfluity of complete lymph node dissection in early stage cancer.

Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer.

Aberrant methylation of promoter CpG that causes silencing of tumor suppressor genes (TSGs) may play a key role in the carcinogenesis of many cancer types. RASSF1A, regarded as a TSG, has been extensively studied in lung cancer and other malignant tumors, whereas RASGRF2 has only been reported to possibly play a role in the pathogenesis of pancreatic cancer cell lines. The aims of our study were to i) determine the methylation profile of RASGRF2 and ii) compare the methylation profiles of RASGRF2 with RASSF1A in lung cancer. We examined RASGRF2 expression by reverse transcription PCR and aberrant methylation of RASGRF2 by methylation-specific PCR in lung cancer cell lines. Loss of RASGRF2 expression was presented in 36% lung cancer cell lines while aberrant methylation of RASGRF2 was present in 30% (3/10) non-small cell lung cancer (NSCLC) cell lines and in 25% (1/4) small cell lung cancer (SCLC) cell lines. The concordance between loss of expression and aberrant methylation of RASGRF2 was 86% (12/14). RASGRF2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all four cell lines tested that downregulated RASGRF2 expression. Among primary NSCLC, RASGRF2 and RASSF1A methylation was observed in 34% (39/114) and 39% (44/114) of cases respectively, while it was observed in only 7% (4/57) and none of the corresponding non-malignant lung tissue. There is no correlation between RASGRF2 and RASSF1A methylation status. Both RASGRF2 and RASSF1A methylation did not associate with clinical characteristics. Frequent methylation and silencing of RASGRF2 in tumor cells may play an important role, different from that of RASSF1A, in the carcinogenesis of NSCLC.

Spontaneous regression of bone metastasis from renal cell carcinoma; a case report.

BACKGROUND: Spontaneous regression of metastatic renal cell carcinoma is rarely observed. CASE PRESENTATION: Metastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells. CONCLUSION: We report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously.

Aberrant methylation: common in thymic carcinomas, rare in thymomas.

Thymic carcinoma, which is a rare epithelial neoplasm of the thymus gland, is different from thymoma in its clinical and pathological features. To clarify the mechanism underlying the aggressive behavior of thymic carcinoma, we examined the clinicopathologic features, aberrant methylation patterns of the tumor suppressor genes, and epidermal growth factor receptor (EGFRs) mutation in both thymic carcinomas and thymomas. Clinical data of 11 thymic cancers and 13 thymomas were reviewed. Resected samples of 5 thymic cancers and 6 thymomas selected from 24 cases were used for methylation and mutation studies. Positive tumor markers were more frequent in thymic cancers than in thymomas (p=0.0233), and the methylation index, which reflects the overall methylation pattern, was significantly higher in thymic carcinomas (p=0.0053). No tumors showed a mutation of EGFR, KRAS, and HER2. Thymic carcinoma is distinct from thymoma not only with respect to clinicopathological features, but also aberrant methylation patterns of the tumor suppressor genes.

Phase I study of vinorelbine plus gemcitabine as third-line chemotherapy for refractory non-small cell lung cancer.

For non-small cell lung cancer (NSCLC), which is refractory for both platinum-based chemotherapy and docetaxel, no standard regimen has yet been established. We conducted a phase I study of a combination of vinorelbine and gemcitabine as third-line chemotherapy for refractory NSCLC to determine both the maximum tolerated dose (MTD) and the recommended dose (RD). Twenty patients with NSCLC refractory for both platinum and docetaxel were enrolled, and all patients were eligible for this phase I study. Cohorts of three to seven patients received vinorelbine at doses ranging from 20 to 25 mg/m(2), and gemcitabine at doses ranging from 600 to 1000 mg/m(2), on days 1 and 8 every 3 weeks. The dose-limiting toxicities were treatment delay, serum gammaGTP elevation, diarrhea and cerebral infarction, which were resolved without serious sequela, and there was no treatment-related death. The MTD was vinorelbine at 25 mg/m(2) and gemcitabine at 1000 mg/m(2) and the RD was vinorelbine at 25 mg/m(2) and gemcitabine at 800 mg/m(2). The median overall survival time was 6.8 months for all 20 patients eligible. As third-line chemotherapy, the combination of vinorelbine and gemcitabine was feasible and promising for NSCLC which is refractory for both platinum and docetaxel.

Aberrant methylation of FBN2 in human non-small cell lung cancer.

FBN2, a large modular extracellular matrix glycoprotein, is known to be a key component of human elastic fiber. A loss of FBN2 expression due to promoter methylation was recently identified in pancreatic cancer. We examined FBN2 expression by reverse transcription PCR and aberrant methylation of FBN2 by methylation specific PCR in lung cancer cell lines. Aberrant methylation of FBN2 was present in 55% (6 of 11) of non-small cell lung cancer (NSCLC) cell lines, but it absent in small cell lung cancer cell lines. The concordance between loss of expression and aberrant methylation of FBN2 was 88% (14 of 16) in the cell lines. FBN2 expression was restored after treatment with the demethylating agent, 5-aza-2'-deoxycytidine in all six cell lines tested that lacked FBN2 expression. Among primary NSCLC, 49% (62/126) of cases had FBN2 methylation, but only 7% (5/69) of the corresponding nonmalignant lung tissues had it. Although FBN2 methylation was detected even in patients with early stage disease, it occurred frequently in large tumors (p=0.022), with nodal metastasis (p=0.037), or with advanced stages of NSCLC (p=0.014). Methylation and silencing of FBN2 in tumor cells may play an important role in carcinogenesis, invasion, and metastasis of NSCLC.

Multimodality therapy and significance of serum CYFRA21-1 for thymic carcinoma.

Thymic carcinoma is a rare mediastinal neoplasm with a poor prognosis due to delayed diagnosis and highly malignant behavior. To evaluate 7 serum tumor markers and the outcome of treatment, 11 stage III-IVb thymic carcinomas undergoing multimodality treatment were reviewed. High levels of serum CYFRA21-1 were detected in 5 patients (45%) and correlated with the progression of disease. Of the patients, 6 underwent surgery. The median survival time was 38.4 months, and the 5-year survival rate was 15.6%. The metastatic stage (IVb) and treatment without resection were significantly associated with poorer overall survival (p=0.0034 and p=0.0041, respectively). Our data demonstrated that serum CYFRA21-1 may represent a potential new biomarker in thymic carcinoma. Stage may provide a basis for prognosis in stage III-IVb thymic carcinoma, and resection is one of the most important parts of multimodality treatment for advanced thymic carcinoma. Effective neoadjuvant treatment is therefore essential.

The prognostic value of both neuron-specific enolase (NSE) and Cyfra21-1 in small cell lung cancer.

PURPOSE: The aim of this study was to verify the prognostic significance of multiple tumour markers in small cell lung cancer (SCLC). PATIENTS AND METHODS: We examined seven tumour markers [carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA 19-9), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), cancer antigen 125 (CA125), cytokeratin 19 fragment (Cyfra21-1) and ProGastrin-releasing peptide (ProGRP)] in 57 small cell lung cancer (SCLC) patients. RESULTS: Univariate analysis showed that NSE and Cyfra21-1 were independent negative prognostic factors along with gender, therapy and lactate dehydrogenase (LDH). Multivariate analysis showed that both NSE and Cyfra21-1 retained their significance as prognostic factors along with therapy and the respective hazard ratios were 3.918 (p=0.0122) and 2.617 (p=0.0318) among the seven tumour markers. The group with both NSE and Cyfra21-1 positive had a worse prognosis than the only NSE-positive group, with the respective hazard ratios being 10.245 (p=0.0004) and 3.913 (p=0.0123). CONCLUSION: The group with both of the markers NSE and Cyfra21-1 positive had a worse prognosis than the only NSE-positive group.

Arachidonoyl-phospholipid remodeling in proliferating murine T cells.

BACKGROUND: Previous studies have shown that the functional capacity of T cells may be modulated by the composition of fatty acids within, and the release of fatty acids from membrane phospholipids, particularly containing arachidonic acid (AA). The remodeling of AA within membrane phospholipids of resting and proliferating CD4+ and CD8+ T cells is examined in this study. RESULTS: Splenic T cells were cultured in the presence or absence of anti-CD3 mAb for 48 h then labeled with [3H]AA for 20 min. In unstimulated cells, labeled AA was preferentially incorporated into the phosphoglycerides, phosphatidylcholine (PC) followed by phosphatidylinositol (PI) and phosphatidylethanolamine (PE). During a subsequent chase in unlabeled medium unstimulated CD4+ and CD8+ T cells demonstrated a significant and highly selective transfer of free, labeled AA into the PC pool. In contrast, proliferating CD4+ and CD8+ T cells distributed labeled [3H]AA predominantly into PI followed by PC and PE. Following a chase in AA-free medium, a decline in the content of [3H]AA-PC was observed in association with a comparable increase in [3H]AA-PE. Subsequent studies revealed that the cold AA content of all PE species was increased in proliferating T cells compared with that in non-cycling cells, but that enrichment in AA was observed only in the ether lipid fractions. Finally, proliferating T cells preincubated with [3H]AA exhibited a significant loss of labeled arachidonate in the PC fraction and an equivalent gain in labeled AA in 1-alk-1'-enyl-2-arachidonoyl-PE during a chase in unlabeled medium. CONCLUSION: This apparent unidirectional transfer of AA from PC to ether-containing PE suggests the existence of a CoA-independent transacylase system in T cells and supports the hypothesis that arachidonoyl phospholipid remodeling may play a role in the regulation of cellular proliferation.

[An autopsy case of pseudomesotheliomatous adenocarcinoma of the lung complicated with brain stem infarction due to nonbacterial thrombotic endocarditis].

A 53-year-old man was admitted to our hospital for back, left shoulder and upper limb pain. Chest radiography and CT on admission revealed right pleural effusion and a focal plate-like thickening of the major fissure. Pleural effusion cytology revealed adenocarcinoma, which was diagnosed as non-small-cell lung cancer with bone metastasis. The patient suffered from DIC, melena and multiple cerebral infarctions during chemotherapy and died on the eighth day of the second course of chemotherapy. Autopsy revealed a pseudomesotheliomatous adenocarcinoma covering the pleura of the right middle lobe, systemic thromboembolism and vegetations on the aortic valves due to nonbacterial endocarditis. Pseudomesotheliomatous adenocarcinoma of the lung, a rare form of lung cancer, complicated with DIC and nonbacterial endocarditis, is reported.

Positive reactions for both Cyfra21-1 and CA125 indicate worst prognosis in non-small cell lung cancer.

UNLABELLED: We examined four tumour markers [carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), cancer antigen 125 (CA125) and cytokeratin 19 fragment (Cyfra21-1)] in 584 non-small cell lung cancer (NSCLC) patients. RESULTS: After confirmation of a significant correlation between their serum levels and clinical stages, multivariate analysis showed that Cyfra21-1 and CA125 pointed to a negative prognosis; the respective hazard ratios were 2.585 (p = 0.0008) and 2.139 (p = 0.0020) in 121 inoperable adenocarcinoma patients and 2.329 (p = 0.0004) and 1.61 (p = 0.00370) in 205 inoperable NSCLC patients. Also, patients giving positive reactions for both Cyfra21-1 and CA125 had the worst prognoses, with hazard ratios of 6.546 (p < 0.0001) in inoperable adenocarcinoma patients and 4.275 (p < 0.0001) in inoperable NSCLC patients. CONCLUSION: Cyfra21-1 or CA125 tend to imply a negative prognosis. Cyfra21-1 and CA125 together imply the worst prognosis.

A prospective study of indications for mediastinoscopy in lung cancer with CT findings, tumor size, and tumor markers.

BACKGROUND: Biopsies by mediastinoscopy remain the most reliable preoperative staging method for N2 lung cancer. Because it is neither practical nor economical to recommend mediastinoscopy for all candidates for surgery, we developed indicational criteria for video-assisted mediastinoscopy (VAM) and carried out a prospective study to validate its usefulness. METHODS: Patients with resectable primary lung cancer were chosen for VAM when at least one of three clinical indicators was present: (1) computed tomographic evidence of mediastinal adenopathy, (2) elevated levels of serologic tumor markers, and (3) diameters of primary cancers (> 2 to 3 cm). Patients without positive nodes (group 2) underwent thoracotomy, and patients with positive nodes (group 3) received induction therapy. When none of these criteria were met (group 1), thoracotomy with R2b lymph node dissection was performed without VAM. RESULTS: One hundred twenty-one men and 82 women (total, 203) were eligible for the study. The mean age of the patients was 64.4 years (range, 39 to 75 years) with primary lung cancer. The patients were comprised of 135 adenocarcinomas, 46 squamous cell cancers, and 22 other carcinomas. There were 78 patients in group 1, 87 in group 2, and 38 in group 3. The stages of group 2 patients were more advanced (chi2 = 63.2668; p < 0.001) than those of group 1. As the incidence of positive indicators for VAM increased, the ratios of N2 patients increased from 2.5% (all negative) to 90.4% (triple positive: p < 0.001). The correlation of our criteria with the pathology findings revealed a diagnostic sensitivity of 95.8% and a negative predictive value of 97.4%. Using three indicators for N2 prediction, we selected 96% (46 of 48) pN2, N3 patients and avoided 37% (76 of 203) unnecessary VAMs. CONCLUSIONS: We established and validated currently useful criteria for VAMs in the management of primary lung cancer.

The significance of tumour markers as an indication for mediastinoscopy in non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to verify the significance of tumour markers as indicators for mediastinoscopy in non-small cell lung cancer. METHODOLOGY: In the past 4 years, 205 patients with non-small cell lung carcinoma (NSCLC) underwent surgical resection at Chiba Cancer Center, Chiba, Japan. The correlation between the serum levels of eight tumour markers (CEA, AFP, CA19-9, SCC, NSE, CA125, CYFRA, ProGRP) and the presence of N2 disease was analysed. Univariate and multivariate analyses were performed to determine the relationship between both marker levels and clinical findings and N2 disease. RESULTS: In multivariate analysis, positive CEA was significantly associated with the diagnosis of N2 disease. We also demonstrated that when CA125, CYFRA and ProGRP were positive, they were individually significantly associated with N2 disease. However, CEA was superior to the other markers and equivalent to a combination of various tumour markers. CONCLUSION: It was concluded that evaluation of CEA in addition to CT is of use in the diagnosis of N2 disease in NSCLC patients and should be used as an indication for mediastinoscopy.