Impact of the coronavirus disease 2019 pandemic on primary and metastatic lung cancer treatments in Japan: A nationwide study using an interrupted time series analysis.

BACKGROUND: The coronavirus disease 2019 pandemic prompted healthcare providers to use different approaches from the current standards of care. We aimed to identify the changes in the number of treatments for primary non-small cell lung cancer (NSCLC) and metastatic lung cancer during the pandemic. METHODS: We used nationwide insurance claims data from January 2015 to January 2021, and estimated changes in the number of treatments using an interrupted time series analysis. RESULTS: The number of surgical resections for primary NSCLC significantly decreased in April 2020 (-888; 95% confidence interval [CI]: -1530 to -246) and July 2020 (-1314; 95% CI: -1935 to -694), while the number of stereotactic body radiotherapies (SBRTs) increased in April 2020 (95; 95% CI: 8-182) and July 2020 (111; 95% CI: 24-198). The total number of treatments for primary NSCLC remained unchanged; however, non-significant decreases were observed in 2020. The number of surgical resections for metastatic lung cancer significantly decreased in April 2020 (-201; 95% CI: -337 to -65), but it eventually increased in July 2020 (170; 95% CI: 32-308). Additionally, the number of SBRTs significantly increased in April 2020 (37; 95% CI: 3-71) and October 2020 (57; 95% CI: 23-91). The total number of treatments for metastatic lung cancer was maintained, with an initial decrease in April 2020 followed by a subsequent increase in July and October 2020. CONCLUSION: In Japan, surgical triage for primary and metastatic lung cancer are likely to have been implemented during the pandemic. Despite these proactive measures, patients with primary NSCLC may have been untreated, likely owing to their undiagnosed disease, potentially leading to a deterioration in prognosis. By contrast, patients diagnosed with cancer prior to the pandemic are presumed to have received standard management throughout the course of the pandemic.

Impact of the COVID-19 pandemic on gastric surgery in Japan: A nationwide study using interrupted time-series analyses.

BACKGROUND AND AIM: Changes in the number of surgeries for gastric cancer during the coronavirus disease 2019 (COVID-19) pandemic have been reported, but data are insufficient to understand the impact at the national level. This study aimed to determine the impact of the COVID-19 pandemic on gastric surgery in Japan. METHODS: Insurance claims data registered from January 2015 to January 2021 were used. Changes in the number of endoscopic resections and gastrectomies for gastric cancer were estimated using an interrupted time-series analysis. RESULTS: The number of endoscopic resections significantly decreased in July 2020 (-1565; 95% confidence interval [CI]: -2022, -1108) and January 2021 (-539; 95% CI: -970, -109), and the number of laparoscopic surgeries significantly decreased in July 2020 (-795; 95% CI: -1097, -492), October 2020 (-313; 95% CI: -606, -19), and January 2021 (-507; 95% CI: -935, -78). Meanwhile, the number of open gastrectomies remained unchanged, and the number of robot-assisted gastrectomies steadily increased since their coverage by public health insurance in April 2018. CONCLUSIONS: The decreased number of endoscopic resections and laparoscopic surgeries in Japan suggests a decline in early-stage gastric cancer diagnosis, likely due to the suspension of gastric cancer screening and diagnostic testing during the pandemic. Meanwhile, the number of open and robot-assisted gastrectomies remained unchanged and increased, respectively, indicating that these applications were not affected by the pandemic-related medical crisis. These findings highlight that procedures for cancer diagnosis, including screening, should still be provided during pandemics.

Association of hyaluronan and proteoglycan link protein 1 gene with the need of home oxygen therapy in premature Japanese infants with bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) has a lasting effect on the respiratory function of infants, imposing chronic health burdens. BPD is influenced by various prenatal, postnatal, and genetic factors. This study explored the connection between BPD and home oxygen therapy (HOT), and then we examined the association between HOT and a specific single-nucleotide polymorphism (SNP) in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene among premature Japanese infants. MATERIALS AND METHODS: Prenatal and postnatal data from 212 premature infants were collected and analyzed by four SNPs (rs975563, rs10942332, rs179851, and rs4703570) around HAPLN1 using the TaqMan polymerase chain reaction method. The clinical characteristics and genotype frequencies of HAPLN1 were assessed and compared between HOT and non-HOT groups. RESULTS: Individuals with AA/AC genotypes in the rs4703570 SNP exhibited significantly higher HOT rates at discharge than those with CC homozygotes (odds ratio, 1.20, 95% confidence interval, 1.07-1.35, p = .038). A logistic regression analysis determined that CC homozygotes in the rs4703570 SNP did not show a statistically significant independent association with HOT at discharge. CONCLUSIONS: Although our study did not reveal a correlation between HAPLN1 and the onset of BPD, we observed that individuals with CC homozygosity at the rs4703570 SNP exhibit a reduced risk of HOT.

Changes in colorectal cancer treatment during the COVID-19 pandemic in Japan: Interrupted time-series analysis using the National Database of Japan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic forced us to accept changes in our usual diagnostic procedures and treatments for colorectal cancer. This study aimed to determine the impact of the pandemic on colorectal cancer treatment in Japan. METHODS: The number of colorectal surgeries, stoma constructions, stent placements or long tube insertions, and neoadjuvant chemoradiotherapies were determined each month using sampling datasets from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. The observation periods before and during the pandemic were January 2015 to January 2020 and April 2020 to January 2021, respectively. An interrupted time-series analysis was used to estimate the changes in the number of procedures during the pandemic. RESULTS: The number of endoscopic surgeries for colon cancer significantly decreased in April and July 2020 and for rectal cancer in April 2020. Additionally, the number of laparoscopic and open surgeries for colon cancer significantly decreased in July 2020 and October 2020, respectively. The number of stoma constructions and stent placements or long tube insertions did not increase during the observation period. Neoadjuvant chemoradiotherapy for rectal cancer significantly increased in April 2020 but levels returned shortly thereafter. These results suggest that the recommendations to overcome the pandemic proposed by expert committees, including the replacement of laparoscopic surgery with open surgery, stoma construction to avoid anastomotic leak, and replacement of surgery on the ileus with stent placement, were not widely implemented in Japan. However, as an exception, neoadjuvant chemoradiotherapy for rectal cancer was performed as an alternative treatment to delay surgery in small quantities. CONCLUSION: A declining number of surgeries raises concerns about cancer stage progression; however, we found no evidence to suggest cancer progression from the trajectory of the number of stoma constructions and stent placements. In Japan, even during the pandemic, conventional treatments were performed.

Impact of coronavirus disease 2019 pandemic on breast cancer surgery using the National Database of Japan.

Various countries have reported a decrease in breast cancer surgeries during the coronavirus disease 2019 (COVID-19) pandemic; however, inconsistent results have been reported in Japan. This study revealed changes in the number of surgeries during the pandemic using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) from January 2015 to January 2021, where insurance claims data from Japan as a whole are comprehensively accumulated. The number of breast-conserving surgeries (BCS) without axillary lymph node dissection (ALND) significantly decreased in July (- 846; 95% confidence interval (CI) - 1190 to - 502) and October 2020 (- 540; 95% CI - 861 to - 218). No decrease was observed for other types of surgery, BCS with ALND, and mastectomy with or without ALND. In the age-specific subgroup analysis, significant and transient reduction in BCS without ALND was observed in all age groups (0-49, 50-69, and ≥ 70 years). The number of BCS without ALND significantly decreased for a relatively short period in the early pandemic stages, suggesting reduced surgery for patients with a relatively low stage of cancer. Some patients with breast cancer might have been left untreated during the pandemic, and an unfavorable prognosis would be a concern.

Changes in the number of cancer diagnosis practices due to the COVID-19 pandemic: interrupted time-series analysis using the National Database of Japan.

PURPOSE: This study aimed to reveal the impact of coronavirus disease 2019 on the number of practices commonly used for cancer diagnosis in Japan. METHODS: The sampling dataset of the National Database of Japan from January 2015 to January 2021 was used to generate 25-point time-series data for the number of practices (21 points before and 4 points during the pandemic outbreak). The decreased number was estimated by interrupted time-series analysis using a seasonal autoregressive integrated moving average model. Using the pre-pandemic data, expected counterfactual numbers during the pandemic were predicted, and decreased rate was calculated. RESULTS: In most practices, the number dramatically decreased in the early stage of the pandemic and recovered rapidly thereafter. As of April 2020, gastric endoscopy decreased at the top of the practices (- 42.1%, with 95% confidence intervals of - 50.5% and - 33.7%), followed by gastric biopsy (- 38.6%, with 95% confidence intervals of - 46.7% and - 30.6%). The period of declined practices for lung cancer was relatively prolonged. The number of sentinel lymph node biopsies for breast cancer and colposcopies and biopsies for cervical cancer did not decrease in April 2020, but significantly decreased later in July 2020, which is assumed to be the time lapse after the primary testing before surgical treatment or intense scrutiny. CONCLUSION: In general, the number of practices for cancer diagnosis in Japan showed only a temporary decline, which was concordant with reports from several other countries.

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease.

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population.

Coronary artery disease (CAD) including myocardial infarction is one of the leading causes of death in many countries. Similar to other common diseases, its pathogenesis is thought to result from complex interactions among multiple genetic and environmental factors. Recent large-scale genetic association analysis for CAD identified 15 new loci. We examined the reproducibility of these previous association findings with 7990 cases and 6582 controls in a Japanese population. We found a convincing association of rs9319428 in FLT1, encoding fms-related tyrosine kinase 1 (P=5.98 × 10(-8)). Fine mapping using tag single-nucleotide polymorphisms (SNPs) at FLT1 locus revealed that another SNP (rs74412485) showed more profound genetic effect for CAD (P=2.85 × 10(-12)). The SNP, located in intron 1 in FLT1, enhanced the transcriptional level of FLT1. RNA interference experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory adhesion molecules. Expression of FLT1 was observed in endothelial cells of human coronary artery. Our results indicate that the genetically coded increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that might eventually lead to CAD.

SNPs in BRAP associated with risk of myocardial infarction in Asian populations.

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population. Here we identify BRAP (BRCA1-associated protein) as a galectin-2-binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 x 10(-18), OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 x 10(-6), 862 cases and 1,113 controls and P = 4.7 x 10(-3), 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-kappaB, a central mediator of inflammation.

Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients.

Inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis are characterised by chronic transmural, segmental and typically granulomatous inflammation of the gut. Each has a peak age of onset in the second to fourth decades of life and prevalence has been increasing significantly in both Western countries and Japan over the last decade, while their pathogenesis remains largely unknown. Recently, positive association of CD with the variants in interleukin 23 receptor (IL23R), autophagy-related 16-like 1 (ATG16L1) genes and chromosome 5p13.1 locus was reported through genome-wide association studies which are now recognised as a robust tool for the identification of susceptibility genes for complex diseases. To examine an association of reported susceptible variants in the three loci with Japanese CD patients, a total of 484 CD patients and 439 controls were genotyped. No evidence of positive association for any of these loci with CD was found in the Japanese population, even after clinically stratified subgroups of CD were used. Our result revealed a distinct ethnic difference of genetic background of CD that we reported previously in other genes between Japanese and Caucasian populations. Further genetic studies are required to confirm our findings with ethnically divergent populations.

Association analysis of SLC22A4, SLC22A5 and DLG5 in Japanese patients with Crohn disease.

Crohn disease (CD) is an inflammatory bowel disease characterized by chronic transmural, segmental, and typically granulomatous inflammation of the gut. Recently, two novel candidate gene loci associated with CD, SLC22A4 and SLC22A5 on chromosome 5 known as IBD5 and DLG5 on chromosome 10, were identified through association analysis of Caucasian CD patients. We validated these candidate genes in Japanese patients with CD and found a weak but possible association with both SLC22A4 (P=0.028) and DLG5 (P=0.023). However, the reported genetic variants that were indicated to be causative in the Caucasian population were completely absent in or were not associated with Japanese CD patients. These findings imply significant differences in genetic background with CD susceptibility among different ethnic groups and further indicate some difficulty of population-based studies.

CD40 ligand gene and Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis syndrome of infants and young children. Although its etiology is largely unknown, epidemiological findings suggest that genetic factors play a role in the pathogenesis of KD. To identify genetic factors, affected sib-pair analysis has been performed. One of the identified peaks was located on the Xq26 region. A recent report of elevated expression of CD40 ligand (CD40L), which maps to Xq26, during the acute-phase KD, and its relationship to the development of coronary artery lesions (CAL) prompted us to screen for polymorphism of CD40L and to study the association of the gene to KD. A newly identified SNP in intron 4 (IVS4+121 A>G) is marginally over-represented in KD patients as compared to controls (109/602, 18.1 vs 111/737, 15.1%). When male KD patients with CAL were analyzed as a patient group, the SNP was significantly more frequent than in controls (15/58, 25.9%, vs 111/737, 15.1%, OR=2.0, 95% CI=1.07-3.66; P=0.030). Interestingly, this variation was extremely rare in a control Caucasian population (1/145, 0.7%). Our results suggest a role of CD40L in the pathogenesis of CAL and might explain the excess of males affected with KD.