Globally, a decreasing incidence of male esophageal squamous cell carcinoma (ESCC) has been observed in recent decades. We evaluated the determinants of esophageal distinct iodine‐unstained lesions ...(DIULs), high‐cancer‐risk lesions and ESCC, among 3858 Japanese alcohol‐dependent men (40‐79 years) who underwent chromoendoscopic screening between 2003 and 2018. The initial screening detected DIULs ≥ 5 mm in 541 patients (dysplasia in 319 and SCC in 129) and multiple DIULs in 640. The detection rates for DIULs and chronic atrophic gastritis (CAG), pack‐years, and the mean corpuscular volume (MCV) decreased over the course of the study period, while the detection of hiatal hernia and/or columnar‐lined esophagus (HH/CLE) and the carriers of inactive heterozygous aldehyde dehydrogenase‐2 (ALDH2, rs671) increased. Multiple logistic regression analyses showed that an older age, larger number of pack‐years, smaller body mass index, larger MCV, presence of a slow‐metabolizing alcohol dehydrogenase‐1B genotype (rs1229984), presence of an inactive heterozygous ALDH2 genotype, and more advanced degree of CAG increased the odds ratios (ORs) for DIULs, while the 2008‐2013 and 2014‐2018 screening periods had lower ORs for DIULs than the 2003‐2007 screening period. The presence of HH/CLE decreased the OR for multiple DIULs and was associated with a more proximal location of ESCC. In conclusion, the detection of DIULs in an alcohol‐dependent population decreased between 2003 and 2018. In addition to reported determinants of ESCC, CAG and HH/CLE were associated with the risk of DIULs. Enigmatically, however, the decline in the detection of DIULs was not adequately explained by these factors and warrants further research.
The detection of large or multiple esophageal iodine‐unstained lesions including cancer decreased between 2003 and 2018 in an alcohol‐dependent population. In addition to reported determinants of esophageal cancer, chronic atrophic gastritis and hiatal hernia/columnar‐lined esophagus were associated with the risk of these lesions. Enigmatically, however, the declining trend in these lesions was not adequately explained by these factors and warrants further research.
Objective The risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing and aldehyde dehydrogenase-2 (ALDH2, rs671) and alcohol ...dehydrogenase-1B (ADH1B, rs1229984) genotypes, all of which are known to determine AD susceptibility in Asians. Previous studies have focused on men, since women account for a smaller proportion of AD subjects. Methods Case control studies were conducted between 3721 male and 335 female AD Japanese and 610 male and 406 female controls who were asked about their current or former tendency to experience facial flushing after drinking a glass of beer and underwent ALDH2 and ADH1B genotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated. Results Current alcohol flushing, the inactive ALDH2*1/*2 genotype, and the fast-metabolizing ADH1B*2 allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by the ALDH2 and ADH1B genotypes, multiple logistic model showed that never or former flushing and the genotype combinations were independent strong risk factors of AD in men and women. Never or former flushing (vs. current flushing) markedly increased the odds ratios of AD in carriers of each of the ALDH2 and ADH1B genotype combinations. The temporal profiles for drinking and flushing in former-flushing AD subjects revealed that the flushing response disappeared soon after or before the start of habitual drinking during young adulthood, regardless of the ALDH2 genotype. Conclusion Although alcohol flushing is influenced by the ALDH2 and ADH1B genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and the ALDH2 and ADH1B genotypes can provide a better new strategy for AD risk assessment than the alcohol flushing status alone or the genotypes alone in Asian men and women.
Abstract
Background
Second primary head and neck cancers after endoscopic resection of esophageal squamous cell carcinoma adversely affect patients’ outcomes and the quality of life; however, an ...adequate surveillance schedule remains unclear.
Methods
We analyzed 330 patients with early esophageal squamous cell carcinoma who underwent endoscopic resection and were registered in the multicenter cohort study to evaluate adequate surveillance for detection of second primary head and neck cancers. Gastrointestinal endoscopists examined the head and neck regions after 3–6 months of endoscopic resection for esophageal squamous cell carcinoma and subsequently every 6 months. An otolaryngologist also examined the head and neck regions at the time of endoscopic resection for esophageal squamous cell carcinoma and at 12 months intervals thereafter.
Results
During the median follow-up period of 49.4 months (1.3–81.2 months), 33 second primary head and neck cancers were newly detected in 20 patients (6%). The tumor site was as follows: 22 lesions in the hypopharynx, eight lesions in the oropharynx, two lesions in larynx and one lesion in the oral cavity. The 2-year cumulative incidence rate of second primary head and neck cancers was 3.7%. Among them, 17 patients with 29 lesions were treated by transoral surgery. One patient with two synchronous lesions was treated by radiotherapy. Two lesions in two patients were not detected after biopsy. All patients were cured with preserved laryngeal function.
Conclusions
Surveillance by gastrointestinal endoscopy every 6 months and surveillance by an otolaryngologist every 12 months could detect second primary head and neck cancers at an early stage, thereby facilitating minimally invasive treatment.
Background & Aims Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this ...process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. Methods We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol-voiding lesions: A, no lesion; B, 1–9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. Results Over the 2-year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C ( P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C ( P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C ( P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25–0.91; P = .025), whereas smoking abstinence did not. Conclusions Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466.
Nogo receptor-1 (NgR1) and its ligands inhibit neuronal plasticity and limit functional recovery after brain damage such as ischemic stroke. We have previously shown that lateral olfactory tract ...usher substance (LOTUS) antagonizes NgR1-mediated signaling. Here, we investigated whether LOTUS enhances neuronal plasticity and functional recovery after brain focal ischemia in adult mice. Focal ischemic infarcts were induced in wild-type and LOTUS-overexpressing transgenic mice via middle cerebral artery occlusion. Endogenous LOTUS expression was increased in brain and cervical spinal cord of the contralateral side of ischemia in the chronic phase after brain ischemia. LOTUS overexpression accelerated midline-crossing axonal sprouting from the contralateral side to the ipsilateral side of ischemia in the medullar reticular formation and gray matter of denervated cervical spinal cord. Importantly, LOTUS overexpression improved neurological score highly correlated with laterality ratio of corticoreticular fibers of the medulla oblongata, indicating that LOTUS overexpression may overcome the inhibitory environment induced by NgR1 signaling for damaged motor pathway reconstruction after ischemic stroke. Thus, our data suggest that LOTUS overexpression accelerates neuronal plasticity in the brainstem and cervical spinal cord after stroke and LOTUS administration is useful for future therapeutic strategies.
In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 ...patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio HR, 0.38; 95% confidence interval CI, 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients (www.clinicaltrials.gov; NCT00949650).
In subgroup analyses of LUX‐Lung 3, afatinib significantly improved progression‐free survival versus cisplatin/pemetrexed in Japanese patients with EGFR mutation‐positive lung adenocarcinoma. Overall survival was significantly improved with afatinib in Japanese patients with Del19 mutation, while overall survival in Japanese patients with L858R mutation was similar between treatment arms.
Philip Brooks and colleagues discuss evidence linking the alcohol flushing response (predominantly due to ALDH2 deficiency) with a much higher risk of esophageal cancer from alcohol consumption.
The presence of large or multiple esophageal distinct iodine-unstained lesions (DIULs) is a strong predictor of field cancerization in the upper aerodigestive tract. Several risk factors for DIULs, ...including genetic polymorphisms of alcohol and aldehyde dehydrogenases (ADH1B, rs1229984; ALDH2, rs671), have been demonstrated in Japanese alcohol-dependent men. However, few evaluations of alcohol-dependent women have been conducted in this field.
Using multiple logistic regression models, we investigated the results of screening using esophageal iodine staining and the identification of determinants for esophageal DIULs in 472 Japanese alcohol-dependent women.
DIULs ≥5 mm, multiple DILUs, and both characteristics were observed in 35 (7.4%), 31 (6.6%), and 16 (3.4%) patients, respectively. DIULs ≥5 mm were histologically diagnosed as low-grade intraepithelial neoplasia in 26 patients and superficial squamous cell carcinoma in 9 patients. Although the inactive heterozygous ALDH2*1/*2 genotype was more common (33.3% vs. 11.4%, p = 0.002) in the group with DIULs ≥5 mm than in the group without DIULs ≥5 mm, no significant differences in the results of a questionnaire asking about current and past facial flushing after a glass of beer were seen between the groups with and without DIULs ≥5 mm. When individuals with current or former flushing were assumed to have inactive ALDH2, the sensitivity and specificity of current or former flushing to identify the presence of inactive ALDH2 were 50.0% and 93.5%, respectively; these values were previously reported to be 88% and 92%, respectively, in a Japanese general female population. The low sensitivity in the present study suggests that a lack of alcohol flushing may play a crucial role in the development of alcohol dependence in women with inactive ALDH2. No significant differences in age, usual alcohol consumption, or smoking habits were observed according to ADH1B and ALDH2 genotypes. Multiple logistic regression analyses showed that the slow-metabolizing ADH1B*1/*1 genotype (odds ratio 95% confidence interval, 12.5 4.82-32.4 and 9.89 3.50-27.9), the inactive heterozygous ALDH2*1/*2 genotype (2.94 1.18-7.38 and 3.79 1.40-10.3), a lower body mass index per -1 kg/m2 (1.17 1.02-1.35 and 1.38 1.14-1.67), and a mean corpuscular volume ≥106 fl (3.70 1.56-8.81 and 3.27 1.24-8.64) increased the risk of DIULs ≥5 mm and multiple DIULs, respectively. The combination of ADH1B*1/*1 and ALDH2*1/*2 markedly increased the risk of esophageal DIULs ≥5 mm (39.3 10.6-146).
Japanese alcohol-dependent women shared several common risk factors for esophageal squamous cell neoplasia with alcohol-dependent men, but with considerably different magnitudes.
Mycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect ...evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.
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