De novo Hepatitis B Virus Reactivation During Treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in a Patient with Advanced Lung Cancer: A Case Report.

A 71-year-old woman was treated with osimertinib for stage IV adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Treatment led to improvements in the primary tumor, multiple lung metastases, and multiple bone metastases. However, nine months later, she presented with marked liver dysfunction and jaundice. Chest and abdominal computed tomography did not show abnormal findings in the liver parenchyma or biliary system. However, blood tests were positive for hepatitis B surface antigen and hepatitis B virus DNA, suggesting hepatitis B virus reactivation. The patient died of liver failure despite treatment with steroids and antiviral drugs.

Radical Resection for Second EGFR-mutated Primary Lung Cancer Following Immune Checkpoint Inhibitor Monotherapy for Stage IV Lung Adenocarcinoma.

A 78-year-old woman with multiple lung nodules, epithelial growth factor receptor (EGFR) exon 20 insertion mutations, and diagnosed with advanced lung adenocarcinoma (cT4N3M1a, stage IVA), was referred to our hospital. She received immune checkpoint inhibitor (ICI) therapy. The therapy showed remarkable antitumor effects; only a single nodule remained in the right upper lobe. The nodule was diagnosed as adenocarcinoma through a biopsy. We subsequently performed right upper lobectomy for multiple primary lung cancer (MPLC). The surgical specimen contained EGFR exon 19 deletion mutations and not exon 20 insertion mutations.

Possible Pseudo-progression of Non-small Cell Lung Carcinoma in a Patient With Clinical Hyper-progression Associated With Trousseau Syndrome Who Was Treated With Pembrolizumab: A Case Report.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have recently been shown to have clinical benefits in patients with advanced non-small cell lung cancer (NSCLC). The novel tumour responses to these agents are changing the management of patients with cancer. Pseudo-progression of disease (pseudo-PD), that is, an initial flare followed by shrinkage of the tumour, has been described as a distinctive response to ICIs. However, pseudo-PD manifest initial progression and is difficult to segregate with hyper progressive disease (HPD). We, therefore, analysed a case with pseudo-PD histologically. PATIENTS AND METHODS: A 68-year-old Japanese man with stage IV non-small cell lung carcinoma (NSCLC) was treated by anti-PD-1 antibody (pembrolizumab). Four weeks later after second time treatment with pembrolizumab, the patient showed severe melena followed by Trousseau syndrome and died at day 174 after first treatment by pembrolizumab, suggesting HPD clinically. Primary lesion and metastatic lesions were analysed histologically. RESULTS: Histological analysis revealed that NSCLC cells expressed PD-L1, and CD8+ tumor-infiltrated lymphocytes (TILs) were observed. CD8+ TILs showed higher rates of PD-1 indicating that lesions were of the inflamed type and the case was pseudo-PD. Furthermore, it was found that cancer cells expressed MUC1. CONCLUSION: The clinical appearance of the case was aggressive after treatment by pembrolizumab, and the case seemed to be HPD; however, histological analysis revealed that the case was likely pseudo-PD. Therefore, careful histological evaluation is important when investigating the clinical response to an ICI and mucin expression might be a predictive marker for Trousseau syndrome.

Resected thymic large cell neuroendocrine carcinoma: report of a case.

BACKGROUND: Thymic large cell neuroendocrine carcinoma (LCNEC) is extremely rare. The detailed clinical features of thymic LNCECs remain unknown. CASE PRESENTATION: A 90-year-old man with a history of diabetes mellitus, chronic renal failure, and an abdominal aortic aneurysm underwent computed tomography for follow-up, which showed an anterior mediastinal tumor, measuring 31 mm × 28 mm in diameter. Magnetic resonance imaging showed an iso-intensity mass on T1-weighted images and high intensity on T2-weighted images. 18F-Fluorodeoxyglucose-positron emission tomography showed marked uptake in the mass, which was diagnosed as invasive thymoma or thymic carcinoma. Video-assisted thoracic surgery through the left thoracic cavity was converted to median sternotomy due to severe adhesions between the left lung and the chest wall. Partial thymectomy and combined partial resection of left upper lobectomy and the first and the second costal cartilages were performed. The pathologic diagnosis was thymic LCNEC, Masaoka stage III. The patient developed pleural dissemination and left lung metastases in 5 months and died 12 months after surgery. CONCLUSIONS: Thymic LCNEC has high malignant potential. More cases need to be studied.

Whole genome analysis of a multidrug-resistant Streptococcus pneumoniae isolate from a patient with invasive pneumococcal infection developing disseminated intravascular coagulation.

Multidrug-resistant Streptococcus pneumoniae strains were isolated from blood and sputum of a patient with disseminated intravascular coagulation in Sapporo city, Japan. These antibiograms were only susceptible to vancomycin, linezolid, daptomycin, some carbapenems, and some fluoroquinolones. Identical antibiograms, serotypes (19F), and sequence types (ST10017) suggested a shared origin of these isolates. Only one ST10017 strain has been isolated in the same city in Japan previously (2014), and the 2014 isolate is still susceptible to macrolides. The whole genome of the blood-derived isolate was sequenced. The strain harbored resistance mutations in parC, gyrA, pbp1a, pbp2a, pbp2b, and pbp2x, and harbored the resistance genes, ermB and tetM. The nucleotide sequences of parC and pbp2x genes of strain MDRSPN001 were clearly different from those of other S. pneumoniae strains and were similar to those of oral streptococci strains. These findings suggest that strain MDRSPN001 has been rapidly and drastically evolving multidrug resistance by gene replacement and accumulation of genes originating from other strains, such as oral streptococci, Streptococcus mitis.

Complete Genome Sequence of Multidrug-Resistant Streptococcus pneumoniae Serotype 19F Isolated from an Invasive Infection in Sapporo, Japan.

Invasive infection of multidrug-resistant Streptococcus pneumoniae is a serious clinical concern. Here, we report the complete genome sequence of a multidrug-resistant S. pneumoniae serotype 19F strain isolated from a patient with an invasive infection in Sapporo, Japan.

Conducting Online Behavioral Research Using Crowdsourcing Services in Japan.

Recent research on human behavior has often collected empirical data from the online labor market, through a process known as crowdsourcing. As well as the United States and the major European countries, there are several crowdsourcing services in Japan. For research purpose, Amazon's Mechanical Turk (MTurk) is the widely used platform among those services. Previous validation studies have shown many commonalities between MTurk workers and participants from traditional samples based on not only personality but also performance on reasoning tasks. The present study aims to extend these findings to non-MTurk (i.e., Japanese) crowdsourcing samples in which workers have different ethnic backgrounds from those of MTurk. We conducted three surveys (N = 426, 453, 167, respectively) designed to compare Japanese crowdsourcing workers and university students in terms of their demographics, personality traits, reasoning skills, and attention to instructions. The results generally align with previous studies and suggest that non-MTurk participants are also eligible for behavioral research. Furthermore, small screen devices are found to impair participants' attention to instructions. Several recommendations concerning this sample are presented.

Multiple myeloma emerging after prolonged gefitinib treatment for non-small cell lung carcinoma.

The coexistence of lung cancer and multiple myeloma (MM) is rare. A search of the English literature revealed only 5 case reports to date. We describe a case of MM that presented in a 78-year-old lung cancer patient after 20 months of treatment with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor. We also review previously reported cases of concurrent development of lung cancer and MM.

Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in the south of Thailand and identification of a novel variant (G6PD Songklanagarind).

Two hundred and twenty-five G6PD-deficient subjects in Songklanagarind Hospital in the south of Thailand comprising 210 males and 15 females were studied. Neonatal jaundice was detected in 85% of these patients. Acute hemolysis related to infection was detected in 17.3% of the G6PD-deficient subjects. Drug-induced acute hemolysis was detected in 1.8% and favism was observed in 3.6% of G6PD-deficient patients. The molecular analysis was performed on 134 G6PD-deficient individuals by a combination of PCR-RFLP, multiplex polymerase chain reaction by multiple tandem forward primers and a common reverse primer assay (MPTP) and DNA sequencing to characterize the mutations of the samples with abnormal MPTP bands. We found 10 different missense G6PD mutations and the three most common variants were G6PD Viangchan 871,G-->A (31.3%), G6PD Kaiping 1388,G-->A (20.1%) and G6PD Mahidol 487,G-->A (17.2%) followed by G6PD Canton 1376,G-->T (9.7%), G6PD Union 1360,C-->T (2.2%), G6PD Gaohe 95,A-->G (1.5%), G6PD Quing Yuan 392,G-->T (0.7%), G6PD Mediterranean 563,C-->T (0.7%), G6PD Songklanagarind 196,T-->A (0.7%), silent mutation 1311,C-->T (6.7%), and uncharacterized variant (9%). A novel missense mutation at codon 196, TTC-->ATC in exon 4 of the G6PD gene predicting a single amino acid substitution, Phe66Ile was identified and we designated this novel class II variant as G6PD Songklanagarind. The G6PD variants among the Thais in the southern part are heterogeneous and G6PD Viangchan, Kaiping, Mahidol, and Canton variants account for about 78% of the cases. Our findings provide some evidence that G6PD Viangchan and Mahidol are common Southeast Asian variants and support the theory of genetic drifts throughout Southeast Asia.

C677T mutation in the MTHFR gene was not found in patients with frontoethmoidal encephalocele in East Java, Indonesia.

BACKGROUND: Frontoethmoidal encephalocele (FEE) is a neural tube defect (NTD) characterized by a congenital bone defect in the anterior cranium and herniation of the intracranial mass through the defect. The C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) has been reported as a genetic risk factor for spina bifida. However, the role of the MTHFR in the pathogenesis of FEE remains to be clarified. METHODS: A hospital-based survey of FEE patients who were referred to the Department of Neurosurgery and Plastic Surgery, Malang General Hospital, East Java, Indonesia was conducted. Genetic screening of MTHFR substitutions in 13 patients and eight mothers from 11 affected families were performed using a combination of polymerase chain reaction (PCR), denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. RESULTS: In total, 130 patients with FEE among 138 NTD patients (94.2%) were identified. The ratios of cranial encephalomeningocele to spinal meningocele (32 : 1) and of FEE to occipital encephalomeningocele (32 : 1) were higher than those in other populations. Five substitutions were detected in the MTHFR: C121T, C677T, C1060T, A1298C, and G1793A. No significant differences were found in the frequency of each nucleotide substitution between patients or mothers and controls. In addition, none of the subjects in this study were homozygous for T at nucleotide position 677. CONCLUSION: FEE is the most common form of NTD in East Java, Indonesia. Genetic analysis of 11 affected families suggests that the MTHFR gene is not associated with the development of FEE, although the number of FEE families analyzed in this study was very limited.

High prevalence of Southeast Asian ovalocytosis in Malays with distal renal tubular acidosis.

Southeast Asian ovalocytosis (SAO) is a red blood cell abnormality common in malaria-endemic regions and caused by a 27 nt deletion of the band 3 protein gene. Since band 3 protein, also known as anion exchanger 1, is expressed in renal distal tubules, the incidence of SAO was examined in distal renal tubular acidosis (dRTA) in Malays in Kelantan, Malaysia. Twenty-two patients with dRTA and 50 healthy volunteers were examined for complication of SAO by both morphological and genetic analyses. SAO was identified in 18 of the 22 dRTA patients (81.8%), but only two of the 50 controls (4%). The incidence of SAO was significantly high in those with dRTA (p<0.001), indicating a dysfunctional role for band 3 protein/anion exchanger 1 in the development of dRTA.

Screening for glucose-6-phosphate dehydrogenase deficiency using a modified formazan method: a pilot study on Filipino male newborns.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency has increased prevalence rates in tropical Africa, tropical and subtropical Asia and some parts of the Mediterranean. Earlier studies on G6PD deficiency in the Philippines have shown prevalence rates of 4.5% to 25.7%. METHODS: In the present study, 3278 male newborns were screened for G6PD deficiency using the modified formazan method, a simple screening procedure affordable in the setting of a developing country. Subjects with positive screening results were recalled for confirmatory testing using a commercial assay kit for quantitative enzyme determination. RESULTS: Of the 3278 boys studied, 186 revealed positive screening results. Of the 186, 65 boys had confirmatory testing. Of these 65 boys, 45 were confirmed to have G6PD deficiency and 20 had normal results. This study reveals an incidence of G6PD deficiency of 3.9% among male Filipinos. CONCLUSIONS: This study recommends the inclusion of G6PD deficiency in the panel of disorders for newborn screening among Filipino newborns.

Glucose-6-phosphate dehydrogenase deficiency: molecular heterogeneity in southeast Asian countries.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in malaria endemic regions and is estimated to affect more than 400 million people worldwide. Deficient subjects are mostly asymptomatic but clinical manifestations range from neonatal jaundice due to acute hemolytic anemia to chronic non-spherocytic hemolytic anemia. To date, biochemical parameters allowed more than 400 different G6PD variants to be distinguished thereby suggesting a vast genetic heterogeneity. So far, only a small portion of this heterogeneity has been confirmed at the DNA level with the identification of about 90 different point mutations in the G6PD coding sequence. To determine the molecular background of G6PD deficiency in Southeast Asian countries, we conducted molecular analyses of G6PD patients from the Philippines, Malaysia, Singapore, Vietnam and Indonesia. The most prevalent mutation identified differs from country to country, thus suggesting independent mutational events of the G6PD gene.

Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Malays in Malaysia.

Multiplex polymerase chain reaction (PCR) using multiple tandem forward primers and a common reverse primer (MPTP) was recently established as a comprehensive screening method for mutations in X-linked recessive diseases. In the work reported here, MPTP was used to scan for mutations of the glucose-6-phosphate dehydrogenase (G6PD) gene. Mutations in exons 3,4,5,6,7,9, 11, and 12 of the G6PD gene were screened by MPTP in 93 unrelated Malaysian patients with G6PD deficiency. Of the 93 patients, 80 (86%) had identified mutations. Although all of these were missense mutations, identified nucleotide changes were heterogeneous, with 9 mutations involving various parts of the exons. These 9 mutations were G-to-A nucleotide changes at nucleotide 871 of the G6PD gene (G871A), corresponding to G6PD Viangchan, G6PD Mediterranean (C563T), G6PD Vanua Lava (T383C), G6PD Coimbra (C592T), G6PD Kaiping (G1388A), G6PD Orissa (C131G), G6PD Mahidol (G487A), G6PD Canton (G1376T), and G6PD Chatham (G1003A). Our results document heterogeneous mutations of the G6PD gene in the Malaysian population.