Should Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Be Continued beyond Progressive Disease?

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is almost exclusively effective in patients with activating EGFR mutations, and median time to progression in such patients is generally up to 12 months. Usually, treatment with EGFR-TKI is terminated when disease progression is confirmed; however, acute exacerbation after the withdrawal of EGFR-TKI has been reported. In this paper, we report a case of a 35-year-old patient whose disease rapidly progressed after discontinuation of gefitinib and then rapidly regressed after reintroduction of gefitinib. In addition, we summarize the cases of 3 other patients who could be safely treated with continued erlotinib in combination with pemetrexed after disease progression. Currently, the mechanism of acquired resistance is intensively investigated and a number of new agents, such as irreversible EGFR inhibitors or MET inhibitors, are under development; however, they are still unavailable in clinical setting. We believe that continuing EGFR-TKI treatment after disease progression should be an option in patients who previously responded to EGFR-TKI under the present circumstances

Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer

Background: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. Methods: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). Results: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1–25 months). In particular, the group with a good postoperative performance status score (0–2) was shown to have a better median postoperative survival of 13 months. Conclusions: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor

Quantification of (–)-Epigallocatechin-3-gallate Inhibition of Anaplastic Thyroid Cancer Cell Line Adhesion and Proliferation Using Real-time Cell Analysis

Anaplastic thyroid cancer (ATC) has a poor prognosis because of immediate metastasis. Several studies in humans and animals have suggested that the ingestion of green tea or its active ingredient (–)-epigallocatechin-3-gallate (EGCG) may decrease the risk of cancer. Using a recently developed real-time cell analysis (RTCA) system, we have shown previously that EGCG inhibits cell migration and the invasion of oral cavity cancers by suppressing matrix metalloproteinases. In the present study we used RTCA to investigate the effects of EGCG on cell adhesion to fibronectin-coated plates using three cancer cell lines: one ATC cell line (TCO-1) and two poorly differentiated oral squamous cell carcinomas (OSCCs) cell lines (SAS and HO-1-u-1; originating from the tongue and floor of the mouth, respectively). EGCG (50µM) inhibited the adhesion of all three cell lines. In addition to its effects on cell adhesion, 50µM EGCG inhibited the cell proliferation of TCO-1 cells. Furthermore, EGCG decreased αV integrin (ITGAV) mRNA levels in all three cell lines, suggesting that EGCG inhibits the cell adhesion and proliferation of OSCC and ATC cells via suppression of integrin expression. Therefore, EGCG represents a useful dietary constituent or a lead compound for counteracting metastasis of oral cavity cancers and thyroid cancers

Validation of the Burden Index of Caregivers (BIC), a multidimensional short care burden scale from Japan

BACKGROUND: We constructed a concise multidimensional care burden scale that reflects circumstances unique to Japan, with a focus on intractable neurological diseases. We surveyed 646 family caregivers of patients with intractable neurological diseases or stroke using 28 preliminary care burden scale items obtained from qualitative research. The results were used to finalize the feeling of care burden scale (BIC: burden index of caregivers), and verify its reliability and validity. METHODS: The survey was conducted among caregivers providing home health care to patients with intractable neurological diseases (PD [Parkinson's disease], SCD [spinocerebellar degeneration], MSA [multiple system atrophy], and ALS [amyotrophic lateral sclerosis]) or CVA (cerebrovascular accident) using a mailed, self-administered questionnaire between November, 2003 and May, 2004. RESULTS: Response rates for neurological and CVA caregivers were 50% and 67%, respectively, or 646 in total (PD, 279; SCD, 78; MSA, 39; ALS, 30; and CVA, 220). Item and exploratory factor analyses led to a reduction to 11 items, comprising 10 items from the 5 domains of time-dependent burden, emotional burden, existential burden, physical burden, and service-related burden; and 1 item on total burden. Examination of validity showed a moderate correlation between each domain of the BIC and the SF-8 (Health related quality of life scale, Short Form-8), while the correlation coefficient of the overall BIC and CES-D was 0.62. Correlation between the BIC and ZBI, a preexisting care burden scale, was high (r = 0.84), while that with the time spent on providing care was 0.47. The ICC (Intraclass correlation coefficient) by test-retest reliability was 0.83, and 0.68 to 0.80 by individual domain. CONCLUSION: These results show that the BIC, a new care burden scale comprising 11 items, is highly reliable and valid

Design and baseline characteristics of a prospective cohort study for determinants of osteoporotic fracture in community-dwelling elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and osteoporotic fracture in men are significant public health problems in an aging society. However, information on male osteoporosis remains impressively lacking, especially for Asians. We designed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study as an ancillary study of a cohort study, the Fujiwara-kyo study, to determine risk factors for osteoporotic fractures in Japanese men.</p> <p>Methods/Design</p> <p><it><b>Design</b></it>: A community-based single-centre prospective cohort study with at least a 5-year follow-up</p> <p><it><b>Subjects</b></it>: All the male participants of the Fujiwara-kyo study who were living in the four cities studied, aged 65 years and older, and able to walk without aid from others.</p> <p><it><b>Primary outcome</b></it>: Incidence of osteoporotic fractures including vertebral and clinical non-vertebral fractures.</p> <p><it><b>Additional outcomes</b></it>: Change in bone mineral density (BMD), change in hip geometry, onset of receiving benefits from Long-term Care Insurance (LCI), health-related quality of life, and mortality.</p> <p><it><b>Baseline measurements</b></it>: BMD at the lumbar spine (LS) and hip (TH), hip geometry, vertebral deformity assessment, bone turnover markers, physical and cognitive performance, various medical and lifestyle factors, and geriatric psychosocial measures confirmed by interviews based on self-administrated questionnaires.</p> <p><it><b>Outcome surveillance</b></it>: Annual mail surveys and a follow-up survey at the fifth year comprising similar items to the baseline study will be used to determine the outcomes. Receipt of benefits from LCI and mortality will be obtained from the city governments.</p> <p><it><b>Current status</b></it>: The baseline study was conducted for 2174 eligible men, and 2012 completed the study and were eligible for follow-up. Prevalence rates of osteoporosis (BMD 2.5 SD or more below the young adult mean (YAM)) and low BMD (BMD 1 SD or more below YAM) in at least one of LS and TH were calculated to be 4.4% and 41.8%, respectively. The proportion of men with low BMD only at TH showed a significant increasing trend with aging (p < 0.0001) while that only at LS showed a decreasing trend (p = 0.0386). The prevalence rate of osteoporosis was underestimated when diagnosed using only BMD at LS. Other baseline measurements were successfully obtained.</p> <p>Discussion</p> <p>FORMEN baseline study was performed as designed and the FORMEN cohort study was successfully launched.</p

A Connexin40 Mutation Associated With a Malignant Variant of Progressive Familial Heart Block Type I

Background-Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation. Methods and Results-We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2 ± 1.7 nS, n=14; Cx40-Q58L, 0.56 ± 0.34 nS, n=14; P <0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ̃ 50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques. Conclusions-Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Planar Catechin Conjugated with DTPA as a Promising Antioxidant Triggered by Fe3+ Coordination

The main effects mediated by reactive oxygen species (ROS) relate to its potential to cause oxidative damage in cells and tissues. Therefore, a ROS burst contributes to cellular dysfunction and can cause a wide range of chronic diseases. Polyphenol, such as catechin and resveratrol, is capable of scavenging ROS, resulting in the prevention of oxidative stress related diseases. In this study, planar catechin (PCat), in which the geometry of catechin is constrained to be planar, was conjugated to metal cheater, DTPA. the antioxidative activity of the compound (PCat-DTPA) was evaluated in terms of the capacity to scavenge 2,2-diphenhydramine-1-picrylhydrazyl (DPPH) radical as an oxyl radical species. The compound (PCat-DTPA) showed weak antioxidative activity compared to the planar catechin due to intramolecular hydrogen bonding between DTPA with catechol moiety of the catechin structure. Alternatively, in the presence of Fe(3+), the antioxidative activity of PCat-DTPA greatly increased 345-fold, which was 3-fold compared to that of PCat. The strong antioxidative activity of PCat-DTPA in the presence of Fe(3+) was also shown by the Fenton system and hypoxanthin-xanthin oxidase system. The enhanced radical-scavenging activity of PCat-DTPA compared to PCat suggested that the reduction of the DPPH radical with PCat-DTPA accelerated by Fe(3+) mediated electron transfer. Transition metal ions, which have an ability to produce ROS by redox cycle, demonstrate the role of positive oxidative stress in age-related diseases. However, PCat-DTPA exhibits more potent antioxidative activity by coordinating with Fe(3+). Therefore, the compound is a promising seed for the new antioxidant for the treatment of the oxidative stress-related diseases.ACS Fall 2019 National Meeting & Exp