Photodynamic Therapy in Macular Diseases of Asian Populations: When East Meets West

Purpose

We reviewed the indications, safety, and efficacy of photodynamic therapy with verteporfin in various macular diseases and vasculopathies, which are common in Asian populations, and compared the outcomes of photodynamic therapy in Asian patients with the outcomes in Caucasian patients.

Methods

Relevant clinical and laboratory original articles, case reports, and review articles that have been published in the literature between January 1999 and October 2004 were searched in Medline. The potential differences in the response to photodynamic therapy between Asian and Caucasian patients were evaluated. Articles in foreign languages with English abstracts were included.

Results

Macular diseases commonly seen in Asian populations, including choroidal neovascularization (CNV) of age-related macular degeneration, secondary to pathologic myopia or from an idiopathic cause, and choroidal vasculopathies such as central serous chorioretinopathy and polypoidal choroidal vasculopathy were included in the review. The results were tabulated and the differences with Caucasian populations were compared and highlighted.

Conclusion

Photodynamic therapy has been found to be an effective and noninvasive treatment for various subfoveal CNV and choroidal vasculopathies of the macula. Diverse behavior in different ethnic groups is observed. Jpn J Ophthalmol 2006;50:161–169 © Japanese Ophthalmological Society 2006     

γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138⁺ but not CD3⁺ patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFNγ, IL2, and TNFα) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory/central memory subsets and CD8/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.Subject terms: Cancer immunotherapy, Immunotherapy     

A phase I study of myo-inositol for lung cancer chemoprevention.

INTRODUCTION: A phase I, open-label, multiple dose, dose-escalation clinical study was conducted to assess the safety, tolerability, maximum tolerated dose, and potential chemopreventive effect of myo-inositol in smokers with bronchial dysplasia. MATERIALS AND METHODS: Smokers between 40 and 74 years of age with >or= 30 pack-years of smoking history and one or more sites of bronchial dysplasia were enrolled. A dose escalation study ranging from 12 to 30 g/d of myo-inositol for a month was first conducted in 16 subjects to determine the maximum tolerated dose. Ten new subjects were then enrolled to take the maximum tolerated dose for 3 months. The potential chemopreventive effect of myo-inositol was estimated by repeat autofluorescence bronchoscopy and biopsy. RESULTS: The maximum tolerated dose was found to be 18 g/d. Side effects, when present, were mild and mainly gastrointestinal in nature. Using the regression rate of the placebo subjects from a recently completed clinical trial with the same inclusion/exclusion criteria as a comparison, a significant increase in the rate of regression of preexisting dysplastic lesions was observed (91% versus 48%; P = 0.014). A statistically significant reduction in the systolic and diastolic blood pressures by an average of 10 mm Hg was observed after taking 18 g/d of myo-inositol for a month or more. CONCLUSION: myo-Inositol in a daily dose of 18 g p.o. for 3 months is safe and well tolerated. The potential chemopreventive effect as well as other health benefits such as reduction in blood pressure should be investigated further.     

Relationship between Tissue Concentrations of Polycyclic Aromatic Hydrocarbons and DNA Adducts in Green-Lipped Mussels (Perna viridis)

Green-lipped mussels (Perna viridis) were collected from a site in Hong Kong which is relatively free from polycyclic aromatic hydrocarbon (PAH) contamination, and maintained in situ at this and three other sites with different degrees of PAH contamination. The transplanted mussels were retrieved after a 30-day field exposure. DNA adducts in the gill tissues were quantified, and tissue concentrations of benzo[a]pyrene as well as total PAHs (with potential carcinogenicity) determined for individual mussels. Results indicate that (1) tissue concentration of PAHs and adduct levels in mussels collected from a single site can be highly variable; and (2) adduct levels were related to tissue concentrations of benzo[a]pyrene as well as total PAHs of individual animals.     

Epidemiology, prevention, and early detection of breast cancer.

Globally, breast cancer is the third most common form of cancer and the most common among women. The age-adjusted incidence rates of breast cancer are 176% higher in developed than in developing nations. Male breast cancer is rare, but important studies provided risk factor information for comparison with studies of female breast cancer. There has been considerable interest in a possible role of organochlorines and polychlorinated biphenyls in the etiology of breast cancer, but the results of several null studies indicate the likelihood of such associations is extremely remote, providing reassuring news for the public. Prophylactic mastectomy was observed to significantly reduce a woman's chances of developing breast cancer, but it does not lower the risk to zero. Tamoxifen was found to be an effective chemopreventive agent in the Breast Cancer Prevention Trial, but this result was not replicated in two randomized trials in Europe. Striking reductions in the risk for breast cancer were observed for raloxifene in a randomized, placebo-controlled trial that had been designed for the prevention of osteoporosis. A large-scale, randomized trial of tamoxifen-verus-raloxifene among women at increased risk for developing breast cancer is now underway.     

Mandibular invasion in carcinoma of the lower alveolus.

PURPOSE: Efforts to conserve the mandible in resection for oral cancer tend to bring the resection margin progressively closer to the tumor front. This study of the manner of mandibular invasion by carcinoma of the lower alveolus provides added information regarding the behavior of the cancer within the bone. MATERIALS AND METHODS: Twenty-four resected specimens of squamous carcinoma of the lower alveolus were studied with x-rays and step-serial whole-organ histological sections. RESULTS: In 19 of the 21 specimens showing bone invasion, the spread was in the form of a broad front. Insinuation of tumor beyond the tumor front was extensive in 9 of 13 tumors showing deep mandibular invasion. Horizontal subcortical spread took place in 5 of 18 specimens for a distance of up to 1 cm. Perineural spread along the inferior alveolar nerve was found in 4 of 13 specimens in which the tumor extended to the canal; tumor spread along the canal, without neural involvement, was never seen. Preoperative orthopantomogram correctly estimated the extent of mandibular invasion in 16 of 24 patients. CONCLUSIONS: The tumor front of mandibular invasion by carcinoma of the lower alveolus is usually broad. In the absence of deep invasion, which is defined by invasion reaching the alveolar canal, there is little or no insinuation of cancer cells beyond the tumor front, and no spread along the alveolar canal. Marginal mandibulectomy can be applied more widely, taking a margin of 1 cm in all directions.     

Overestimation of Peer Smoking Prevalence Predicts Smoking Initiation Among Primary School Students in Hong Kong

PurposeTo investigate the relationship between perceived prevalence of smoking and smoking initiation among Hong Kong primary second- to fourth-grade-students.MethodsA cohort of 2,171 students was surveyed in 2006 and again in 2008. Students who perceived ever-smoking prevalence in peers as “none” or “some” were considered as correct (reference group), whereas those who perceived it as “half” (overestimation) or “most/all” (gross overestimation) were considered as incorrect.ResultsAt baseline, overestimation was found to be cross-sectionally associated with ever-smoking (p < .01). At follow-up, 7.2% of never-smoking students with incorrect estimation at baseline had started smoking, which was 79% (95% confidence interval: 3%–213%), greater than that of 3.7% for those with correct estimation. Among the never-smoking students with incorrect estimation, subsequent correct estimation was associated with 70% (95% confidence interval: 47%–83%) lower risk of smoking initiation compared with persistent incorrect estimation.ConclusionOverestimation of the prevalence of peer smoking predicted smoking initiation among children. Interventions should be carried out to evaluate whether correcting children's overestimation of peer smoking could reduce smoking initiation.     

Association between p.Leu54Met polymorphism at the paraoxonase-1 gene and plantar fascia thickness in young subjects with type 1 diabetes

OBJECTIVE— In type 1 diabetes, plantar fascia, a collagen-rich tissue, is susceptible to glycation and oxidation. Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme. PON1 polymorphisms have been associated with susceptibility to macro- and microvascular complications. We investigated the relationship between plantar fascia thickness (PFT) and PON1 gene variants, p.Leu54Met, p.Gln192Arg, and c.-107C>T, in type 1 diabetes.RESEARCH DESIGN AND METHODS—This was a cross-sectional study of 331 adolescents with type 1 diabetes (162 male and 169 female). PFT was assessed by ultrasound, PON1 was assessed by genotyping with PCR and restriction fragment–length polymorphism, and serum PON1 activity was assessed by rates of hydrolysis of paraoxon and phenylacetate.RESULTS—Median (interquartile range) age was 15.4 (13.5–17.3) years, and diabetes duration was 7.6 (4.9–10.6) years. The distribution of p.Leu54Met genotypes was LL 135 (40.8%), ML 149 (45%), and MM 47 (14.2%). PFT was abnormal (>1.7 mm) in 159 adolescents (48%). In multivariate analysis, predictors of abnormal PFT were ML/LL versus MM p.Leu54Met polymorphism (odds ratio 3.84 [95% CI 1.49–9.82], P = 0.005); BMI (percentile) (1.02 [1.01–1.03], P = 0.007); systolic blood pressure (percentile) (1.01 [1.00–1.02], P = 0.03); and male sex (3.29 [1.98–5.46], P < 0.001).CONCLUSIONS—Thickening of the plantar aponeurosis occurs predominantly in overweight and male adolescents with type 1 diabetes. The MM genotype at PON1 p.Leu54Met is associated with a reduced risk of abnormal PFT.Paraoxonase-1 (PON1) is a calcium-dependent HDL-associated enzyme that protects LDLs from oxidation. In type 1 diabetic patients, the serum paraoxonase concentration is lower and HDL is a less efficient antioxidant than in healthy individuals (1). Oxidized LDL is implicated in the pathogenesis of atherosclerosis, diabetic retinopathy, and nephropathy (2). Variations in lipoprotein-related enzymes and genotypes may also promote diabetic microvascular damage (3).Soft-tissue thickening is associated with chronic hyperglycemia and is hypothesized to be due to collagen glycation (4). With use of ultrasound techniques to measure plantar aponeurosis, a collagen-rich tissue, researchers demonstrated previously that people with diabetes have increased plantar fascia thickness (PFT) (5). Recently, this group reported that increased PFT predicted the development of microvascular complications in adolescents with type 1 diabetes and proposed abnormal PFT as a putative marker of soft-tissue glycation (6).The PON gene cluster maps to chromosome 7q21-22 and influences gene expression and serum activity. There is an established link between PON1 and macrovascular disease (7) and emerging evidence linking PON1 to microvascular complications (8,9). In this study we investigated whether the variants c.-107C>T at the promoter region and p.Leu54Met and p.Gln192Arg at the coding regions of PON1 are associated with PFT in type 1 diabetes.