Toxicity profile of bevacizumab in the UK Neurofibromatosis type 2 cohort

Bevacizumab is considered an established part of the treatment strategies available for schwannomas in patients with Neurofibromatosis type 2 (NF2). In the UK, it is available through NHS National Specialized Commissioning to NF2 patients with a rapidly growing target schwannoma. Regrowth of the tumour on suspension of treatment is often observed resulting in prolonged periods of exposure to bevacizumab to control the disease. Hypertension and proteinuria are common events with bevacizumab use and there are concerns with regards to the long-term risks of prolonged treatment. Dosing, demographic and adverse event (CTCAE 4.03) data from the UK NF2 bevacizumab cohort are reviewed with particular consideration of renal and cardiovascular complications. Eighty patients (48 male:32 female), median age 24.5 years (range 11–66 years), were followed for a median of 32.7 months (range 12.0–60.2 months). The most common adverse events were fatigue, hypertension and infection. A total of 19/80 patients (24?%) had either a grade 2 or grade 3 hypertension event and 14/80 patients (17.5?%) had proteinuria. Of 36 patients followed for 36 months, 78?% were free from hypertension and 86?% were free of proteinuria. Logistic regression modeling identified age and induction dosing regime to be independent predictors of development of hypertension with dose of 7.5 mg/kg 3 weekly and age >30years having higher rates of hypertension. Proteinuria persisted in one of three patients after cessation of bevacizumab. One patient developed congestive heart failure and the details of this case are described. Further work is needed to determine optimal dosing regimes to limit toxicity without impacting on efficacy.     

TP53 codon 72 polymorphism and breast cancer risk in Bangladeshi population

Background

Breast cancer, a hereditary or heterogeneous sporadic disease, is the most common cancer in women worldwide. The tumor suppressor TP53 gene has been found to be the most commonly mutated genes in many types of human cancers, including breast cancer. This study aimed to investigate the association of codon 72 polymorphism of TP53 gene with breast cancer risk in Bangladeshi females.

Methods

The study included 125 cases and 125 healthy controls. Genotyping and polymorphism were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis.

Results

The frequencies of the three genotypes Arg/Arg, Arg/Pro, and Pro/Pro were 43.2, 33.6, and 23.2% in cases, whereas 48.8, 40.8, and 10.4% in controls, respectively. The frequency of mutant homozygous (Pro/Pro) genotype was significantly increased in breast cancer patients as compared with controls (23.2 vs 10.4%), and showed 2.52-fold significantly increased risk for breast cancer (OR 2.5199, 95% CI 1.19–5.33, p = 0.0157). The frequencies of Pro/Pro genotype were significantly higher in breast cancer cases with non-breast feeding status. Pro allele frequency was found to be significantly increased in breast cancer cases (OR 1.4978, 95% CI 1.0357–2.1662, p = 0.0318).

Conclusions

Our data suggest that mutant (Pro/Pro) homozygosity at codon 72 of TP53 gene is significantly associated with breast cancer susceptibility in Bangladeshi women. In addition, this association was significantly related to lactating status.

     

Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C

AIM To determine whether hepatitis C virus(HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients. METHODS One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein(Big Dye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28 B gene rs12979860(Custom TaqM an 5' allelic discrimination assay; Applied Biosystems).RESULTS Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response(SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70(R70Q/H) or/and position 91(L91M). The favorable IL28 B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age(P 0.001), urban residence(P = 0.004), IL28 B CC genotype(P 0.001), absence of core mutations(P = 0.005), achievement of rapid virologic response(P 0.001) and early virological response(P 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age(P 0.001), absence of core substitutions(P = 0.04) and IL28 B CC genotype(P 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%. CONCLUSION HCV core mutations can help distinguish between patients who can still benefit from the affordable IFNbased therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.     

Factor XIIIA subunit deficiency due to a homozygous 13-base pair deletion in exon 3 of the A subunit gene

We investigated the molecular basis of factor XIII_A subunit deficiency in a Greek family. Each of the 15 exons of the A subunit gene were individually amplified by polymerase chain reaction, using previously reported oligoprimers. The proband with severe deficiency was found to have a homozygous 13-base pair deletion in the 3′ half of exon 3. The deleted sequence, extending from codons 82–86, results in a frameshift and generates a downstream termination codon in exon 4. Single strand conformation polymorphism (SSCP) analysis detected no additional mutations in the coding or consensus splice sequences of the A subunit gene. Both parents of the proband were heterozygous for the defect. Only one previous microdeletion (AG dinucleotide) has been reported in the A subunit gene, and was located at the intron B-exon 3 boundary. Further studies are necessary to determine whether this region of the gene is a “hot spot” for microdeletion mutations. © 1996 Wiley-Liss, Inc.     

Underweight,Overweight and Obesity among Reproductive Bangladeshi Women: A Nationwide Survey

The double burden of malnutrition is becoming more prevalent among Bangladeshi women. Underweight, overweight, and obesity were examined among women aged 15–49 years using the 2017–2018 Bangladesh Demographic and Health Survey (BDHS). A dataset of 20,127 women aged 15–49 years with complete Body Mass Index (BMI) measurements were extracted and categorized as underweight, normal weight, overweight, and obesity. A multiple logistic regression that adjusts for clustering and sampling weights was used to examine underweight, overweight, and obesity among reproductive age Bangladeshi women. Our analyses revealed that the odds of being overweight and obese were higher among women who completed primary and secondary or more levels of education, rich households, breastfeeding women, and women exposed to media (newspapers and television (TV). Women from the poorest households were significantly more likely to be underweight (AOR = 3.86, 95%CI: 2.94–5.07) than women from richer households. The likelihood of being underweight was higher among women with no schooling, adolescent women, and women not using contraceptives. Conclusions: Overweight and obesity was higher among educated and affluent women while underweight was higher among women from low socioeconomic status, indicating that tailored messages to combat overweight and obesity should target educated and affluent Bangladeshi women while improving nutrition among women from low socioeconomic status.     

Couple communication and sexual satisfaction among withdrawal users in Pakistan

Withdrawal is a popular method of family planning in Pakistan, associated with relatively high continuation and modest failure rates. In 1997, a small, qualitative study was conducted on the circumstances of withdrawal use among 25 married men and 24 married women (not in the same couple) who had ever used withdrawal, with two to three in-depth interviews per respondent. This paper presents findings on couple communication and unsolicited information on sexuality from the study. Withdrawal use was typically initiated by mutual agreement, with neither sex dominating the decision-making. Control over fertility without having to use a modern method (due to fear of side effects) was a primary aim of the women, and supported by their husbands. Information on sexuality was forthcoming from many of the men, though much less from the women. Men and women presented very different perspectives on achieving sexual satisfaction in the context of withdrawal use. While men freely discussed their own sexual satisfaction and that of their wives, and emphasised the importance of their wives'sexual satisfaction, women barely mentioned their own sexual needs. Slightly more mentioned their husbands'needs. Even so, the respondents in this study used withdrawal in a context ofpositive communication and mutual regard, which clearly arises from and enhances their satisfaction with the method.     

Prevalence of IgG antibody against measles, mumps and rubella in bangladeshi children: a pilot study to evaluate the need for integrated vaccination strategy

The present study was carried out to determine the seroprevalence of IgG antibodies in Bangladeshi children against measles (irrespective of vaccination status), mumps and rubella (MMR) to assess strategic need of combined vaccination for these diseases. A total of 456 children of 1 month to 15 years, were studied. Serum IgG antibodies against MMR were measured by enzyme-linked immunosorbent assay (ELISA). By 3 months, protective IgG antibody level (>40 AU for measles and mumps and >15 IU/ml for rubella) for the diseases found to be between 50% and 80% among the studied children. Protective measles antibody (IgG) was not detected in all the children of 3-9 months and significant number of children between 9 months and 5 years were unprotected (87-65%; P < 0.001). Moreover, children of 3-15 months had no protective antibody level against mumps and significant number of children between 15 months and 5 years were unprotected (92-71%; P < 0.001). Between 5 and 15 years of age, significant number of children became protective (63-85%, P < 0.001). Although, a majority of children between 3 months and 5 years had shown to have no protective antibody against rubella (89-71%; P < 0.01-0.001) between >10 and 15 years 71% children had protective level of antibodies (P < 0.001). No significant difference was observed in antibody prevalence regarding socioeconomic classes, nutritional status and parental education. The data showed that: (i) a significant number of children remain unprotected against MMR in childhood and (ii) an extensive nationwide survey is required to suggest an integrated vaccination strategy in order to implement appropriate control measures of the three infectious diseases.     

Is Low Dose a New Dose to Initiate Hemophilia A Prophylaxis? – A Systematic Study in Eastern India

To investigate the effectiveness of low dose secondary/tertiary prophylaxis in severe Hemophilia A children and determine improvements in their daily life. Thirty Hemophilia A children (≤ 12 y) with factor VIII <2% and less than two joint bleeds without inhibitors, were given prophylaxis with recombinant Fc fusion long acting factor VIII (ELOCTATE) at 10 IU.kg−1 twice weekly for 1 y. Earlier, patients received on-demand FVIII for a minimum of six months. Outcome was measured in terms of annual bleeding rate, Hemophilia Joint Health Score (HJHS) and child activity/participation was measured in terms of school absenteeism, School Activity Participation Score and Daily Activity Score according to Beijing Children Hospital assessment scale. A total of 30 children were included in the study. There was reduction in annual joint bleeds by 85.76% (14.5 to 2.2) and school absenteeism (days/month) by 86% (17.38 to 2.42) before and after prophylaxis respectively. Majority (43%) showed moderate improvement in daily activity score. Mean HJHS score was 8.3. There was mild improvement in School Activity Participation Score in 57%. Mean annual hospitalization rate reduced from 8.7 to 1.1 with improvement in joint scores. Mean annual factor consumption decreased from 1944.2 IU.kg−1 to 1560.3 IU.kg−1. With low dose secondary/tertiary prophylaxis, there is significant reduction in the annual joint bleed rate with improvement in joint health and child activity. As factor consumption is reduced, this has a positive effect on cost benefit; and is a very feasible option in developing countries.