Dietary risk factors for hypopharyngeal cancer in India

Objective  The Indian subcontinent has among the highest rates of hypopharyngeal cancer worldwide. The purpose of this study was to examine the associations between the Indian diet and hypopharyngeal cancer. Methods  We used data from a hospital-based case–control study of 513 incident hypopharyngeal cancers and 718 controls from four centers in India. Dietary information was assessed using a 67-item semi-quantitative food frequency questionnaire. Intakes of related foods were combined across food groups and were categorized by quartile. We used unconditional logistic regression modeling, stratified by ever tobacco use, to analyze the association between food intakes and hypopharyngeal cancer. Results  Among persons who had ever smoked or chewed tobacco, protective associations were seen at the highest quartiles of total fruit intake (OR = 0.37, 0.20–0.69), curds (OR = 0.35, 0.17–0.69), and leafy green (OR = 0.25, 95% CI 0.13–0.51), root (OR = 0.22, 95% CI 0.11–0.43), and cruciferous vegetable intakes (OR = 0.41, 0.20–0.84). Results were similar, although not as robust, among persons who had never smoked or chewed tobacco. An increased risk of disease was seen among tobacco users who drank milk daily (OR = 1.84, 1.14–2.98). Conclusions  Dietary factors might contribute to the high risk of hypopharyngeal cancer observed in India.     

Combined venous sinus angioplasty and low-dose thrombolytic therapy for treatment of hemorrhagic transverse sinus thrombosis in a pediatric patient

We describe the successful treatment of a 5-year-old girl with rapidly evolving left hemispheric hemorrhagic infarcts resulting from left transverse and sigmoid sinus thrombosis using combined endovascular dural sinus angioplasty and local low-dose thrombolytic therapy.     

Detection of haptenated proteins in organotypic human skin explant cultures exposed to dapsone.

Bioactivation of parent drug to reactive metabolite(s) followed by protein haptenation has been suggested to be a critical step in the elicitation of cutaneous drug reactions. Although liver is believed to be the primary organ of drug bioactivation quantitatively, other organs including skin may also metabolize drugs. Cultured human epidermal keratinocytes and dermal fibroblasts have been shown to be capable of bioactivating sulfonamides and sulfones, giving rise to haptenated proteins. It is, however, unclear whether metabolic events in these isolated cells reflect bioactivation in vivo. Hence, split-thickness human skin explants were exposed to dapsone (DDS) or its arylhydroxylamine metabolite (dapsone hydroxylamine, D-NOH) and probed for protein haptenation. DDS and D-NOH were applied either epicutaneously or mixed in the medium (to mimic its entry into skin from the systemic circulation). DDS-protein adducts were readily detected in skin explants exposed to either DDS or D-NOH. Adducts were detected mainly in the upper epidermal region in response to epicutaneous application, whereas adducts were formed all over the explants when DDS/D-NOH were mixed in the culture medium. In addition, adducts were visible in HLA-DR+ cells, indicating their presence in the dendritic cell population in the skin. Our results demonstrate the ability of intact human skin to bioactivate DDS leading to protein haptenation.     

Intake of arsenic from water, food composites and excretion through urine, hair from a studied population in West Bengal, India.

To evaluate the main intake source of arsenic by the villagers from arsenic-affected families in Jalangi and Domkol blocks in Mushidabad district, West Bengal-India, we determined the concentrations of arsenic in tube-well water and in food composites, mainly including vegetables and cereals collected from the surveyed families which were cultivated in that region. The daily dietary intakes of arsenic by the villagers were estimated and the excretions of arsenic through urine and hair were determined. The arsenic concentrations in hair and urine of the studied population living in mild (2.78 microg/L), moderate (30.7 microg/L) and high (118 microg/L) arsenic-affected families were 133, 1,391 and 4,713 microg/kg and 43.1, 244 and 336 microg/L, respectively. The linear regressions show good correlations between arsenic concentrations in water vs hair (r(2)=0.928, p<0.001) and water vs urine (r(2)=0.464, p<0.01). Approximately 29.4%, 58.1% and 62.1% of adult population from mild, moderate and high arsenic-affected families were suffering from arsenical skin manifestations. The mean arsenic concentrations of food composites (vegetables and cereals) in high arsenic-affected families are not significantly different from mild arsenic-affected families. The daily dietary intakes of arsenic from water and food composites of the studied population, living in high, moderate and mild arsenic-affected families were 568, 228 and 137 microg, respectively. The linear regressions show good correlations between arsenic concentrations in hair vs daily dietary intake (r(2)=0.452, p<0.001) and urine vs daily dietary intake (r(2)=0.134, p<0.001). The water for drinking contributed 6.07%, 26.7% and 58.1% of total arsenic in our study from mild, moderate and high arsenic-affected families. The result suggested that the contaminated water from high arsenic-affected families should be the main source for intake of arsenic. On contrary, the contribution of arsenic-contaminated food composites from mild and moderate arsenic-affected families might be the main source for intake of arsenic. The Food and Agriculture Organization/World Health Organization (FAO/WHO) provisional tolerable weekly intake (PTWI) values of arsenic in our study were 3.32, 5.75 and 12.9 microg/kg body weight/day from mild, moderate and high arsenic-affected families, respectively, which is higher than the recommended PTWI value of arsenic (2.1 microg/kg body weight/day).     

Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Role of human cyclooxygenase-2 in the bioactivation of dapsone and sulfamethoxazole.

Sulfamethoxazole (SMX) and dapsone (4,4'-diaminodiphenylsulfone, DDS) are believed to mediate their adverse effects subsequent to bioactivation to their respective arylhydroxylamine and arylnitroso metabolites, resulting in covalent adduct formation with intracellular proteins. Various bioactivating enzymes, such as cytochromes P450 and myeloperoxidase, have been shown to be capable of catalyzing the N-oxidation of these compounds. We assessed the role of human cyclooxygenase-2 (COX-2) in the metabolism and subsequent adduct formation of DDS and SMX using recombinant human COX-2. Using an adduct-specific enzyme-linked immunosorbent assay, we found that the complete enzyme system gave rise to covalent adducts. However, the nonspecific COX inhibitor indomethacin did not reduce the amount of covalent adduct formed. Formation of the arylhydroxylamine metabolites was demonstrated via high performance liquid chromatography coupled with UV absorption. Metabolite formation was found to be secondary to the H2O2 in the incubation mixture and was not enzyme-mediated. Hence, COX-2 does not play a direct role in the bioactivation of these parent drugs to their arylhydroxylamine metabolites.     

Chemical analysis of sound and carious enamel of permanent tooth

Enamel consists mainly of inorganic material (96%) and only a small amount of organic substance and water (4%). The inorganic material is similar to apatite. The originally found apatite mineral remains basically unchanged except at the surface in contact with the oral tissues, where diffusion processes operate. Enamel reflects the trace element environment present in the tissue fluids at the time of tissue development. These are variations of types and concentration of inorganic elements found in permanent and deciduous enamel. Variations are also seen in sound and carious enamel.     

Port retrieval for salvage of tissue expansion in case of lost or malfunctioning port

Tissue expansion though a promising modality of reconstructive surgery is fraught with many complications. In addition to expander-related complications, subcutaneous port-related mishaps during tissue expansion, though infrequent, can result in procedure failures. We are reporting two patients with port-related complications. In one patient, there was failure to localise the port and the other had a leaking port. Both the expanders were salvaged by retrieving the ports. In the former, as the port was competent, it was simply exteriorised. But in the later case, the connecting tube was retrieved and the incompetent port was replaced with a Luer lock external port. Both the cases were successfully salvaged without any further complications. Expansions were completed and requisite reconstructive end points were achieved.     

Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients

Purpose The aim of this study was to analyse the alterations of the genes in the CDKN2A/CCND1/CDK4/RB1 pathway in the G1-S phase of the cell cycle during development of head and neck squamous cell carcinoma (HNSCC).Methods The alterations of these genes were analysed in 22 dysplastic lesions, 26 stage-I/II and 33 stage-III/IV HNSCC tumours of Indian patients.Results The alterations [mutation, hypermethylation, homozygous deletion and loss of heterozygosity/microsatellite size alteration (LOH/MA)] in the CDKN2A were found to be highest in 57% of the samples, followed by CCND1 amplification and LOH/MA at the RB1 locus in 14% and 8.5% of the samples, respectively. No dominant CDK4 Arg24Cys mutation was seen in our samples. Comparatively high frequency of CDKN2A alterations (except homozygous deletion) was found in dysplastic head and neck lesions and remained almost constant or increased during progression of the tumour, whereas the homozygous deletion of CDKN2A and the alterations in CCND1 and RB1 genes were seen mainly in the later stages of the tumour.Conclusions Our study suggested that mutation/hypermethylation/allelic alterations (LOH/MA) of CDKN2A were associated with the development of dysplastic head and neck lesions. All the other alterations might provide some cumulative effect during progression of later stages of the tumour to have selective growth advantages.