Adherence to Antiretroviral Therapy Among Children Living with HIV in South India

Adherence to ART, fundamental to treatment success, has been poorly studied in India. Caregivers of children attending HIV clinics in southern India were interviewed using structured questionnaires. Adherence was assessed using a visual analogue scale representing past-month adherence and treatment interruptions >48 h during the past 3 months. Clinical features, correlates of adherence and HIV-1 viral-load were documented. Based on caregiver reports, 90.9 % of the children were optimally adherent. In multivariable analysis, experiencing ART-related adverse effects was significantly associated with suboptimal adherence (p = 0.01). The proportion of children who experienced virological failure was 16.5 %. Virological failure was not linked to suboptimal adherence. Factors influencing virological failure included running out of medications (p = 0.002) and the child refusing to take medications (p = 0.01). Inclusion of drugs with better safety profiles and improved access to care could further enhance outcomes.     

Detection by (18)F-FDG PET of unsuspected extensive bone marrow metastases in a case of basosquamous carcinoma of the cheek

Basosquamous carcinoma (BSC) is a rare type of malignancy with features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with a potential for aggressive behaviour infiltration and destruction. First reported by MacCormac in 1910 in a series of rodent ulcers, this entity does have an increased risk of recurrence and metastases as well, which distinguish it from other forms of basal cell carcinoma. The overall incidence of basosquamous carcinoma ranges from 1.2% to 2.7%. An unusual case of basosquamous carcinoma (BSC) is presented where 18- fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) scan diagnosed unsuspected extensive metastatic disease in the bone marrow, which was further proven histopathologically. The patient was a 32 years old man with history of recently diagnosed basosquamous carcinoma of left cheek involving left lower eyelid and left eyeball. Contrast enhanced computed tomography(ceCT) of the head and neck demonstrated involvement of the left cheek skin by the malignancy along with erosion of zygomatic bone and phthisis bulbi of the left eye. The serum alkaline phosphatase was elevated (255units, normal range 50-150units). The patient was referred for (18)F-FDG PET, for disease status evaluation. The scan showed intense tracer uptake in the left zygomatic region, the site of known primary disease. Intense tracer uptake was noted in the multiple lesions of bone marrow of axial as well as appendicular skeleton. The scan appearance was highly suggestive of metastatic bone marrow involvement. A bone marrow biopsy was performed to confirm the scan findings. Guided by the (18)F-FDG PET scan findings, bone marrow biopsy was performed and metastatic basosquamous carcinoma was diagnosed. We believe this is the first reported case of basosquamous carcinoma where extensive metastatic bone marrow disease was diagnosed with the aid of (18)F-FDG PET. At first diagnosis, an advanced stage of BSC is often present. Due to its metastatic potential, extensive primary surgical resection of BSC, possibly completed by radiation or photodynamic adjuvant treatment is recommended. Given the aggressive nature of basosquamous carcinoma, whole body (18)F-FDG PET is very useful in diagnosing metastatic BSC. In conclusion, this is the first reported case of the use of (18)F-FDG PET study for diagnosing metastatic bone marrow disease in a patient with basosquamous carcinoma.     

Relevance of cytochrome P450s in plants: also one of Ron Estabrook's research interests

I worked with Dr. Ronald Estabrook for nearly 10 years at The University of Texas Southwestern Medical Center in Dallas, Texas. In Ron's lab, when I joined I was initially involved in the isolation, purification, and characterization of cytochrome P450s and NADPH-P450(c) reductase(s) from plants, which was his new exploratory project at the time. We developed methods for the isolation, solubilization, and purification of P450s and NADPH-P450(c) reductase from plant tissue microsomes. We carried out number of in vitro experiments to study the involvement P450s and NADPH-P450(c) reductase in the biosynthesis of number of phytoalexins. We successfully isolated, purified, and cloned NADPH-P450(c) reductase from etiolated mung bean (Vigna radiate) seedlings. In addition, a series of studies were undertaken to show that purified mung bean NADPH-P450(c) reductase was able to catalyze P450-supported reactions for mammalian and bacterial P450s. My stay in Ron's lab was very educational and productive. He provided the necessary support and led the way through the maze in different research projects in the lab, which allowed me to understand the roles of P450s in humans, animals, plants, and microorganisms. He liked to teach and discover new things everyday in the lab. He is a great scientist, as well as loving and caring mentor.     

Desmoplastic astrocytoma of infancy--a case report

Desmoplastic cerebral astrocytoma of infancy (DCAI) is a rare tumor which shows spindle cells embedded in an extremely desmoplastic stroma. We describe a case of DCAI seen in the frontoparietal region of brain in a three-month-old infant. Microscopically classic histology of DCAI was seen. On immunohistochemistty the tumor showed strong Vimentin, S-100 and Glial Fibrillary Acidic Protein (GFAP) positivity. The brain adjacent to the tumor-showed multi-cystic transformation and the tumor formed a solid area in the wall of this cystic structure. This adjacent brain showed mild disarray of architecture and gliosis. Three months after surgery this infant was alive and well.     

Mediastinal lymphadenopathy in a patient with previously treated T-cell acute lymphoblastic leukaemia

Mediastinal lymphadenopathy in a patient with previously treated T-cell acute lymphoblastic leukaemia is a diagnostic problem. The differential diagnosis in an adult is sarcoidosis, metastases, lymphoma or, rarely, tuberculosis. Mediastinal lymph node involvement is uncommon in tuberculosis. In view of its relative rarity but good prognosis, it is important to distinguish tuberculous mediastinal lymphadenitis in adults from other causes of mediastinal masses.     

Differential regulation of sunitinib targets predicts its tumor-type-specific effect on endothelial and/or tumor cell apoptosis

Purpose

Sunitinib is an inhibitor of tyrosine-kinase receptors, and no biomarker predictive of sunitinib response is available. The purpose of this preclinical study was to show whether sunitinib molecular targets could be used as biomarkers to assess tumor response to sunitinib in human cancer cell line xenografts of three different tumor types.

Methods

Using mice xenografted with liver, breast and renal carcinoma cell lines, we sequentially analyzed the effect of 7-day sunitinib treatment on tumor and vascular compartments.

Results

In all xenografts, microvessel damage occurred from Day 1. Tumor damage also occurred in liver, breast, but not in renal xenografts. Using specific human and mouse probes for genes encoding sunitinib targets, we showed a significant relation between apoptotic tumor cell numbers and human PDGFRΒ and RET mRNA expression in liver cancer and to human VEGFR2 expression in breast cancer xenografts. In contrast, in renal cancer xenografts, vascular effect evaluated by measuring endothelial cell apoptosis was related to mouse Vegfr1, Vegfr2 and Vegfa-164 expression.

Conclusion

This study identifies sunitinib vascular and tumor effects according to different tumor types and shows that sunitinib molecular targets used as biomarkers enable assessment of therapeutic response.     

Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma

Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs.In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts.Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC.Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC.     

Biotransformation of the anti-angiogenic compound SU5416.

SU5416 [3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1, 3-dihydro-indol-2-one], an inhibitor of VEGF (vascular endothelial growth factor) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2) is in advanced clinical trials for treatment of AIDS-related Kaposi's sarcoma and colorectal and nonsmall cell lung cancers. Since this chemical class has not been studied previously with therapeutic intent, the present study was designed to investigate the in vitro metabolism of SU5416 by mouse, rat, dog, monkey, and human liver microsomes and to identify the major metabolites of SU5416. An HPLC procedure was developed and validated to resolve and quantify SU5416 and its metabolites. To evaluate the in vitro metabolism of SU5416, pooled liver microsomes from mice, rats, dogs, monkeys, and humans were incubated with SU5416 (25 microM) in the presence of an NADPH-generating system. In the presence of NADPH, mouse, rat, dog, monkey, and human liver microsomes converted SU5416 to at least 12, 9, 9, 7, and 6 polar metabolites, respectively. Microsomal metabolism of SU5416 showed marked species differences in the levels of different metabolites formed. The overall rate of SU5416 metabolism by liver microsomes from the species examined followed the rank order: monkey > or = mouse approximately rat > dog > human. Two major metabolites of SU5416 were identified, a hydroxymethyl derivative of SU5416 (M12) and a carboxylic acid derivative of SU5416 (M6), by spectroscopic methods and comparison with authentic compounds. Both of these oxidative metabolites were further metabolized in vivo through glucuronidation. The metabolic fate of SU5416 in microsomes from various species as well as data from in vivo biotransformation in the rat are discussed.