New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents

A series of bis-phenoxyacetic acids 2 were prepared starting from corresponding unsubstituted/substituted 1,4-quinols 1. The fusion of bis-phenoxyacetic acids 2 with thiocarbohydrazide gave the corresponding bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl-methyleneoxy]phenylenes (3) in a one pot reaction. The reaction of bis-triazoles 3 with various reagents afforded N-bridged heterocycles 4-6 in good yields. The newly synthesised compounds were screened for their anticancer activity against a panel of 60 cell lines derived from seven cancer types namely, lung, colon, melanoma, renal, ovarian, CNS and leukemia. Some of the tested compounds showed promising anticancer properties.     

Hemodialysis vascular access dysfunction from basic biology to clinical intervention

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over 1 billion dollars per annum. Venous stenosis and thrombosis as a result of venous neointimal hyperplasia are the major causes of hemodialysis vascular access dysfunction. Despite the magnitude of the clinical problem, there are currently no effective therapies for this condition. We believe that this could be because of an inadequate understanding of the pathogenesis of this condition. At a histological level, venous neointimal hyperplasia (both in human specimens and in a pig model) is characterized by the presence of smooth muscle cells/myofibroblasts, microvessel formation (angiogenesis), and the accumulation of extracellular matrix components, all of which could be potential targets for therapeutic intervention. In particular, polytetrafluoroethylene dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia. The current review describes the lesion of venous neointimal hyperplasia in human samples and in a pig model and suggests possible future directions for the development of effective local therapies for this condition.     

Essential thrombocythaemia

A case of essential thrombocythaemia which responded to aspirin and hydroxyurea is presented.     

Juvenile nasopharyngeal angiofibromas: A study of recurrence pattern and role of pre-Operative embolization - ‘a decade’S experience’

This study is a retrospective analysis of 30 consecutive cases of Juvenile Nasopharyngeal Angiofibroma (JXA) operated at. Department of Head and Neck Surgery, Kidwai Memorial Institute of Oncology Bangalore, India: la tertiary referral centre) after prior emohilization by an interventional neuro-radiologisl (1996-2002). This study discusses critically the planning of surgical approach, based on anatomico-radiological factors and highlights the efficacy of preoperalive embolization in expediting total re moral of the tumor in 25 out of JO cases with advanced stage JNA. Objectives: To analyze the utility of pre-operatire embolisation in surgical extirpation of large JNAs; planning of the surgical approaches based on CT topography of the tumor; to study the various complications of embolisation and surgery associated with JXA & lastly to evaluate the puttern and location of recurrent tumor thus correlating with the original topography. Setting: Tertiary care cancer referral centre. Patients: Patients ranged in age from ’)- 24 years. all being males. Interventions: Majority of them were accessed by transfacial surgical approach(26). and in the recent past via midfacial degloving(4) within 4H hours of angioembolisation. Results: Complete removal of the tumor was achieved in 25 out of 30 cases with advanced stage JNA. Post surgical CT scans revealed tumor residua in 5 individuals, where the tumor was documented in - the temporal fossa 12), para-cavernous sinus region (I), cavernous sinus! I) and pterygo palatine fossa (I). Only the lesion in pterygopalaline fossa was successfully re-i>xcised & this alongwith the recurrence at para-cavernous & cavernous sinus & another were treated with radiotherapy; the 2 cases in the temporal fossa are under observation. The average blood loss during the procedure was 546.60 ml. Conclusions: Today, advances in radiologie imaging-complemented by interventional neuro-radiological expertise in angio-embolisation have expedited complète excision with minimal morbidity and acceptable recurrence rate. This study has justified pre-operative embolisation and M currently the standard of care for advanced JXA.     

Ingested IFN-alpha: results of a pilot study in relapsing-remitting MS

OBJECTIVE: To investigate whether ingested human recombinant interferon-alpha2a (IFN-alpha2a) was safe and whether treatment reduces the number of gadolinium-enhanced lesions on serial MRI in patients with active relapsing-remitting MS (RRMS). METHODS: Entry criteria included clinically definite RRMS and one or more gadolinium-enhanced lesions on a screening MRI. RESULTS: Of 80 patients screened, 33 were eligible and 30 patients were enrolled for treatment. Patients were randomized (10 per group) to placebo, 10,000 or 30,000 IU IFN-alpha2a ingested on alternate days for 9 months. They were examined clinically and with monthly cerebral MRI. Sample size projections were based on the assumption of a parenteral IFN-like effect, a 90% reduction of enhancing lesions evident within 1 month of the initiation of treatment in the active treatment groups sustained during the 9-month study as the primary outcome variable. RESULTS: There was no significant effect on enhancing lesions. However, post hoc analysis suggested a possible treatment effect in the 10,000 IU group. By direct monthly comparison of placebo and 10,000 IU group in treatment month 5, there were 73% (p < 0.05) fewer enhancements in the 10,000 IU group than in the placebo group. There was a decrease of tumor necrosis factor-alpha protein secretion at months 4 and 5. Relapses and adverse events were not different among the treatment groups. Ingested IFN-alpha2a did not induce systemic anti-IFN-alpha antibodies. CONCLUSIONS: This trial showed no benefit based on the primary outcome measure. Because changes were detected in immune response and post hoc analysis suggested that a smaller dose could have an effect, IFN-alpha may deserve further study.     

SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors

Vascular endothelial growth factor, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors. Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor beta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP. Cocrystallographic studies of SU6668 in the catalytic domain of FGF receptor 1 substantiated the adenine mimetic properties of its oxindole core. Molecular modeling of SU6668 in the ATP binding pockets of the FIk-1/KDR and PDGF receptor kinases provided insight to explain the relative potency and selectivity of SU6668 for these receptors. In cellular systems, SU6668 inhibited receptor tyrosine phosphorylation and mitogenesis after stimulation of cells by appropriate ligands. Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin. Furthermore, intravital multifluorescence videomicroscopy of C6 glioma xenografts in the dorsal skinfold chamber model revealed that SU6668 treatment suppressed tumor angiogenesis. Finally, SU6668 treatment induced striking regression of large established human tumor xenografts. Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials.     

Supracricoid laryngectomy with Cricohyoidopexy--a clinico oncological & functional experience

Supracricoid laryngectomy with Cricohyoidopexy (CHP) is a procedure that is commonly practiced in France & Canada. Eight such procedures were carried out at Kidwai Memorial Institute of Oncology, Bangalore during the period from 1991 through 1996. Four Glottic, 3 transglottic & one supraglottic cancers were subjected to this procedure. The study comprised of 7 males & 1 female. The average age was 52 years. Two procedures were done as salvage procedures for radiotherapy (RT) failures. The patients have a follow-up ranging from one year to six years, except for one who died soon after discharge from hospital secondary to myocardial infarction. Median follow up was four years. The three year acturial disease free survival was 83%. Six out of 8 (75%) were decannulated, and physiologic deglutition without aspiration was established in all patients. Hospital stay ranged from 11 to 62 days averaging 29 days. The speech was analyzed together with other partial laryngectomies and was found to be qualitatively worse than speech after other partial laryngectomy procedures. In addition speech intensity levels after CHP were lower than in other partial laryngectomy procedures. The speech however allowed normal social interaction. This procedure certainly has distinct oncological advantage in encompassing circumferential horse-shoe lesions with minimal subglottic extension which in the past would have received total laryngectomy and needs to be included in the repertoire of speech restorative surgery in laryngeal cancers.     

Parotid tuberculosis simulating malignancy

An interesting case of parotid tumour simulating malignancy is reported. The rarity of this lesion and the associated clinical and diagnostic problems are emphasized together with the relevant literature.