Compensator-based intensity-modulated radiotherapy in head and neck cancer: our experience in achieving dosimetric parameters and their clinical correlation

AimsTo review the Batra Hospital and Medical Research Centre experience of using compensator-based intensity-modulated radiotherapy (IMRT) to treat head and neck cancer.Materials and methodsBetween October 2003 and August 2004, 18 patients underwent IMRT for head and neck cancer at our institution. IMRT was delivered using partial transmission high-resolution compensator blocks.ResultsWith a median follow-up of 13.3 months, two patients had residual disease and two failed in the gross tumour volume (GTV). The complete response rate after surgical salvage was 94.5%. Both the locoregional relapse-free and disease-free survival rates were 81.8%. The target coverage in terms of average maximum, mean and minimum dose (in Gy) delivered was 78.6, 73.5 and 58.4 to the GTV–planning target volume, 82.3, 70.9 and 47.3 to clinical target volume 1 (CTV1) and 82.9, 66.2 and 29.6 to CTV2. The dose constraint of 30 Gy to less than 50% of the contralateral parotid volume was achieved in 12 (66.7%) patients. If the dose constraint was revised to 35 Gy, at least 50% of the parotid volume was spared in 17 (94.5%) patients. On average, 75% of the contralateral parotid volume received a dose less than 35 Gy in 13 (72.3%) patients with grade I xerostomia, whereas this was 49.3% in five (27.7%) patients with grade II xerostomia, and the difference was statistically significant (P = 0.001).ConclusionsIn our initial experience, compensator-based IMRT is feasible with regard to target coverage and parotid volume sparing. The parotid volume dose has significant clinical implications on the grade of xerostomia. Our results invoke rethinking into the issues of the parotid volume dose constraint in our subpopulation.     

Functional characterization of a naturally occurring Cx50 truncation

PURPOSE: Lens connexins undergo proteolytic cleavage of their C termini during fiber maturation. Although the functional significance of this is unknown, cleavage has been correlated with changes in channel-gating properties. This study evaluates the functional consequences of this endogenous truncation by characterizing the properties of a C-terminal truncated Cx50 protein. METHODS: Murine and human Cx50 were truncated at amino acids 290 and 294, respectively, before expression in paired Xenopus oocytes or mammalian cells. Protein expression was evaluated by immunocytochemistry. Dual whole-cell voltage clamp techniques were used to analyze macroscopic and single-channel conductance, voltage-gating properties, and kinetics; pH gating sensitivity was measured by superfusion with 100% CO2-saturated media. RESULTS: Cx50tr290 channels exhibited an 86% to 89% reduction in mean macroscopic conductance compared with full-length Cx50. Heterotypic channels formed functional gap junctions, displayed an intermediate level of coupling, and exhibited unaltered voltage-gating properties. C-terminal truncation did not alter single-channel gating characteristics or unitary conductance. Interestingly, truncated and full-length Cx50 channel conductances were reversibly blocked by cytoplasmic acidification. CONCLUSIONS: C-terminal truncation of Cx50 did not inhibit the formation of homotypic or heterotypic channels. However, a significant decrease in conductance was observed for truncated channels, a phenomenon independent of alterations in voltage-gating sensitivity, kinetics, or chemical gating. These results provide a plausible explanation for the 50% decrease in junctional coupling observed during lens fiber maturation.     

One-year results of a pilot study using oral 13-cis retinoic acid as a treatment for subfoveal predominantly occult choroidal neovascularization in patients with age-related macular degeneration

PURPOSE: To evaluate the safety and evidence of efficacy for oral 13-cis retinoic acid as a treatment for patients with subfoveal occult choroidal neovascularization (CNV) due to age-related macular degeneration (ARMD). METHODS: Patients with active, subfoveal occult CNV with no prior treatment of the subfoveal component were eligible for inclusion. Patients received 40 mg of 13-cis retinoic acid twice daily for 5 months, stopped treatment for 2 months, and then resumed treatment for 5 months. Patients were observed monthly with Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA), clinical examination, fluorescein angiography, and laboratory testing. RESULTS: Eleven patients, aged 64 to 88 years, were enrolled and followed for 1 year. Initial VA ranged from 55 (20/40) to 5 (20/400) ETDRS letters (median 48 letters). Mild drug-related side effects (dry skin, chapped lips) occurred in all 11 patients. Three patients experienced more severe side effects (muscle aches, mood swings) and did not resume treatment after the drug holiday. Moderate VA loss occurred in 36% at both 6 and 12 months. CONCLUSIONS: Oral 13-cis retinoic acid is too toxic to be useful in patients with ARMD. Oral 13-cis retinoic acid did not improve vision although it may have slowed visual acuity loss in patients with ARMD with occult subfoveal CNV.     

7'-substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors

We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).     

An in vivo model to assess factors that may stimulate the generation of an immune reaction to erythropoietin

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (s.c.) administration of epoetin alfa (EPREX) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, in vivo models were developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). It was difficult to generate anti-EPO antibodies in mice. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to increase both the frequency of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some mice exhibited a reduction in hematocrit, suggesting neutralization of endogenous EPO by anti-EPO antibodies. To evaluate the primary lead identified in the technical investigation, leachates from the uncoated syringe stoppers of EPREX syringes, a surrogate antigen (chicken egg albumin, OVA) was used to avoid possible interferences that could arise from the use of an endogenous protein like EPO. These leachates yielded a positive, concentration-dependent antibody response in the OVA animal model, demonstrating their adjuvant properties and providing support for the hypothesis generated through the technical investigation that leachates were capable of enhancing the immune response to rHuEPO.     

Syntheses, molecular targets and antitumor activities of novel triptycene bisquinones and 1,4-anthracenedione analogs

Novel substituted triptycene bisquinones and 1, 4-anthracenediones were synthesized and screened for their anti-cancer activities. A number of analogs were synthesized utilizing various synthetic transformations and found to elicit interesting antitumor effects. Analogs included water-soluble pro-drugs and ammonium salts. These potent antitumor drugs are DNA topoisomerase inhibitors that induce DNA strand breaks, inhibit DNA, RNA and protein syntheses and reduce tumor cell proliferation in the nanomolar range in vitro. They induce cytochrome c release, caspase-9, -3 and -8 activities, poly(ADP)-ribose polymerase-1 (PARP) cleavage, and internucleosomal DNA fragmentation by a mechanism which involves caspase-2 activation but not Fas signaling. Moreover, these drugs remain effective in multidrug-resistant tumor cells and have the advantage of blocking nucleoside transport and inducing a rapid loss of mitochondrial transmembrane potential. Based on their effects in tumor cells and isolated mitochondria, it is hypothesized that these drugs might, directly and indirectly, target components of the permeability transition pore to induce mitochondrial permeability transition and the release of proapoptotic factors. This review provides a summary of synthetic efforts and mechanistic endeavor.     

Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy

Fatty acids are essential for bacterial growth and viability, with the type II fatty acid synthesis (FAS II) pathway being a potential antibacterial target. A new, selective, and highly sensitive whole cell-based antisense strategy has been designed to screen for natural product inhibitors of FabH/F of the FAS II pathway using a high-throughput two-plate agar-based differential sensitivity assay (FabF(2)p). An antisense assay along with the FASII enzyme prepared from Staphylococcus aureus was used for bioactivity-guided fractionation, leading to the isolation of phomallenic acids A-C (1-3) from a leaf litter fungus identified as Phoma sp. Compounds 1-3 exhibited minimum detection concentrations (MDC) of 0.63, 0.31, and 0.15 microg/mL in the FabF(2P) assay, IC(50) values of 22, 3.4, and 0.77 microg/mL in the FASII enzyme assay, and minimum inhibitory concentrations (MIC) of 250, 7.8, and 3.9 microg/mL, respectively, against wild-type S. aureus. Phomallenic acid C (3), the analogue with the longest chain, exhibited the best overall activity within the phomallenic acids obtained and was superior to cerulenin and thiolactomycin, the two most studied and commonly used FabF inhibitors.     

Diffusion of diagnostic medical devices and policy implications for India

OBJECTIVES: This study describes the diffusion of advanced diagnostic devices in India and assess implications for efficiency in resource use and equity. METHODS: Commodity-level import statistics, household survey data, and interviews with medical device sellers are used to assess the spread of diagnostic devices. Published qualitative evidence, case studies of diagnostic service providers, and cross-country analyses are used to identify the reasons underlying the spread of medical devices in India. Case studies of public and private providers and data from 150 hospitals in one Indian state are used to assess efficiency in resource use and the distributive impacts of diagnostic devices. RESULTS: High-end medical device inflows rose during the 1990s, with both supply- and demand-side factors influencing this trend. Although our results suggest that the overall quantity of advanced diagnostics in India is not excessive, there is some evidence of inefficiency in public facilities and possibly unethical practices in private diagnostic facilities. The unequal geographical distribution of magnetic resonance imaging facilities, coupled with inefficient use of medical devices in public facilities suggests inequality in access. CONCLUSIONS: The study points to major regulatory gaps and health system inefficiencies and suggests ways in which these gaps can be addressed.