Insights into Mechanisms of Cisplatin Resistance and Potential for Its Clinical Reversal

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.     

Renal artery aneurysm endovascular repair.

A 68-year-old woman with a left renal artery aneurysm underwent successful endovascular repair with the use of a commercial type self-expanding stent-graft. Complete aneurysm exclusion was achieved after stent-graft expansion. A side branch vessel was occluded after stent-placement, resulting in a small upper lobe renal perfusion defect. There were no other complications. The aneurysm remained excluded and its greatest diameter has been reduced from 2.6 cm to 1.95 cm, 10 months after treatment. Renal function remained normal.     

Marked hypodiploidy in blast phase chronic myelogenous leukemia: report of a case and review of the literature

The emergence of a near-haploid clone of cells in blast phase chronic myelogenous leukemia is an unusual event. We report such a case and review eight other cases described in the English literature. The significance of the substantial loss of genetic material is discussed as is the phenotypic and genotypic heterogeneity observed in this group of patients.     

Prolonged exposure of intraocular lens implant with preservation of globe integrity and visual function.

A 70-year-old woman had corneal ulcer and melting after complicated cataract surgery with polymethylmethacrylate lens implant insertion. A conjunctival flap was initially used to cover the defect with a plan to perform keratoplasty later. Fifteen months postoperatively, she presented with total absence of central corneal tissue and iris and exposure of the implant. The eye was not inflamed, painful, or hard on palpation and visual acuity was counting fingers at 3 m. The preservation of globe integrity despite exposure of the polymethylmethacrylate implant implies a stable adhesion between polymethylmethacrylate and residual corneal tissue and may prove useful in keratoprosthesis design.     

Zur Physiologie der Thränensecretion

Ohne Zusammenfassung     

Vasoactive amines and eicosanoids interactively regulate both polymorphonuclear leukocyte diapedesis and albumin permeability in vitro

Previously we reported that cultured endothelial cells (ECs) can promote or inhibit polymorphonuclear leukocyte (PMN) diapedesis and albumin permeability in vitro by altering monolayer intercellular integrity (an activity influenced by pretreatment with exogenous amines). Endothelial eicosanoid release was also seen to stimulate both PMN motility and diapedesis. We now demonstrate that these endothelial activities are related. Thromboxane (Tx) B2 pretreatment of ECs results in increased diapedesis and permeability across the monolayers whereas 6-keto-PGF1 alpha pretreatment has the opposite effects, demonstrating that these eicosanoids exert direct effects upon ECs, in addition to their direct effects upon PMNs as previously described. Norepinephrine (NE) or serotonin (5HT) pretreatment of ECs inhibits the release of TxB2 and 6-keto-PGF1 alpha, with the result that the stimulation of PMN motility by these EC metabolites is eliminated. In contrast, histamine increases the endothelial release of eicosanoids, resulting in a further increase in PMN motility. We conclude that histamine directly reduces EC monolayer integrity (by altering the endothelial cytoskeleton) and also increases eicosanoid release, actions which both enhance PMN motility and further reduce monolayer integrity. Conversely, NE and 5HT both increase intercellular integrity and decrease eicosanoid release, thereby decreasing PMN motility, diapedesis, and albumin permeability.     

Dopamine transporters, D2 receptors, and glucose metabolism in corticobasal degeneration.

Alterations in presynaptic and postsynaptic dopaminergic system and cerebral glucose metabolism in corticobasal degeneration (CBD) were assessed to evaluate the potential usefulness of different imaging methods for CBD. (123)I-FP-CIT/(123)I-beta-CIT SPECT and (123)I-IBZM SPECT as well as (18)F-FDG PET were performed in eight CBD patients. Decreased presynaptic dopamine transporter binding was found in all CBD patients while D2 receptor binding was reduced in only one patient. (18)F-FDG PET displayed a contralateral hypometabolism in cortical and subcortical areas in seven out of eight patients. Our results demonstrate that glucose metabolism and DAT are reduced, while D2 receptors may be frequently preserved in CBD.     

Endoscopic diode laser welding of mucosal grafts on the larynx: A new technique

Epithelial coverage of a laryngotracheal wound is an important factor in preventing stenosis, and endoscopic transplantation of a free mucosal graft without stents or sutures would be a significant therapeutic advance. In vitro and in vivo canine studies were performed to explore the feasibility of transplantation with a low-power diode laser (400 mW) enhanced by indocyanine green dye-doped albumin. The tensile strength of graft adherence in 10 cadaver larynges was strong (35.25 ± 10.39 g). Survival studies in live canine models with a specially designed endoscopic instrument set showed excellent healing at 6, 14, and 28 days. Healing was documented with photography and by histologic examination. Successful endoscopic transplantation of a free mucosal graft should improve results of treatment for laryngotracheal stenosis and laryngeal reconstructive surgery.     

Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center

Aspergillus isolates (n = 103) collected from cancer patients were screened to determine the taxonomic distribution and quantity of gliotoxin production. Gliotoxin was detected in 93% of Aspergillus fumigatus, 75% of A. niger, 25% of A. terreus, and 4% of A. flavus cultures. Gliotoxin concentrations were highest in cultures of A. fumigatus.