On the effect of biochemotherapy in metastatic malignant melanoma: an immunopathological evaluation

Although immunotherapy and biochemotherapy have shown promise, producing a subset of durable responses, for the majority of patients with metastatic melanoma the prognosis is still poor. Therefore there is a great need for predictive tests to identify patients with a high probability of responding. Furthermore, there is also a need for a better understanding of the mechanisms of action during treatment in order to be able to monitor the relevant antitumour reactivity during treatment and to optimize the efficacy of future immunotherapy and biochemotherapy. In the present study histopathological regression criteria were used to study the efficacy of biochemotherapy. Thirty-two patients with metastatic malignant melanoma (18 with regional disease and 14 with systemic disease) were treated with biochemotherapy (cisplatin 30 mg/m2 intravenously on days 1-3, dacarbazine 250 mg/m2 intravenously on days 1-3 and interferon-alpha2b 10 million IU subcutaneously 3 days a week, every 28 days). Pre-treatment fine needle aspirates were obtained from metastases to analyse the number of tumour-infiltrating CD4+ lymphocytes. Therapeutic efficacy was evaluated in metastases resected after treatment using histopathological criteria of tumour regression. Comparisons were also made with metastases from 17 untreated patients, all with regional disease. Regressive changes of 25% or more (of the section area) were found in two of the 17 untreated patients with regional disease compared with 13 of the 18 patients with regional disease and 10 of the 14 patients with systemic disease after biochemotherapy. Fifty per cent of the patients with regional disease showed a high degree of regressive changes (75-100% of the section area) after biochemotherapy. These results demonstrate the occurrence of an antitumour reactivity in the majority of patients. Patients with extensive regressive changes in 75-100% of the analysed biopsies were also found to have a longer overall survival (P = 0.019). In patients with regional disease there was a close correlation between a larger number of CD4+ lymphocytes pre-treatment and a higher degree of regressive changes post-treatment (P < 0.05). Thus, immunohistochemical analysis of tumour biopsies shortly after treatment seems to be a good surrogate endpoint. This technique also allows detailed analysis of antitumour reactivity and escape mechanisms.     

Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG)

Stage melanoma IV has a poor prognosis, with a median survival time between 3 and 11 months from the diagnosis of distant metastases. Response rates in first-line regimens are around 20%. To date, no second-line treatment has been established. We performed a randomized, multicentre, second-line clinical phase II study of paclitaxel either as monotherapy or combined with carboplatin given on an outpatient basis. In arm A, paclitaxel was administered at a dose of 100 mg/m2 intravenously on day 1 each week for 6 weeks. In arm B, paclitaxel was administered at a dose of 80 mg/m2 intravenously followed by carboplatin 200 mg/m2 on day 1 each week for 6 weeks. The next cycle was administered after a 2 week intermission. The response rate, survival time, time-to-progression and toxicity were assessed in both arms. The study was stopped after 40 patients because the overall response rate was below 10% in both arms. The median survival time after initiation of second-line treatment was 209 days (+/- 196 days) for patients treated with paclitaxel only, and 218 days for those treated with paclitaxel/carboplatin. The median time-to-progression was around 56 days in both arms. Two partial responses were observed after 16 weeks, lasting for 8 and 12 weeks, respectively. Although both treatment modalities were well tolerated, haematological toxicity was higher in the combination arm. This is so far the largest second-line clinical phase II study reported in melanoma. However, paclitaxel with or without carboplatin had only limited efficacy, and the combination of these drugs adds significantly to haematological toxicity without improving response or survival rates.     

Intratumoral cisplatin/adrenaline injectable gel for the treatment of patients with cutaneous and soft tissue metastases of malignant melanoma

Local therapies have been highly effective in the treatment of melanoma. The objective of this study was to evaluate the use of a novel intralesional chemotherapy - cisplatin/adrenaline injectable gel - for the treatment of refractory or recurrent cutaneous and soft tissue melanoma metastases. The gel is injected directly into the lesion and delivers high concentrations of cisplatin at the injection site, where it is retained for extended periods, with little systemic exposure. A total of 28 patients with refractory or recurrent melanoma were enrolled in this open-label, multicentre study. Of these, 25 patients with 244 lesions were evaluable for efficacy. Lesions were injected with 0.5 ml (2 mg cisplatin + 0.05 mg adrenaline) of gel/cm(3) of tumour. Patients received up to six weekly treatments within an 8 week period. The objective response rate (complete responses [CRs] plus partial responses [PRs]) for all the tumours treated (1-72 per patient) was 53% (130 out of 244; 114 CRs, 16 PRs). The response rate for the target tumours (i.e. each patient's single, most symptomatic, largest or most threatening tumour) was 44%. The median response duration for all tumours was 347 days (range 30-783 days) and median number of treatments per tumour was five (range one to twelve). Systemic toxicity was negligible; local adverse reactions such as erythema, necrosis or pain occurred frequently, but were easily managed in most cases. In conclusion, cisplatin/adrenaline injectable gel was well tolerated, easy to administer, and effective in treating metastatic melanoma confined to the skin or soft tissues.     

Comparison of hexamethylhypericin and tetrabromohypericin to hypericin for their in vivo efficacy as PDT tools

The present study was performed to evaluate the PDT efficacy, the singlet oxygen yield, and the plasma binding profile of the natural photosensitizer hypericin and two hypericin derivatives, hexamethylhypericin and tetrabromohypericin. All compounds exhibited an excellent 1O2 quantum yield, as documented by TEMP spin trapping experiments. The efficacy of PDT with the different compounds using a P388 lymphoma tumour model was clearly dependent on the interval between drug administration and light irradiation of the tumours. The most effective PDT treatment time was obtained with hypericin (5 mg/kg) using a 30-min drug-light interval, whereas a 24-h interval was optimal for a similar dose of tetrabromohypericin. No significant difference in survival between control animals and animals treated with PDT using tetrabromohypericin (5 mg/kg) was noted when a 30-min, 2- or 6-h interval was used. PDT with hexamethylhypericin (5 mg/kg) using different drug-light intervals was unable to prolong the life span of the tumour-bearing mice. In contrast, a dose of 20 mg/kg hexamethylhypericin, especially when administered 30 min prior to light exposure, produced a profound local reduction of tumour mass and a concomitant significant increase in survival time. The binding of the hypericins to human plasma was evaluated using density-gradient ultracentrifugation. It was found that tetrabromohypericin exhibits an affinity for plasma constituents almost similar to hypericin, in contrast to the more hydrophilic hexamethylhypericin that mainly binds to heavy proteins (e.g. albumin). Since the latter compound showed an efficacy profile similar to hypericin, no correlation could be found between the optimal drug-light interval and the plasma protein binding of the compounds.     

Design of selective peptidomimetic agonists for the human orphan receptor BRS-3

New tool substances may help to unravel the physiological role of the human orphan receptor BRS-3 and its possible use as a drug target for the treatment of obesity and cancer. In continuation of our work on BRS-3, the solid- and solution-phase synthesis of a library of low molecular weight peptidomimetic agonists based on the recently developed short peptide agonist 4 is described. Functional potencies of the compounds were determined measuring calcium mobilization in a fluorometric imaging plate reader (FLIPR) assay. Focusing on the N-terminus, the d-Phe-Gln moiety of 4 was modified in a combinatorial SAR-oriented medicinal chemistry approach. With the incorporation of N-arylated glycine and alanine building blocks azaglycine, piperazine, or piperidine and the synthesis of semicarbazides and semicarbazones, a number of highly potent and selective compounds with a reduced number of peptide bonds were obtained, which also should have enhanced metabolic stability.     

2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels

To locate general anesthetic binding sites on ligand-gated ion channels, a diazirine derivative of the potent intravenous anesthetic, R-(+)-etomidate (2-ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate), has been synthesized and characterized. R-(+)-Azietomidate [2-(3-methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate] anesthetizes tadpoles with an EC(50) of 2.2 microM, identical to that of R-(+)-etomidate. At this concentration both agents equally enhanced GABA-induced currents and decreased binding of the caged-convulsant [(35)S]TBPS to GABA(A) receptors. In all of the above actions R-(+)-azietomidate is about an order of magnitude more potent than S-(-)-azietomidate, an enantioselectivity comparable to etomidate's. R-(+)-Azietomidate also inhibits acetylcholine-induced currents in nicotinic acetylcholine receptors, with about twice the potency of the parent compound. [(3)H]Azietomidate photoincorporated into Torpedo nicotinic acetylcholine receptor-rich membranes. Desensitization decreased photoincorporation into the delta-subunit and increased that into the alpha-subunit. The latter increase was confined to a proteolytic fragment containing the first three transmembrane segments. Thus, R-(+)-azietomidate is a potent stereoselective general anesthetic and an effective photolabel.     

Vascular protective effects of dihydropyridine calcium antagonists. Involvement of endothelial nitric oxide

Dihydropyridine calcium antagonists play an important role in the treatment of hypertension and angina pectoris. They lower blood pressure by a well-characterized mechanism of blocking L-type calcium channels in smooth muscle cells. Additionally, there is growing evidence that dihydropyridines also modulate endothelial functions by other mechanisms, since macrovascular endothelial cells do not express L-type calcium channels. A number of studies have demonstrated that dihydropyridine calcium antagonists enhance bioavailability of endothelial nitric oxide (NO). Endothelium-derived NO plays a pivotal role in the regulation of vasorelaxation, leukocyte adhesion and platelet aggregation and an impaired NO release is associated with the genesis and progression of atherosclerotic diseases. This review summarizes results from experimental findings that dihydropyridine calcium antagonists increase endothelial NO formation as well as studies which demonstrate these effects in vivo both in animals and humans. Moreover, the influence of dihydropyridine calcium antagonists on the progression of atherosclerosis is discussed. These pleiotropic effects of dihydropyridine calcium antagonists may underlie or contribute to antiatherosclerotic effects of this substance class.     

Hope as a predictor of entering substance abuse treatment

Identification of characteristics that predict entry into substance abuse treatment programs may facilitate efforts to make effective programs more attractive to people who could benefit from them. We examined dispositional hope as a predictor of entering a voluntary substance abuse treatment program for federal prison inmates. Controlling statistically for demographics, comorbid diagnoses, and drug-use history, increased hope was associated with lower probability of entering treatment. Discussion focused on the possibility that in the context of incarceration and substance abuse, high levels of hope may serve as a marker of excessive self-reliance and underestimation of the need for professional treatment.     

Worldwide evaluation of a defibrillation lead with a small geometric electrode surface for high-impedance pacing

Background

Pacing leads with a small electrode surface for high-impedance stimulation have been shown to prolong pacemaker longevity, but no sufficient data is available on the safety and feasibility of a defibrillation lead with this novel design.

Methods

We evaluated the clinical performance of a tined, steroid-eluting defibrillation lead with a small electrode surface area (model 6944) in a prospective multicenter study. A total of 542 patients with conventional indications for an implantable cardioverter defibrillator were randomized 1:1 to receive either the model 6944 or a tined, steroid-eluting defibrillation lead with a conventional sized electrode surface area (model 6942). Device performance and electrical parameters were evaluated at implant and 1, 3, 6, and 12 months thereafter (mean follow-up 11.3 ± 5.6 months).

Results

Baseline characteristics, lead implant success rates, and defibrillation thresholds did not differ significantly between the 2 groups. While pacing thresholds did not differ significantly during follow-up, pacing impedance was approximately twice as high in the model 6944 as in the model 6942 lead (P < .0001). Mean R-wave amplitudes were smaller in patients with a 6944 (9.1 ± 3.1 mV vs 9.8 ± 3.6 mV for model 6942, P < .05), but remained stable within both groups throughout the observation period. The total number of ventricular lead-related adverse events and patient survival did not differ significantly between the 2 groups.

Conclusions

The use of a defibrillation lead with a small electrode surface for high-efficiency pacing is safe and feasible and increases pacing impedance without significantly compromising clinical performance.