MRI after magnetic drug targeting in patients with advanced solid malignant tumors

The purpose of this study was to evaluate the ability of MRI to detect magnetic particle uptake into advanced solid malignant tumors and to document the extension of these tumors, carried out in the context of magnetic drug targeting. In a prospective phase I trial, 11 patients were examined with MRI before and after magnetic drug targeting. The sequence protocol included T1-WI and T2-WI in several planes, followed by quantitative and qualitative evaluation of the signal intensities and tumor extensions. In nine patients, a signal decrease was observed in the early follow-up (2–7 days after therapy) on the T2-weighted images; two patients did not show a signal change. The signal changes in T1-WI were less distinct. In late follow-up (4–6 weeks after therapy), signal within nine tumors reached their initially normal level on both T1-WI and T2-WI; two tumors showed a slight signal decrease on T2-WI and a slight signal increase on T1-WI. Within the surveillance period, tumor remission in 3 out of 11 patients was observed, and in 5 patients tumor growth had stopped. The remaining three patients showed significant tumor growth. There was no statistically significant correlation between signal change and response. MRI is a suitable method to detect magnetite particles, deposited at the tumor site via magnetic drug targeting. MRI is therefore eligible to control the success of MDT and to assess the tumor size after the end of therapy.The used data are part of the thesis of M.-I. Senfft von Pilsach.     

Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells

Although the existence of a humoral response against tumor-associated antigens is well appreciated, a systematic analysis of its possible induction by the tumor remains missing. We compared the specific IgG response of Stage IV melanoma patients during vaccination. Patients had been treated within 2 clinical trials with autologous tumor cells gene-modified for IL-7 or IL-12. A panel of 27 tumor-associated antigens (HD-MM-01 to HD-MM-27) was isolated by a SEREX screening of a testis cDNA library using a pool of 5 sera from patients after vaccination. All antigens were retested with individual sera of 12 patients both pre- and post-vaccination. A serological response was induced during vaccination against 18 antigens. Remarkably, induction was detected only in patients included in the screening pool. The low overlap between sero-reactivity of the 12 patients suggested a very individualized immunological reaction. Two of 5 sera included in the screening pool exhibited a high frequency of induced humoral responses. The same patients had been shown to have a high Karnovsky index and had generated lytic cytotoxic T cells against the tumor. Besides 2 known cancer-germline genes (SCP-1 and PLU-1), the other isolated antigens were expressed in a non-tumor-specific fashion as analyzed by virtual Northern blot or RT-PCR. The properties of homologues to several of the identified tumor-antigens, especially PLU-1, SCP-1, DNEL2, CLOCK, and PIASx-alpha, suggest further investigation of their possible function in malignant melanoma. We conclude that a strong humoral response against tumor-associated antigens is inducible by tumor cells and that this response is very individual.     

Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis

OBJECTIVE: Lupus nephritis (LN) is a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is evidence that polymorphisms in the genes of inflammatory mediators may predispose to the development of LN in patients with SLE. In this study, we examined the role of a functional monocyte chemoattractant protein 1 (MCP-1) polymorphism in SLE and LN. METHODS: DNA and paired urine and serum samples were obtained from 134 SLE patients (> or =4 American College of Rheumatology criteria for SLE; 49 with and 85 without LN) and 118 controls. MCP-1 genomic variants were detected by polymerase chain reaction followed by restriction enzyme-fragment analysis. Urinary and serum MCP-1 levels and MCP-1 production by peripheral blood macrophages were measured by enzyme-linked immunosorbent assay. RESULTS: The A/A genotype was more common in controls than in SLE patients (P = 0.0002), whereas both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE patients. The A/A genotype was observed in only 23% of the patients with LN compared with 58% of those without LN (P < 0.0001). MCP-1 production by peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes was markedly higher than the production by cells from patients with the A/A genotype. Urinary levels of MCP-1 were significantly higher in patients with LN. CONCLUSION: These results suggest that an A/G or G/G genotype may predispose to the development of SLE and further indicate that SLE patients with these genotypes may be at higher risk of developing LN. Moreover, measurement of urinary levels of MCP-1 may be a useful tool for the detection and management of LN.     

Screening for mutations of the IRP2 gene in Parkinson’s disease patients with hyperechogenicity of the substantia nigra

Summary. IRP2 plays an important role in brain iron metabolism. We recently identified an increased amount of iron in patients with Parkinsons disease (PD) and hyperchogenicity of the substantia nigra (SN). Therefore, the IRP2 gene was screened for mutations in 176 PD patients with increased echogenicity of the SN. We identified one non-synonymous polymorphism (I888V) in exon 21 and a –88C > T polymorphism in the promoter region of IRP2 at similar frequencies in patients and controls without increased SN iron levels. In one patient a –74C > T variation was found which was not present in the control group. Our data indicate that mutations in the IRP2 gene are not a common cause of PD associated with SN iron accumulation.     

Effectiveness of a multidisciplinary treatment program for chronic daily headache

BACKGROUND: Chronic daily headache (CDH: headache on fifteen days a month or more) is one of the most common forms of chronic pain. The relative efficacy of different treatment methods for these patients needs to be determined. OBJECTIVE: To compare treatment outcomes for patients with CDH treated in a traditional office-based pharmacological treatment program with a second group treated in a multidisciplinary management program. METHODS: Patient outcomes were measured using changes in the Headache Disability Inventory (HDI) and the Short-Form-36 (SF-36) over the treatment period. Outcomes from seventy patients treated in an office setting were compared to thirty-seven patients treated in a multidisciplinary headache treatment program. Both groups received similar pharmacological treatment. All patients treated in the office setting and the majority of patients in the multidisciplinary program had transformed migraine. RESULTS: Even though a reduction in headache days per month occurred, mean headache related disability (measured by HDI) and mean Health Related Quality of Life (HRQoL measured by SF-36) did not improve for the patient group treated in the office setting but did improve significantly for the patient group treated in the multidisciplinary headache program. CONCLUSION: For patients with CDH, headache-related disability and HRQoL is more likely to improve with management in a multidisciplinary headache treatment program as compared to the traditional specialist consultation-family physician office-based setting.     

Effects of verteporfin therapy on central visual field function

PURPOSE: To evaluate the effect of photodynamic therapy with verteporfin on the maintenance of central visual field function. DESIGN: Randomized controlled clinical trial. PARTICIPANTS: Forty-six consecutive patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration including a classic component were randomly assigned. Thirty-three participants received standard verteporfin therapy, and 13 received placebo and laser treatment. METHODS: The trial was performed as a single-center, double-masked study. Patients were examined before therapy and continuously in 3-month intervals during 2 years of follow-up. A scanning laser ophthalmoscope (SLO) was used to perform macular microperimetry. Absolute and relative scotomas were documented at each visit, and size was measured in square millimeters. MAIN OUTCOME MEASURES: The change in size of central scotoma in the verteporfin group compared with the placebo group. RESULTS: An absolute scotoma was seen in 88%, and a relative scotoma was seen in 100% of eyes before therapy. Absolute defects were associated with the classic CNV component localized angiographically. In the verteporfin group, the absolute scotoma grew from 2.5 mm(2) at baseline to a final size of 7.3 mm(2) at month 24. In the placebo group, the mean lesion size of the absolute scotoma enlarged from an initial size of 2.7 mm(2) to 31.5 mm(2) after 24 months. The relative scotoma increased from 7.9 mm(2) at baseline to 20.8 mm(2) at month 24 in the verteporfin group, whereas a progression from 8.5 mm(2) initially to 48.3 mm(2) at the final presentation was measured in the placebo group. Statistical analysis showed that both the mean absolute and relative scotoma sizes were significantly smaller in the verteporfin group than the placebo group for all intervals from 6 to 24 months (P<0.001). CONCLUSIONS: Documentation of macular function with SLO perimetry demonstrated a significant benefit of verteporfin therapy for the preservation of the central visual field. Absolute and relative scotoma sizes remained smaller after therapy. This may influence reading ability and visual rehabilitation.     

Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour

The suppression and eradication of malignant tumours by targeting the endothelial cells of the tumour is one of the rapidly evolving new approaches to cancer therapy. Head and neck tumours, because of their high levels of vascularization, present themselves as ideal candidates for such antiangiogenic strategies. We report a heavily pretreated patient with a tumour 15 cm in diameter representing fourth relapse of squamous cell carcinoma, which had its origin in the upper left jaw. The patient was treated with the antiangiogenetic, cyclic peptide, EMD 121974 [cilengitide] (600 mg/m2 over 60 minutes i.v.) on day 1 and 4 in combination with gemcitabine (1000 mg/m2 over 30 minutes) administered days 1 and 8 every 3 weeks for five months, and a partial remission was achieved. This resulted in a clinical improvement in the ability of the patient to eat and smell. The patient remained stable for 12 months on cilengitide mainenance therapy, with no tendency towards spontaneous bleeding. This clinical case demonstrates the clinical efficacy of the antiangiogenetic agent cilengitide, in combination with gemcitabine, in inhibiting rapid growth of highly vascularized tumour and highlights the potential of this new therapeutic agent