Biomedical subjects

Henrik Schmidt

Publications and source records attributed to Henrik Schmidt.

14 recordsLinked to original sources

PubMed2006

Elevated serum level of YKL-40 is an independent prognostic factor for poor survival in patients with metastatic melanoma.

BACKGROUND: YKL-40 is a growth factor for connective tissue cells and stimulates migration of endothelial cells. Cancer cells, macrophages, and neutrophils secrete YKL-40. Its function in cancer is unknown. High serum YKL-40 levels have been associated with a poor prognosis in patients with several solid tumors. The prognostic impact of serum YKL-40 in metastatic melanoma was evaluated. METHODS: YKL-40 was measured in serial serum samples from 110 patients with metastatic melanoma obtained immediately before and during treatment and from 245 healthy subjects. RESULTS: Patients had higher serum YKL-40 values than healthy subjects (P < 0.001). Pretreatment serum YKL-40 was elevated in 45% of the patients and correlated to site of metastases (P = 0.03) and poor performance status (P = 0.002). Multivariate Cox analysis showed that serum YKL-40 (hazard ratio [HR] = 1.9; 95% confidence interval [CI], 1.2-2.8; P = 0.004) and serum lactate dehydrogenase (LDH) (HR = 1.9; 95% CI, 1.2-2.9; P = 0.004) were independent prognostic factors for survival. A combination variable of elevated serum YKL-40 and LDH quadrupled the risk of early death (HR = 4.4; 95% CI, 2.5-7.7; P < 0.001) compared with patients with normal levels. The combination of YKL-40 and LDH had a stronger prognostic impact than the American Joint Committee on Cancer (AJCC) Stage IV classification. Furthermore, serum samples were available from 12 patients during followup. In 9 of 11 patients a significant increase in serum YKL-40 was observed together with disease progression. In one patient with a lasting complete response, serum YKL-40 remained normal. CONCLUSIONS: An elevated serum YKL-40 was an independent prognostic factor for poor survival in patients with metastatic melanoma. When combining serum YKL-40 and LDH, patients could be separated into three prognostic groups based on the number of elevated biomarkers. The findings should be validated in an independent study.

Adipokines↗

PubMed2006

Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2 restricted MART-1 T-cell receptor: a phase I trial in metastatic melanoma.

PURPOSE: We did a phase I dose-escalation trial to evaluate the feasibility and safety of intratumoral injections of C Cure 709, an allogeneic, continuous CTL cell line that, restricted by HLA-A2, recognizes MART-1-positive tumor cells through transduction with a T-cell receptor encoding gene. EXPERIMENTAL DESIGN: Cells were administered intratumorally in four dose levels ranging from 10(8) to 10(9) cells/d on days 1, 4, 7, 10, 14, and 28 of each treatment cycle to patients with metastatic melanoma. Main inclusion criteria were HLA-A2 tissue type, MART-1-positive tumor cells, and metastases suitable for ultrasound-guided injections. Patients were assessed for toxicity and response. Three to six patients were treated per dose level. Patients without progressive disease were offered up to three treatment cycles. RESULTS: Fifteen patients received a total of 24 treatment cycles with a total of 266 injections of C Cure 709. Toxicity was minor to moderate and most common injection site reactions were fever, fatigue, nausea/vomiting, and arthralgia/myalgia. Side effects disappeared in general within 24 hours. Toxicity was not dose dependent. One patient obtained a partial response, encompassing both metastases used and not used for intratumoral injections. Remaining patients did not achieve an overall response. In addition, we observed local regression of metastases used for injection in two patients and of metastases not used for injection in one patient. CONCLUSION: Intratumoral injections of C Cure 709 are feasible, safe, and capable of inducing tumor regression. Further investigation in a phase II setting is warranted.

Adult↗

PubMed2006

[Levosimendan--an alternative to conventional inotropic treatment of patients with acute heart failure?].

In acute heart failure the myocardial function is acutely reduced and the oxygenation of the tissues becomes inadequate. Traditional inotropic drugs improve the haemodynamics and give symptomatic relief, but the evidence of injurious effects on morbidity and mortality restricts their use. The need for new inotropic drugs which can also reduce morbidity and mortality is for that reason obvious. Levosimendan is such a new drug in a new class (Ca2+ sensitizers) of positive inotropic drugs with favourable effects compared to existing treatment possibilities.

Cardiotonic Agents↗

PubMed2006

Serum YKL-40 predicts relapse-free and overall survival in patients with American Joint Committee on Cancer stage I and II melanoma.

PURPOSE: To evaluate the novel tumor biomarker YKL-40 in serial serum samples from patients with American Joint Committee on Cancer (AJCC) stage I and II melanoma from the time of diagnosis and during routine follow-up. Macrophages, neutrophils, and cancer cells secrete YKL-40, and a high serum level has been associated with poor prognosis in patients with several cancer types. PATIENTS AND METHODS: Serum samples from 234 patients with stage I (n = 162) and II (n = 72) melanoma were analyzed for YKL-40 by enzyme-linked immunosorbent assay. Serial samples were obtained before definitive primary surgery and during follow-up. RESULTS: After a median follow-up period of 66 months (range, 1 to 97 months), 41 relapses (18%) and 39 deaths (17%) were observed. Serum YKL-40 treated as an updated continuous covariate were analyzed together with the covariates sex, age, primary tumor site, ulceration, thickness, Clark level and histologic subtype in a Cox proportional hazard model. Serum YKL-40 was an independent prognostic factor of relapse-free survival (hazard ratio [HR], 1.6; 95% CI, 1.1 to 2.5; P = .03) and overall survival (HR, 1.8; 95% CI, 1.2 to 2.6; P = .002) together with thickness and ulceration. The serum level of YKL-40 (dichotomized as normal or elevated) at the time of diagnosis was also an independent prognostic factor for overall survival (HR, 3.6, 95% CI, 1.7 to 7.7; P = .001). CONCLUSION: Serum YKL-40 may be an early biomarker of relapse and survival in patients with AJCC stage I and II melanoma. Serum YKL-40 may also be useful for patient stratification and follow-up in clinical trials. Our results need confirmation in an independent study.

Adipokines↗

PubMed2006

Circulating tyrosinase and MART-1 mRNA does not independently predict relapse or survival in patients with AJCC stage I-II melanoma.

The detection of melanoma cells in peripheral blood has been proposed to select patients with a high risk of relapse. In this study, tyrosinase and melanoma antigen recognized by T cells 1 (MART-1) mRNA expression was evaluated in serial samples obtained before definitive surgery and during follow-up in patients with American Joint Committee on Cancer stage I-II melanoma. Serial samples (n=2,262) were collected from 236 patients from 1997 to 2002. Analyses of the RNA samples were performed with a calibrated reverse transcriptase-PCR assay. Gender, age, primary tumor site, ulceration, thickness, Clark level, and histological subtype were analyzed together with tyrosinase and MART-1 mRNA treated as updated covariates in a Cox proportional-hazard model. After a median follow-up time of 66 months, 42 out of 236 patients (18%) had relapsed. The following variables were significantly associated with relapse-free survival in the univariate analyses: tyrosinase, MART-1, gender, ulceration, thickness, Clark level, and histological subtype. Entering these covariates into a multivariate Cox analysis resulted in thickness as the single independent prognostic factor (P<0.0001), whereas MART-1 (P=0.07) approached significance at the 5% significance level. The serial measurements of tyrosinase and MART-1 mRNA in peripheral blood of stage I-II melanoma patients cannot be demonstrated to have independent prognostic impact on relapse-free survival.

Adult↗

PubMed2006

Tumour-associated macrophages are related to progression in patients with metastatic melanoma following interleukin-2 based immunotherapy.

The aim of the present study was to analyze whether leukocyte subsets in peripheral blood and tumour biopsies obtained before treatment were able to predict response or survival in patients with metastatic melanoma following Interleukin-2 (IL-2) based immunotherapy. Flow cytometry was performed on peripheral blood for CD4(+) T cells, CD8(+) T cells and CD56(+) natural killer (NK) cells. Immunohistochemical analyses were used to identify CD4(+) T cells, CD8(+) T cells, CD57(+) NK cells and CD64(+) (macrophages) cells in tumour biopsies. High numbers of tumour-associated CD64(+) macrophages in tumour biopsies were statistically significantly associated with poor response to treatment. Our data suggest that tumour-associated macrophages may correlate negatively with response, which may be of biological importance for IL-2 based immunotherapy of malignant melanoma.

Adult↗

PubMed2006

Subcritical scattering from buried elastic shells.

Buried objects have been largely undetectable by traditional high-frequency sonars due to their insignificant bottom penetration. Further, even a high grazing angle sonar approach is vastly limited by the coverage rate dictated by the finite water depth, making the detection and classification of buried objects using low frequency, subcritical sonar an interesting alternative. On the other hand, such a concept would require classification clues different from the traditional high-resolution imaging and shadows to maintain low false alarm rates. A potential alternative, even for buried targets, is classification based on the acoustic signatures of man-made elastic targets. However, the elastic responses of buried and proud targets are significantly different. The objective of this work is to identify, analyze, and explain some of the effects of the sediment and the proximity of the seabed interface on the scattering of sound from completely and partially buried elastic shells. The analysis was performed using focused array processing of data from the GOATS98 experiment carried out jointly by MIT and SACLANTCEN, and a new hybrid modeling capability combining a virtual source-or wave-field superposition-approach with an exact spectral integral representation of the Green's functions for a stratified ocean waveguide, incorporating all multiple scattering between the object and the seabed. Among the principal results is the demonstration of the significant role of structural circumferential waves in converting incident, evanescent waves into backscattered body waves, emanating to the receivers at supercritical grazing angles, in effect making the target appear closer to the sonar than predicted by traditional ray theory.

Humans↗

PubMed2005

A phase II trial of low-dose total body irradiation and subcutaneous interleukin-2 in metastatic melanoma.

BACKGROUND AND PURPOSE: Our own experimental data suggests a therapeutic synergism between low-dose total body irradiation (LTBI) and interleukin-2 (IL-2). PATIENTS AND METHODS: Forty-five patients received a maximum of 2 cycles of high dose subcutaneous (s.c.) IL-2 and LTBI. One treatment cycle included 5 weeks treatment followed by 2 weeks break and composed of a single radiation fraction 0.1 Gy on days 1, 8, 22 and 30 and IL-2: 18 MU x 2 daily s.c. on days 2 to 5 and days 16-19 as well as 9 MU x 2 daily s.c. on days 9-12 and 31-34. In 17 patients, flow cytometric analyses of the various subpopulations of immune cells were done on blood samples before the first LTBI fraction and 24h after LTBI as well as after the first week of treatment. RESULTS: Two patients (4.4%) had a partial response (PR) and 13 patients (29%) had stable disease (SD). The duration of the partial remission and stable disease did not exceed 3 months. The median overall survival was 5.8 months (95% CI, 4-8 months). Thirty-four of the 58 treatment cycles (74%) were given in 100% of the intended dose without modification or delay. The dose was modified in 15 cycles (26%) because of progression (6), liver toxicity (3), CNS toxicity (2), thrombocytopenia (1), lung morbidity (1) and itching (1). There were no treatment-related deaths. Flowcytometry data showed a significant increase in the percentage of cells carrying the beta chain of IL-2 receptor (CD122+), a significant increase in the percentage of NK cells (CD56+ cells) as well as a significant reduction in the percentage of B cells (CD20+) and monocytes (CD14+). CONCLUSIONS: This LTBI and IL-2 regimen was well tolerated, however it cannot be recommended because of its low clinical efficacy. No indication of increased efficacy or altered toxicity was seen using LTBI.

Adult↗

PubMed2005

Tyrosinase messenger RNA in peripheral blood is related to poor survival in patients with metastatic melanoma following interleukin-2-based immunotherapy.

This study was conducted to examine the prognostic impact of four biomarkers [tyrosinase and MART-1 messenger RNA (mRNA), S100beta protein and lactate dehydrogenase (LDH)] in patients with metastatic melanoma, together with established clinical factors. Tyrosinase and MART-1 mRNA were measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). S100beta was measured using a commercially available immunoassay, and LDH was analysed conventionally. All markers were measured in blood samples before interleukin-2-based immunotherapy in 85 patients with metastatic melanoma. LDH, S100beta, tyrosinase, number of metastatic sites, location of metastatic sites and performance status were all significant factors for survival in univariate analyses. In multivariate analysis, tyrosinase [hazard ratio (HR)=1.6; 95% confidence interval (CI), 1.1-2.6; P=0.04] and LDH (HR=2.0; 95% CI, 1.1-3.5; P=0.02) were both independent prognostic factors for survival. A combination variable of tyrosinase and LDH remained independently associated with survival (P=0.04) after adjusting for the American Joint Committee on Cancer (AJCC) stage IV classification in a multivariate analysis involving both models. It can be concluded that tyrosinase mRNA and elevated LDH are independent prognostic factors for poor survival in this group of 85 patients. Additional studies are needed before the prognostic value of tyrosinase mRNA in metastatic melanoma can be firmly established. Further evaluation of the combined measurement of tyrosinase mRNA and LDH is warranted.

Adult↗

PubMed2004

S100beta protein in peripheral blood may predict progressive disease during interleukin-2 based immunotherapy in patients with metastatic melanoma.

The aim of this study was to evaluate the biological variation in the serum level of S100beta protein in untreated patients with metastatic melanoma and to use this variation to subsequently evaluate serum levels as a method of monitoring objective response to interleukin-2 (IL2) based treatment. Such an approach has not, to our knowledge, been published previously. Consecutive blood samples were collected before, during and after treatment and in the follow-up period from 66 patients treated with IL2-based immunotherapy. In 11 of these patients, a further three samples were drawn on each of 3 days prior to treatment to evaluate the variation in S100beta. This variation was later used to distinguish between increased, unchanged or decreased S100beta levels during treatment. We observed a significant association between changes in S100beta levels and clinical outcome after the first and second treatment cycles. All responding patients had a decline in S100beta levels or normal values during the first cycle. Changes in S100beta levels after the first cycle and the type of treatment were independent predictive factors for the clinical outcome in multivariate analysis. In conclusion, increasing S100beta values were independently associated with progressive disease, and our data suggest that significant changes in S100beta levels may be valuable for monitoring and predicting clinical outcome during IL2-based immunotherapy and chemoimmunotherapy.

Adult↗

PubMed2004

The influence of immunohistochemistry on mRNA recovery from microdissected frozen and formalin-fixed, paraffin-embedded sections.

Laser-assisted microdissection (LAM) is now widely used to obtain specific cell populations from heterogeneous tissues. A major disadvantage of LAM is poor tissue morphology during microscopy, in part because coverslips are not used. Immunohistochemical labeling can improve identification of target cells but may affect the subsequent analysis of the microdissected tissue. We studied the effect of immunohistochemistry (IHC) on mRNA recovery from labeled cells after microdissection from both frozen and formalin-fixed, paraffin-embedded (FFPE) sections, using Melan-A and Ki-67 staining in lymph nodes with metastatic melanoma as a model. We developed rapid protocols for immunostaining in an attempt to limit loss of mRNA during procedures. A sensitive real-time quantitative reverse transcription-PCR was used to measure mRNA. We found a marked decrease in the mRNA yield from 500 microdissected cells from frozen and paraffin sections after immunostaining for both markers. Recovery of mRNA decreased by up to 89%, comparing the immunostained with the routinely stained sections. Interestingly, the ratio between mRNA for the two markers was similar in all stains, indicating that immunostained sections may be used for mRNA analysis. We also investigated the effect of storing membrane-mounted sections for microdissection under different conditions. Slides mounted with paraffin sections could be stored at room temperature for up to 90 days with no significant decrease in mRNA recovery.

Actins↗

PubMed2003

Spectral integral representations of monostatic backscattering from three-dimensional distributions of sediment volume inhomogeneities.

A theory is developed for generating short time, monostatic reverberation realizations caused by three-dimensionally distributed volume inhomogeneities in stratified media. A wave number integral approach to treating the propagation to and from the scatterers, combined with a two-dimensional spectral representation of the azimuthally averaged scatterer realizations and a novel numerical implementation, combine to yield an efficient, high fidelity reverberation simulator for predicting monostatic backscatter from horizontally stratified sediments.

Journal Article↗

PubMed2002

[Opioid detoxication under general anesthesia].

Antagonist-precipitated opioid detoxification under general anaesthesia has been used extensively since its introduction in 1988. The use of antagonists was believed to shorten the detoxification period. Administration to opioid dependents is followed by a violent activation of the adrenergic system, which results in the development of an acute withdrawal syndrome in the patient. This is usually treated with clonidine. To reduce the subjective discomfort, the procedure is conducted under anaesthesia. From the existing literature, one may conclude that despite more than ten years of development there is currently no sufficient evidence of the effectiveness of antagonist-precipitated opioid detoxification under general anaesthesia conducted under modern anaesthesiological management. Randomised, clinical trials are necessary to document the advantages of this detoxification method as compared to conventional treatment.

Anesthesia, General↗

PubMed2002

[Immunotherapy of cancer].

Significant advances in the understanding of the cells and molecules involved in tumour/host interactions in humans have been made over the last decades. Thus, through studies of the interactions between cells of the immune system and cancer cells, several tumour antigens and their epitopes recognised by human leucocyte antigen class I-restricted cytotoxic T lymphocytes have been identified. Likewise, specialised antigen presenting cells have been characterised and methods developed that allow the use of such cells in clinical immunology. In the clinic, systemic administration of immune stimulatory cytokines, in particular IL-2, has strengthened the notion that the immune system is capable of mediating rejection of cancer. More recently, more sophisticated methods of inducing anti-cancer immune responses have been pursued, for instance the use of antigen presenting cells in combination with various sources of antigen and cytokines for therapeutic vaccinations against cancer. The present paper summarizes current knowledge in the field of tumour immunology, and reviews various approaches undertaken with the aim of inducing strong anti-tumour responses. To this end, we review data from clinical trials, and discuss the potential of these treatment modalities as an adjunct to conventional modes of cancer treatment. Further, novel methodologies for monitoring and analysing cancer patients over the course of immunotherapeutic treatments are described, and future directions put forward.

Antineoplastic Agents↗