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Biomedical subjects

Daniel Fink

Publications and source records attributed to Daniel Fink.

At least 19 recordsLinked to original sources
PubMed2006

Should intraperitoneal chemotherapy be considered as standard first-line treatment in advanced stage ovarian cancer?

Current standard therapy for patients with advanced stage epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy with paclitaxel and carboplatin. Intraperitoneal (IP) chemotherapy has demonstrated improved outcome compared to standard intravenous treatment in three large randomized phase III trials and confirmed by Cochrane meta-analysis. Although compelling evidence suggests that IP therapy provides survival benefit in a selected group of ovarian cancer patients, it remains unclear which group of patients will really benefit from IP therapy, which is the optimal drug, dose and combination, and what is the real benefit of IP treatment alone. Other concerns about IP therapy are difficulties in completing the assigned treatment and management of its pattern of toxic side-effects. Today, IP chemotherapy has yet to gain a role as standard first-line treatment in advanced stage ovarian cancer. In the near future, efforts should aim at developing an effective IP regimen and research undertaken for a better understanding of the peritoneal environment.

Antineoplastic Agents↗
PubMed2006

Low meprin alpha expression differentiates primary ovarian mucinous carcinoma from gastrointestinal cancers that commonly metastasise to the ovaries.

BACKGROUND: Currently, no specific immunohistochemical markers are available to differentiate primary mucinous epithelial ovarian cancer (MOC) from adenocarcinomas originating at other sites that have metastasised to the ovary, which may have an impact on patient management and prognosis. AIM: To investigate the expression of two intestinal markers, galectin 4 and meprin alpha, in mucinous carcinomas of the ovary and gastrointestinal tract. METHODS: Using immunohistochemical analysis, the expression of galectin 4 and meprin alpha was investigated in 10 MOCs and in 38 mucinous adenocarcinomas of colon, pancreas, stomach and appendix, the most common sites of origin of ovarian metastases. RESULTS: Total cytoplasmic galectin 4 expression was relatively consistent between the different carcinomas. Membranous meprin alpha expression was significantly lower in MOCs compared with gastrointestinal carcinomas. Moreover, meprin alpha expression showed greater discrimination between the ovarian and gastrointestinal carcinomas than the cytokeratins CK7 and CK20, the current standard immunohistochemical markers used to determine the tissue origin of mucinous carcinomas involving the ovaries. CONCLUSIONS: Meprin alpha is a useful additional marker in differentiating primary from secondary mucinous adenocarcinomas of the ovary.

Adenocarcinoma↗
PubMed2006

MLH1-deficient tumor cells are resistant to lipoplatin, but retain sensitivity to lipoxal.

Lipoplatin, currently under phase III evaluation, is a novel liposomal cisplatin formulation highly effective against cancers. Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for cisplatin. The objective of the present study was to determine whether the cytotoxic effect of lipoplatin is dependent on the functional integrity of DNA mismatch repair (MMR), a post-replicative DNA repair machinery implicated in cell cycle control and apoptosis. Clonogenic data revealed a significant (P<0.05) 2-fold resistance to lipoplatin of HCT116 human colorectal adenocarcinoma cells lacking MLH1, one of five proteins crucial to MMR function, as compared to MLH1-expressing HCT116 cells. In addition, MLH1-deficient cells were at least 3-fold less susceptible to apoptosis (DNA fragmentation) than MLH1-proficient cells. However, proteolytic processing of caspase-3, caspase-7 and poly(ADP-ribose)polymerase-1 following lipoplatin treatment was comparable in MLH1-deficient cells and -proficient cells. Furthermore, MLH1-deficient cells retained the ability to attenuate cell cycle progression past the G2/M checkpoint following lipoplatin treatment. In conclusion, our results indicate that the lipoplatin-sensitive phenotype of MLH1-proficient cells correlated with increased apoptosis which may occur via caspase-independent pathways. They also suggest that the integrity of MMR function is a relevant determinant accounting for the cytotoxicity of lipoplatin. However, this does not seem to apply to lipoxal, a novel liposomal formulation of oxaliplatin, because MLH1-deficient cells were as sensitive to lipoxal as MLH1-proficient cells.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial.

BACKGROUND: The role of cytoreductive surgery in relapsed ovarian cancer is not clearly defined. Therefore, patient selection remains arbitrary and depends on the center's preference rather than on established selection criteria. The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer (DESKTOP OVAR) trial was undertaken to form a hypothesis for a panel of criteria for selecting patients who might benefit from surgery in relapsed ovarian cancer. METHODS: The DESKTOP trial was an exploratory study based on data from a retrospective analysis of hospital records. Twenty-five member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee (AGO OC) and AGO-OVAR boards collected data on their patients with cytoreductive surgery for relapsed invasive epithelial ovarian cancer performed in 2000-2003. RESULTS: Two hundred and sixty-seven patients were included. Complete resection was associated with significantly longer survival compared with surgery leaving any postoperative residuals [median 45.2 vs. 19.7 months; hazard ratio (HR) 3.71; 95% confidence interval (CI) 2.27-6.05; P < .0001]. Variables associated with complete resection were performance status (PS) [Eastern Cooperative Oncology Group (ECOG) 0 vs. > 0; P < .001], International Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (FIGO I/II vs. III/IV, P = .036), residual tumor after primary surgery (none vs. present, P <.001), and absence of ascites > 500 ml (P < .001). A combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79% of patients. CONCLUSIONS: Only complete resection was associated with prolonged survival in recurrent ovarian cancer. The identified criteria panel will be verified in a prospective trial (AGO-DESKTOP II) evaluating whether it will render a useful tool for selecting the right patients for cytoreductive surgery in recurrent ovarian cancer.

Adult↗
PubMed2006

Does mitral valve intervention have an impact on late survival in ischemic cardiomyopathy?

BACKGROUND: Ischemic mitral regurgitation is associated with reduced survival after coronary artery bypass surgery. OBJECTIVES: To compare long-term survival among patients undergoing coronary surgery for reduced left ventricular function and severe ischemic MR in whom the valve was repaired, replaced, or no intervention was performed. METHODS: Eighty patients with severe left ventricular dysfunction and severe MR underwent coronary bypass surgery. The mean age of the patients was 65 years (range 42-82), and 63 (79%) were male. Sixty-three (79%) were in preoperative NYHA functional class III-IV (mean NYHA 3.3), and 26 (32%) were operated on an urgent/emergent basis. Coronary artery bypass surgery was performed in all patients. The mitral valve was repaired in 38 and replaced in 14, and in 28 there was no intervention. The clinical profile was similar in the three groups, although patients undergoing repair were slightly younger. RESULTS: Operative mortality was 15% (8%, 14%, and 25% for the repair, replacement and no intervention respectively; not significant). Long-term follow up was 100% complete, for a mean of 38 months (range 2-92). Twenty-nine patients (57%) were in NYHA I-II (mean NYHA 2.3). Among the surgery survivors, late survival was improved in the repair group compared to the other groups (P < 0.05). Predictors for late mortality were non-repair of the mitral valve, residual MR, and stroke (P = 0.005). CONCLUSIONS: Patients with severe ischemic cardiomyopathy and severe MR undergoing coronary bypass surgery should have a mitral procedure at the time of surgery. Mitral valve repair offers a survival advantage as compared to replacement or no intervention on the valve. Patients with residual MR had the worst results.

Adult↗
PubMed2006

Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.

Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.

Adaptor Proteins, Signal Transducing↗
PubMed2005

[Obstetric/Prenatal ultrasound: blessing or burden?].

Sonography has led to tremendous advances in prenatal care, but these advances have given rise to expectations that cannot always be fulfilled. In consequence, women who hae had children with malformations not detected antenatally have sought legal recourse. By establishing a system of training, certification and quality control at European level, physicians can actively contribute to the advancement of our field while limiting the potential for unnecessary problems.

Austria↗
PubMed2005

Current concepts of treatment strategies in advanced or recurrent ovarian cancer.

Ovarian cancer is the fifth most common cause of death from cancer in women. The standard first-line treatment for advanced ovarian cancer is a combination of paclitaxel and carboplatin or carboplatin alone. Sequential single-agent therapy is of particular interest in patients with symptom-free disease progression. Age, performance status and treatment preferences of the respective patient are further decisive factors which should be taken into account when selecting single or combination therapy. Second-line treatment depends, for instance, on the duration of response to first-line platinum therapy, previous treatment regimens used, tolerability, the patient's performance status and preference of a particular treatment, and cost-effectiveness. If tumor recurrence occurs within 6 months following platinum-based therapy, other agents such as paclitaxel, pegylated liposomal doxorubicin, topotecan or gemcitabine should be used. If the tumor recurs after 6 months, a combination therapy of platinum and paclitaxel has proven to be the most effective. Reasonable options in progressive disease are treatment with platinum, either alone or combined with other agents, especially investigational compounds.

Antineoplastic Agents↗
PubMed2005

Presence of MLH1 protein aggravates the potential of the HSP90 inhibitor radicicol to sensitize tumor cells to cisplatin.

MLH1 is one of five proteins crucial to DNA mismatch repair (MMR) function the loss of which is associated with a cisplatin resistance phenotype in tumor cells. An experimental approach was designed to determine whether the presence or absence of MLH1 affects the potential of radicicol to increase the sensitivity of tumor cells to cisplatin and oxaliplatin, and whether perhaps radicicol increases sensitivity to cisplatin specifically in cisplatin-resistant, MLH1-deficient cells. Radicicol is a novel specific inhibitor for heat shock protein 90 (HSP90) and structurally unrelated to geldanamycin. Clonogenic data demonstrated that sublethal concentrations of radicicol increased the sensitivity to cisplatin and to oxaliplatin in both MLH1-proficient cells and MLH1-deficient cells. Notably, the radicicol-imposed increase in sensitivity to cisplatin was up to 1.6-fold higher in MLH1-proficient cells than in MLH1-deficient cells, whereas no difference in the extent of the increase in sensitivity between the two sublines was observed for oxaliplatin. This indicates that the presence of MLH1 protein aggravates the radicicol-imposed increase in sensitivity of cells to cisplatin but not to oxaliplatin. However, the increases in platinum drug sensitivity imposed by radicicol observed in the clonogenic assay were not accompanied by reproducible alterations in the susceptibility to apoptosis and to changes in cell cycling. Although not conclusive at this point, the results seem to argue against radicicol as a means to selectively re-sensitize cisplatin-resistant, MLH1-deficient tumor cells to this drug. But they may point to a possible functional relationship between HSP90 and MLH1, where HSP90 might affect the function of MLH1 in a way that this leads to the counter-regulation of cytotoxic pathways initiated by MMR as a consequence of the presence of DNA damage introduced by cisplatin.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Analytical and clinical evaluation of the Bayer ADVIA Centaur automated B-type natriuretic peptide assay in patients with heart failure: a multisite study.

BACKGROUND: B-Type natriuretic peptide (BNP) is released from the left ventricle of the heart into the circulation in response to ventricular stretching and volume overload. Increased BNP concentrations are associated with heart failure (HF). METHODS: We evaluated the analytical and clinical performance of the Bayer ADVIA Centaur BNP assay. Studies included precision, analytical correlation (against the Shionogi ShionoRIA and Biosite Triage BNP assays), BNP results for blood collected in plastic tubes containing EDTA vs other collection tubes, high-dose hook effect, detection limits, and interferences. The clinical performance was tested on 2243 blood samples collected from 983 apparently healthy individuals, 538 patients with chronic disease but without HF (renal insufficiency, chronic obstructive pulmonary disease, diabetes, and hypertension), and 722 patients with HF (New York Heart Association classes I-IV). RESULTS: The ADVIA Centaur assay had total imprecision (CV) of 3.4%, 2.9%, and 2.4% at BNP concentrations of 48, 461, and 1768 ng/L, respectively. The Passing-Bablok correlations to the ShionoRIA and Triage were as follows: ADVIA Centaur = 1.11(ShionoRIA) - 1.19 ng/L (r = 0.98); ADVIA Centaur = 0.78(Triage) + 5.89 ng/L (r = 0.92), respectively. Of the different blood collection tubes, only EDTA plastic tubes (with and without the barrier gel) were acceptable. The lower detection limit was 0.5 ng/L, and there were no interferences from common analytes, other neuropeptides, or unusual antibodies. BNP exhibited different reference intervals according to age and gender. BNP concentrations increased progressively as the severity of HF increased. CONCLUSIONS: The ADVIA Centaur is the first commercially available BNP assay for use on an automated immunochemistry platform. This assay has good analytical and clinical performance characteristics for diagnosing HF.

Adult↗
PubMed2004

USPIO-enhanced MRI for preoperative staging of gynecological pelvic tumors: preliminary results.

The aim of this study was to assess nodal enhancement with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) during preoperative staging of gynecological pelvic tumors within the same imaging session for the primary tumor. Pelvic MRI was performed 18-28 h after intravenous infusion of USPIO (Combidex/Sinerem, 2.6 mg Fe/kg body weight) in 13 women (mean age 51 years) scheduled for surgery for biopsy proven ( n=11) or clinically suspected ( n=2) uterine carcinoma. Axial T1-weighted spin-echo (SE), T2-weighted fast SE (FSE; with fat saturation), fast spoiled gradient-recalled (FSPGR) echo, sagittal and oblique T2-weighted FSE sequences were acquired on a 1.5-T system. Lymph nodes were prospectively staged using standard criteria, i.e., size and shape, as well as USPIO enhancement. Results were correlated with histology findings. MRI correctly staged all primary uterine tumors. In one case, the preoperative diagnosis of stage IV switched the therapeutic approach to radiochemotherapy. Ninety-one (86 benign, 5 malignant) of the histologically characterized nodes could be correlated with their MRI counterparts. One node was false positive; three micrometastases greater than 5 mm and one 5-mm metastasis were missed. On a nodal basis, the sensitivity score was 0.33 and the specificity score, 0.99. On a patient basis, the sensitivity score was 0.25 and the specificity score, 0.80. Our preliminary results indicate that USPIO-enhanced pelvic MRI for preoperative nodal assessment is feasible within one imaging session for primary tumors and that it has a high specificity. However, the low sensitivity in the present study is a limitation for the clinical application of this technique.

Adult↗
PubMed2004

Application of biological glue in repair of intracardiac structural defects.

BACKGROUND: BioGlue (Cryolife Inc, Kennesaw GA) was introduced as an alternative tissue sealant. Its most common application has been in repairs of acute dissections of the aorta. There is no reported experience with its use in the repair of intracardiac structural defects. METHODS: In 5 patients BioGlue was used as an adjunct in repairs of complex intracardiac structural defects. It was used during patch repair of posterior mitral annular defects in 2 patients and aortic annular defect in 1 patient in the presence of active endocarditis. It was also used in 1 patient with a chronic atrioventricular groove pseudoaneurysm following mitral valve replacement, and in 1 patient during repair of a postinfarction posterior ventricular septal rupture. RESULTS: There were no hospital or late deaths. Immediate intraoperative transesophageal echocardiography and late follow-up echocardiography documented complete and durable repair of all defects without recurrence. At follow-up all patients are in New York Heart Association class I-II, 6 to 29 months postoperatively. No patient has suffered late complications or exhibited signs of glue embolization. CONCLUSIONS: BioGlue was found to be an effective adjuvant to the standard techniques used for the repair of intracardiac structural defects of various etiologies. Long-term follow-up is recommended to determine its long-term safety in this application.

Aged↗
PubMed2004

sigmaB-dependent gene induction and expression in Listeria monocytogenes during osmotic and acid stress conditions simulating the intestinal environment.

Listeria monocytogenes must overcome a variety of stress conditions in the host digestive tract to cause foodborne infections. The alternative sigma factor sigma(B), encoded by sigB, is responsible for regulating transcription of several L. monocytogenes virulence and stress-response genes, including genes that contribute to establishment of gastrointestinal infections. A quantitative RT-PCR assay was used to measure mRNA transcript accumulation for the virulence genes inlA and bsh, the stress-response genes opuCA and lmo0669 (encoding a carnitine transporter and an oxidoreductase, respectively) and the housekeeping gene rpoB. Assays were conducted on mid-exponential phase L. monocytogenes cells exposed to conditions reflecting osmotic (0.3 M NaCl) or acid (pH 4.5) conditions typical for the human intestinal lumen. In exponential-phase cells, as well as under osmotic and acid stress, inlA, opuCA and bsh showed significantly lower absolute expression levels in a L. monocytogenes DeltasigB null mutant compared to wild-type. A statistical model that normalized target gene expression relative to rpoB showed that accumulation of inlA, opuCA and bsh transcripts was significantly increased in the wild-type strain within 5 min of acid and osmotic stress exposure; lmo0669 transcript accumulation increased significantly only after acid exposure. It was concluded that sigma(B) is essential for rapid induction of the tested stress-response and virulence genes under conditions typically encountered during gastrointestinal passage. As inlA, bsh and opuCA are critical for gastrointestinal infections in animal models, the data also suggest that sigma(B) contributes to the ability of L. monocytogenes to cause foodborne infections.

Acids↗
PubMed2004

Mutations in DNA mismatch repair genes: implications for DNA damage signaling and drug sensitivity (review).

The DNA mismatch repair (MMR) system functions in the elimination of biosynthetic errors that arise during DNA replication, in DNA damage surveillance, and in the prevention of recombination between non-identical sequences. It therefore substantially contributes to the maintenance of genome integrity. It is thus not surprising that loss of MMR function may lead to cancer. Inherited defects due to germline mutations in the MMR genes underlie the hereditary non-polyposis colon cancer (HNPCC) syndrome in humans, and epigenetic silencing of the hMLH1 gene accounts for sporadic cancers, including those of the endometrium and ovaries. Another hallmark of MMR is its capacity to elicit DNA damage-induced cell death. Although this might seem to make MMR a useful target for anticancer agents, it has become clear that tumor cells with defective MMR display reduced sensitivity to the cytotoxic effect of DNA damaging agents such as alkylating agents and cisplatin. This is of clinical relevance, as these agents provide MMR-deficient tumor cells a growth advantage. This effect is exacerbated by the potential of some agents to cause the de novo generation of MMR-resistant variants. Thus, the discovery of antitumor agents that retain sensitivity against or specifically target MMR-deficient tumor cells, and the development of strategies to overcome MMR-related drug resistance assumes clinical importance. Efforts have been taken in the past years to come to a better understanding of the molecular mechanisms of MMR, including those underlying MMR-related tumorigenesis, those determining the substrate-specificity of MMR-dependent damage recognition, and those linking damage recognition to cell death responses. This information is also expected to contribute to the establishment of diagnostic methods to screen for MMR gene mutations in tumors and to the development of strategies which enable the oncologists to apply appropriate and specific regimens for tumor treatment.

Apoptosis↗
PubMed2003

Kawasaki disease in an infant following immunisation with hepatitis B vaccine.

The known association between hepatitis B and vasculitis has been reported in rare cases in adults after hepatitis B vaccination. We here describe a 35-day-old infant who developed Kawasaki disease 1 day after receiving his second dose of hepatitis B vaccine. Although extremely rare, this possible side effect should be noted and further investigated.

Echocardiography, Doppler↗
PubMed2003

Role of p53 and ATM in photodynamic therapy-induced apoptosis.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) induces cell death through a laser light-activated photosensitizer and is a treatment option for tumors resistant to radio- and chemo-therapy. STUDY DESIGN/MATERIALS AND METHODS: We investigated whether m-THPC-PDT induces cell death by necrosis and/or apoptosis, and whether these responses are modulated by p53 and/or ATM, two cancer-associated genes. Sensitivity of atm(+/+)p53(+/+), atm(+/+)p53(-/-), and atm(-/-)p53(-/-) mouse embryonic fibroblasts to m-THPC-PDT performed at a wavelength of 652 nm was determined by the MTT assay, trypan blue-exclusion, and the TUNEL and caspase3-cleavage apoptosis assays. c-Abl protein level was determined by immunoblotting. RESULTS: m-THPC-PDT rapidly induced cell death in a substantial fraction of cells by p53- and Ataxia telangiectasia mutated (ATM)-independent non-apoptotic processes. However, in the subset of apoptotic cells, apoptosis was reduced by loss of p53 and was even more reduced by the additional loss of ATM. Apoptosis correlated inversely with c-Abl level. CONCLUSIONS: p53 and ATM are not required for necrosis, but may be required for PDT-mediated apoptosis.

Animals↗