Biomedical subjects

Daniel Fink

Publications and source records attributed to Daniel Fink.

28 records · Page 2Linked to original sources

PubMed2003

p53-deficient cells display increased sensitivity to anthracyclines after loss of the catalytic subunit of the DNA-dependent protein kinase.

DNA-dependent protein kinase (DNA-PK) is involved in non-homologous end joining which repairs DNA double-strand breaks introduced by irradiation and radiomimetic agents. DNA-PK interacts with p53 but may also have p53-independent functions. The present study investigated whether disruption of the gene for the catalytic subunit DNA-PKcs affects chemosensitivity in p53-deficient cells. Drug sensitivity of DNA-PKcs(+/+)/p53(+/+), DNA-PKcs(+/+)/p53(-/-), DNA-PKcs(-/-)/p53(+/+), and DNA-PKcs(-/-)/p53(-/-) mouse lung-fibroblasts was determined by the MTT assay, the clonogenic assay, and trypan blue exclusion. Susceptibility to apoptosis was determined by DNA fragmentation (TUNEL) and by caspase-3 cleavage. We show that p53-deficient cells were 2 to 3-fold resistant to treatment with doxorubicin, epirubicin, cisplatin, and docetaxel as compared to wild-type cells. We further demonstrate that the additional loss of DNA-PKcs function in p53-deficient cells resulted in a 2-fold increase in sensitivity to doxorubicin and epirubicin as documented by the MTT assay, clonogenic assay, and trypan blue exclusion. Doxorubicin-induced hypersensitivity in these cells correlated with a transient G2/M checkpoint activation but did not seem to correlate with apoptosis. The data indicate that additional loss of DNA-PKcs in p53-deficient cells reverses anthracycline-resistance imposed by p53-deficiency, and that DNA-PKcs modulates p53-independent pathways responding to DNA damage induced by anthracyclines. They also indicate that processes other than apoptosis may contribute to the increased cytotoxicity to anthracyclines. DNA-PKcs may thus be a potential target for functional inhibition, which might increase the efficacy of some anti-tumour agents in the treatment of cancers mutated in the p53 gene.

Animals↗

PubMed2003

The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells.

BRCA1 is implicated in cellular responses to DNA damage, thereby substantially contributing to maintenance of the genome integrity. Mutations in the BRCA1 gene occur in breast and ovarian cancer and mutations that disable p53 are frequently found in human cancers, often accompanied by mutations in additional genes, contributing to tumor progression or high-grade malignancy. Therefore, the role of BRCA1 in the sensitivity to anticancer agents in p53-deficient cells was investigated using p53-deficient mouse knockout cell lines either deficient or proficient in Brca1 function. We report that Brca1-deficiency in p53-null cells was associated with increased sensitivity to the topoisomerase I poisons camptothecin and topotecan, the topoisomerase II poisons doxorubicin, mitoxantrone and etoposide, and to the platinum compounds carboplatin and oxaliplatin, but not to the antimetabolites 5-fluorouracil and gemcitabine and the taxanes docetaxel and paclitaxel. The increased growth inhibition to doxorubicin after loss of Brca1 correlated with increased cell killing caused by increased apoptosis. The data presented here indicate that Brca1 modulates p53-independent DNA damage response pathways and they support the case of a role of Brca1 to protect cells from apoptosis-mediated cell death in p53-deficient cells. These results suggest a higher chemotherapy susceptibility of cells disabled in both functions and they foster the concept that functional inhibition of BRCA1 may be a valuable adjunct to anticancer agents to increase the efficacy of chemotherapy in the treatment of p53-mutated cancers.

Animals↗

PubMed2002

Frequency and distribution pattern of distant metastases in breast cancer patients at the time of primary presentation.

INTRODUCTION: For routine staging of patients with primary breast cancer, clinical practice guidelines of many medical societies recommend chest X-ray, liver ultrasound and bone scan. With respect to expanding health care costs and patients' psychological distress it has been supposed, that there might be a group of breast cancer patients, who do not need these imaging studies. METHODS: Four hundred and eighty-eight consecutive patients with primary breast cancer who had primary surgery at our institution and complete work-up for distant metastases including chest X-ray, liver ultrasound, and bone scan were studied. RESULTS: We found distant metastases at the time of primary diagnosis in 19 patients (3.9%). Bone metastases were found in 2.7%, liver metastases in 1.0%, and pulmonary metastases in 0.4%. However, in breast tumors smaller than 1 cm, no metastatic lesions were found, whereas 18.2% of the patients with pT4 tumors had metastases. In 2.4% of screening imaging studies, metastases were ruled out by additional imaging. CONCLUSION: Based on our data and a review of the literature, we suggest that chest X-ray, liver ultrasound and bone scan can be omitted in the staging of asymptomatic patients with pT1a or pT1b disease.

Adult↗

PubMed2002

Photodynamic therapy of vulvar and vaginal condyloma and intraepithelial neoplasia using topically applied 5-aminolevulinic acid.

BACKGROUND AND OBJECTIVES: To determine the feasibility of photodynamic therapy (PDT) of vulvar and vaginal condyloma and intraepithelial neoplasia (VIN, VAIN) and to compare PDT results with conventional treatments. STUDY DESIGN/MATERIALS AND METHODS: Thirty-eight patients with vulvar or vaginal intraepithelial neoplasia (VIN) grade II/III (n = 22) or condyloma (n = 16) had 10% 5-aminolevulinic acid (ALA)-gel applied topically. After 2-4 hours, 80-125 J/cm(2) laser light at a wavelength of 635 nm was applied. PDT was compared to conventional treatments for condyloma (CO(2) laser evaporation) and for VIN III (laser evaporation, surgical excision). RESULTS: The complete clearance rate for condyloma treated by PDT was 66% and the rate for IN was 57% (as determined by biopsy). Of the neoplasia patients, none with hyperkeratotic VIN (n = 4) responded, and only one of four with increased pigmentation cleared. No scarring occurred, and postoperative discomfort lasted 4.9 +/- 3.4 days. Reduced disease-free survival (DFS) was associated with multifocal VIN (P = 0.02, OR 2.17, 95% CI 1.15-4.08), but DFS did not vary with treatment mode. CONCLUSIONS: Although PDT is not equally efficacious for all subgroups, PDT for condyloma and intraepithelial neoplasia appears to be as effective as conventional treatments, but with shorter healing time and excellent cosmetic results.

Administration, Topical↗

PubMed2002

Acute type B aortic dissection: surgical therapy.

BACKGROUND: Surgery for acute type B aortic dissection is associated with significant mortality. We report the results for 34 consecutive patients who underwent urgent surgery because they met criteria for operation during the acute phase (< 14 days) of acute type B dissection. METHODS: The average patient age was 64 (32 to 88) years. Indications for surgery were persistent pain (12), threatened exsanguination (18), malperfusion (renal [3], limb [3]), rapid aortic enlargement (4), and uncontrolled hypertension (1). The mean interval from onset of pain to operation was 7 (1 to 14) days. Resection included the proximal descending aorta in 32, the distal aortic arch in 10, extension to the diaphragm in 10, and involved a thoracoabdominal procedure in 3. Surgical techniques included hypothermic circulatory arrest (16 [47%]), distal bypass, monitoring of somatosensory-evoked potentials, sequential intercostal sacrifice (average, 5.6 pairs), cerebrospinal fluid drainage, and steroid administration. RESULTS: There was no hospital mortality. Important complications occurred in 16 patients (47%): 10 respiratory requiring tracheostomy, six infectious, four dialysis, two myocardial infarctions, and two neurologic (one transient stroke, one paraplegia). Mean intensive care unit and hospital stays were 10 (3 to 32) and 35 (7 to 107) days. Survival at 5 and 10 years was 80% and 57%, respectively (mean follow-up, 5.8 years). CONCLUSIONS: Patients meeting criteria for urgent surgery have a low perioperative risk for mortality and paraplegia, and are relatively free from long-term aorta-related complications. These findings warrant consideration of earlier surgery for appropriate patients with acute type B aortic dissection.

Acute Disease↗

PubMed2002

Replacing the ascending aorta and aortic valve for acute prosthetic valve endocarditis: is using prosthetic material contraindicated?

BACKGROUND: The use of prosthetic material (rather than a homograft) for ascending aorta/aortic valve replacement (Bentall procedure) in cases of acute prosthetic valve endocarditis is controversial. We report favorable results using this technique almost exclusively (a homograft was used in only 3 patients with hematological problems) during a 12-year interval. METHODS: Twenty-eight patients (55 +/- 14 years; 22 male) underwent a Bentall procedure for acute prosthetic valve endocarditis between 1988 and 2000. Twenty-five patients had undergone previous aortic valve replacement (1 with concomitant mitral valve replacement, 4 with coronary artery bypass grafting), and 3 had had a previous Bentall operation. The median interval between initial surgery and reoperation was 13 months (range, 1 to 106). Sixty-eight percent of operations were urgent or emergencies. Ninety-three percent of patients had significant aortic regurgitation; complete annuloaortic dehiscence occurred in 71%, and in 57%, an abscess was found. Causative organisms were identified in 25 of 28 patients: Staphylococcus epidermidis (9), Staphylococcus aureus (7), Streptococcus viridans (6), Pseudomonas (2), and Legionella (1). RESULTS: Twenty-three patients had mechanical and 5 had biological valves implanted during the Bentall procedure. Hypothermic circulatory arrest was used in 64%. Hospital mortality was 11%: there was one intraoperative death, and two before discharge (one cardiac, one sepsis). Eighty-nine percent survived without stroke. During follow-up (median, 44.5 months; complete in 92%), 1 patient died of recurrent endocarditis at 4 months. CONCLUSIONS: These results indicate that prosthetic root replacement may be superior to use of a homograft for acute aortic prosthetic valve endocarditis, with only a 4% incidence of recurrent endocarditis and reoperation.

Adult↗

PubMed2002

Microvolt T wave alternans inducibility in normal newborn puppies: effects of development.

INTRODUCTION: The cause of sudden infant death syndrome is unknown, but increased cardiac vulnerability due to repolarization instability may be a contributing factor. The QT interval normally is long at birth and increases further during the first few postnatal months. Although excessive QT intervals indicate increased cardiac vulnerability in the long QT syndrome, the impact of less pronounced QT prolongation during this developmental period is unclear. In adults and older children, the ease of inducing microvolt-level T wave alternans (TWA) is used as a measure of repolarization instability and arrhythmia vulnerability. The aim of this study was to determine if TWA is inducible in normal newborn puppies. METHODS AND RESULTS: Atrial pacing was performed in 15 anesthetized beagle puppies 7 to 35 days old. The pacing drive cycle length was systematically decreased in 20-msec steps from baseline until AV conduction blocked. Pacing was performed for 8 minutes at each cycle length. Three-lead ECGs were recorded continuously during the last 5 minutes of pacing at each cycle length. The recordings were analyzed off-line for the presence of microvolt-level TWA using a sensitive spectral analysis technique. Microvolt-level TWA was present in all puppies. TWA was not present at baseline but developed and increased in amplitude as heart rate increased. The threshold heart rate for TWA did not correlate with age. However, due to age-dependent changes in baseline heart rate, the 7- to 14-day-old animals needed a 50% to 78% increase in heart rate to reach threshold heart rate, whereas the oldest animals needed only a 5% to 25% increase. CONCLUSION: These data suggest that developmentally dependent dynamic repolarization instability exists in puppies as manifest by the inducibility of TWA.

Age Factors↗

PubMed2002

Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall superparamagnetic iron oxide enhancement.

PURPOSE: To evaluate magnetic resonance (MR) imaging with ultrasmall superparamagnetic iron oxide (USPIO) enhancement for preoperative axillary lymph node staging in patients with breast cancer by using histopathologic findings as the standard of reference. MATERIALS AND METHODS: MR imaging was performed with a 1.5-T system within 24-36 hours after the start of intravenous slow-drip infusion of USPIO in 20 patients with breast cancer who were scheduled for surgery, followed by gadolinium-enhanced MR imaging. Lymph nodes were staged prospectively by using newly established criteria, and results were correlated with histologic findings. RESULTS: In two patients, preoperative findings led to a change in therapeutic approach, and neoadjuvant chemotherapy was given; both patients were excluded from statistical analysis. Results of axillary staging with USPIO-enhanced MR imaging were true-positive in nine, true-negative in seven, false-positive in zero, and false-negative in two of 18 patients (sensitivity, 82%; specificity, 100%; positive predictive value, 100%; second reader, kappa = 1.0). Four hundred five lymph nodes were detected with MR imaging. For first and second readers, respectively, lymph node-based sensitivity was 83% and 73% and specificity was 96% and 97% (kappa = 0.68). USPIO as the intravascular contrast agent could not replace gadolinium for assessment of the primary tumor; however, no clinically relevant interaction was seen. Thus, an integrated imaging approach was feasible in all patients. CONCLUSION: USPIO-enhanced MR imaging has the potential to become an adjunct to conventional MR imaging of the breast for preoperative assessment of axillary lymph nodes in patients with breast cancer.

Adult↗

PubMedDate not supplied

Axillary staging using positron emission tomography in breast cancer patients qualifying for sentinel lymph node biopsy.

Axillary lymph node dissection (ALND) is the standard of care for nodal staging of patients with invasive breast cancer. Due to significant somatic and psychological side effects, replacement of ALND with less invasive techniques is desirable. The goal of this study was to evaluate the clinical usefulness of axillary lymph node (ALN) staging by means of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in breast cancer patients qualifying for sentinel lymph node biopsy (SLNB). FDG-PET was performed within 1 week before surgery in 24 clinically node-negative breast cancer patients with tumors smaller than 3 cm. Sentinel lymph nodes (SLNs) were identified by preoperative lymphoscintigraphy following peritumoral technetium 99m-labeled colloid albumin injection, and by intraoperative gamma detector and blue dye localization. Following SLNB, a standard ALND was performed. Serial sectioning and immunohistochemistry of the SLN as well as standard histologic examination of the non-SLN was performed. FDG-PET detected all primary breast cancers. Staging of ALNs by PET was accurate in 15 of 24 patients (62.5%), whereas PET staging was false negative in 8 of 10 node-positive patients and false-positive in 1 patient. The sensitivity, specificity, positive predictive value, and negative predictive value of FDG-PET for nodal status was 20%, 93%, 67%, and 62%, respectively. The mean diameter of false-negative ALN metastases was 7.5 mm (range 1-15 mm). Lymph node staging using FDG-PET is not accurate enough in clinically node-negative patients with breast cancer qualifying for SLNB and should not be used for this purpose.

Adult↗

PubMedDate not supplied

Aortic valve replacement under deep hypothermic circulatory arrest.

BACKGROUND: Aortic valve replacement (AVR) in the presence of a calcified aorta or patent grafts may preclude clamping of the ascending aorta. We employed deep hypothermic circulatory arrest in order to circumvent this problem. METHODS: Between January 1993 and December 2000, 415 patients underwent AVR in our department. Eight of these were operated using deep hypothermic circulatory arrest. There were 5 males, and mean age was 72 years (range 56-81). Indications for using circulatory arrest were reoperation with patent grafts and/or severe calcification of the ascending aorta. In six patients, cardiopulmonary bypass was achieved via femoro-femoral bypass, and in two via aortic-right atrial cannulation. Retrograde cerebral perfusion was employed in five. Mean bypass time was 155 minutes (range 122-187), and mean circulatory arrest time was 38 minutes (range 31-49). RESULTS: There was no operative mortality, and no patient suffered any neurologic sequelae. Echocardiography showed all valves to be functioning well. CONCLUSIONS: AVR under deep hypothermic circulatory arrest can be accomplished with an acceptable degree of safety. It should be considered as an alternative in patients in whom aortic clamping is prohibitive, and might otherwise be considered inoperable. The ability to connect the patient to bypass and the presence of a "window" to allow aortotomy are prerequisites for employing this method.

Aged↗