Validation of the pedigree assessment tool (PAT) in families with BRCA1 and BRCA2 mutations.

BACKGROUND: The lifetime risk of breast cancer (BC) in patients with hereditary breast cancer syndromes is as high as 80%. The Pedigree Assessment Tool (PAT) is a scoring system to aid in identifying these patients. This validation study compares the PAT to BRCA gene mutation probability models in predicting suitability for genetic referral. METHODS: Retrospective review identified subjects undergoing genetic counseling and BRCA testing from 2001 to 2008 at two institutions. PAT score and BRCA mutation probabilities were calculated using Myriad II and Penn II models. Comparisons were made between models in ability to discriminate patients appropriate for genetic evaluation based on accuracy in predicting a positive test result. RESULTS: Records evaluated represent 520 families. BRCA testing revealed 146 mutation-positive and 374 mutation-negative families. c-Statistic analysis was used to compare the discriminating ability of the models to correctly assign families as mutation (+) and (-). Both the PAT and Penn II model outperformed the Myriad II model. Using a threshold PAT score >or=8 and mutation probability >or=10% to assign families as mutation (+) versus (-), sensitivity, specificity, and positive and negative predictive values were calculated for each model. The PAT was more sensitive than the Myriad II model and more specific than the Penn II model. CONCLUSIONS: In overall performance, the PAT is at least comparable to the Myriad II and Penn II models in screening women appropriate for genetic referral. Simplicity and identification of families with non-BRCA hereditary BC syndromes suggest that the PAT is better suited for BC risk screening.

Infusion of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in isolated mouse hearts.

BACKGROUND: Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival. We hypothesized that circulating monoclonal LC may directly impair cardiac function, in addition to any mechanical effects of amyloid fibril deposition. Therefore, we examined the effects of amyloid LC proteins on diastolic and systolic cardiac function, as measured in an isolated mouse heart model. METHODS AND RESULTS: LC were obtained from patients with nonamyloid disease or from those with noncardiac, mild cardiac, and severe cardiac involved AL amyloidosis. Saline or LC (100 microgram/mL) was infused into a Langendorff-perfused, isovolumically contracting mouse heart. Saline and control, noncardiac, and mild-cardiac LC infusions did not alter ex vivo cardiac function. In contrast, infusion of sever cardiac LC resulted in marked impairment of ventricular relaxation with preservation of contractile function. CONCLUSION: These results demonstrate that infusion of LC from patients with AL amyloidosis result in diastolic dysfunction similar to that observed in patients with cardiac involved AL amyloidosis, and they suggest that amyloid LC proteins may contribute directly to the pathogenesis and the rapid progression of amyloid cardiomyopathy, independent of extracellular fibril deposition.

Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction.

BACKGROUND: Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. We examined whether supplementing infarcted myocardium with skeletal myoblasts would (1) result in viable myoblast implants, (2) attenuate deleterious remodeling, and (3) enhance in vivo and ex vivo contractile performance. METHODS AND RESULTS: Experimental MI was induced by 1-hour coronary ligation followed by reperfusion in adult male Lewis rats. One week after MI, 10(6) myoblasts were injected directly into the infarct region. Three groups of animals were studied at 3 and 6 weeks after cell therapy: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI+cell). In vivo cardiac function was assessed by maximum exercise capacity testing and ex vivo function was determined by pressure-volume curves obtained from isolated, red cell-perfused, balloon-in-left ventricle (LV) hearts. MI and MI+cell hearts had indistinguishable infarct sizes of approximately 30% of the LV. At 3 and 6 weeks after cell therapy, 92% (13 of 14) of MI+cell hearts showed evidence of myoblast graft survival. MI+cell hearts exhibited attenuation of global ventricular dilation and reduced septum-to-free wall diameter compared with MI hearts not receiving cell therapy. Furthermore, cell therapy improved both post-MI in vivo exercise capacity and ex vivo LV systolic pressures. CONCLUSIONS: Implanted skeletal myoblasts form viable grafts in infarcted myocardium, resulting in enhanced post-MI exercise capacity and contractile function and attenuated ventricular dilation. These data illustrate that syngeneic myoblast implantation after MI improves both in vivo and ex vivo indexes of global ventricular dysfunction and deleterious remodeling and suggests that cellular implantation may be beneficial after MI.

[Diagnosis of deep pelvic and leg vein thromboses by imaging procedures]. / Diagnostik der tiefen Becken- und Beinvenenthrombosen durch bildgebende Verfahren.

The gold standard for the diagnosis of deep venous thrombosis (pelvis and lower limb) is still phlebography--sometimes supplemented by DSA to clarify findings in the pelvic region. The indication for phlebography can, however, be markedly reduced by noninvasive procedures and restricted to the clarification of uncertain findings or the confirmation of the diagnosis for subsequent invasive therapy. Ultrasound techniques, particularly color-coded duplex sonography, presently appear to take priority among the noninvasive procedures.

[Life-threatening hemorrhage in pelvic fractures of polytraumatized patients. Diagnostic issues and embolization treatment]. / Lebensbedrohliche Blutungen bei Beckenfrakturen polytraumatisierter Patienten. Diagnostische Problematik und Embolisationsbehandlung.

Between 1984-1987 6 multiple trauma patients with pelvic fractures and bleeding from pelvic vessels were treated by transcatheter embolization. Although diagnosis and therapy were early in two cases, there was an overall time delay of median 17 hours (1-38 h) until localisation of bleeding lesions. In this period multiple transfusions (median: 33.7 units of packed erythrocytes, 14.5 units of fresh frozen plasma) could not control hemorrhage. After successful transcatheter embolization circulation stabilized immediately and durably. 4 patients died, 2 of them from septic-toxic multi-organ-failure.

[Percutaneous radiotherapy in thyroid malignancies--curative and palliative viewpoints]. / Perkutane Strahlentherapie bei Schilddrüsenmalignomen--kurative und palliative Gesichtspunkte.

The treatment results of percutaneous radiotherapy of 85 patients with thyroid malignomas treated between 1972 and 1979 are presented in a retrospective study. 49 patients were treated for curative purposes, 36 patients suffering from metastases were submitted to palliative therapy. Primary radiotherapy was performed as pendulum or oblique-field irradiation up to 60 Gy, and patients with metastases or local recurrences were submitted to stationary-field or contralateral irradiation up to 40 (-50) Gy depending on the tumor site. In both groups, prognosis and survival time depend much more on the histologic differentiation than on the tumor dimension and the age of the patient. If the thyroid malignomas were well differentiated, we observed survival times of several years, even in case of extended, eventually filiarized tumors. On the other hand, the average survival time of patients with dedifferentiated thyroid tumors was only four months, with even worse results in case of only subtotally operable or completely inoperable anaplastic tumors. In these cases we should like to avoid an indication for percutaneous radiotherapy and to recommend, if possible, palliative surgical measures the effect of which will be seen more rapidly.

[Combination treatment of small cell bronchial carcinoma]. / Zur kombinierten Behandlung des kleinzelligen Bronchialkarzinoms.

35 cases with micro-cellular bronchial carcinoma are described. The patients are treated with a combination of a modified ACO scheme and fractionated irradiations with 50 to 60 Gy to the primary tumor and 30 Gy to the encephalic skull. Among 14 patients with local disease, ten had a complete remission and three a partial remission. Among 21 patients with advanced disease, six had a complete remission and eight a partial remission. The side effects were not important, and they were not reinforced by the higher dose of the primary irradiation. The local recurrence rate was decreased, but the average survival times were not prolonged, because these are still dependent upon the hematogenic formation of metastases.