Breast cancer in patients carrying a germ-line CHEK2 mutation: Outcome after breast conserving surgery and adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Women carrying mutations in the CHEK2 gene are at an increased breast cancer risk. Data about outcome and prognosis for these patients after standard multimodality treatment are scarce at present. MATERIALS AND METHODS: One-hundred and fifty (150) patients with non-metastasized early-stage breast cancer (T1-2) receiving postoperative radiotherapy following breast-conservative surgery at our department were included in this analysis. Carriers were identified using mutation-specific restriction enzyme-based screening assays in previous investigations. Twenty-five breast cancer patients were heterozygous for one of three CHEK2 gene mutations (I157T, n=13; 1100delC, n=10; IVS2+1G>A, n=2). The comparison group consisted of 125 early-stage breast cancer patients without a CHEK2 gene mutation (non-carriers). Median follow-up was 87 months for the total cohort of patients. RESULTS: Local recurrences occurred in 13 patients (carriers, 3 (12%); non-carriers, 10 (8%)) and distant metastases occurred in 27 patients (carriers, 8 (32%); non-carriers, 19 (15%)). Twenty-five patients had deceased (carriers, 8 (32%); non-carriers, 17 (14%)) with all but 3 deaths related to breast cancer. Actuarial 7-year local relapse-free survival was 86% in carriers versus 90% in non-carriers (p=0.48). Actuarial metastasis-free, disease-free and overall survival at 7 years were 64% vs. 84% (p=0.045), 59% vs. 78% (p=0.07) and 69% vs. 87% (p=0.10), respectively. In a multivariate step-wise Cox regression analysis presence of a CHEK2 mutation remained a borderline significant discriminator for metastasis-free survival (p=0.048; OR=0.4; 95% CI 0.2-1.0) next to T-stage (p=0.001; OR 0.3; 95% CI 0.1-0.6). CONCLUSIONS: Heterozygosity for a germline CHEK2 mutation appears to represent an adverse prognostic factor in patients with early-stage breast cancer. If confirmed in larger studies these data may serve as a basis for future surveillance and treatment strategies taking into account individual germline mutational status.     

Age dependent secretion of LH and ACTH in healthy men and patients with erectile dysfunction

OBJECTIVES: Age dependent secretion of testicular and adrenal androgens was examined in healthy men and patients with erectile dysfunction (ED). METHODS: In 95 healthy men (age 20-74 years) and 739 patients with ED, luteineizing hormone (LH, n = 739), adrenocorticotropic hormone (ACTH, n = 480) and the secretion products of testis and adrenal gland testosterone (T, n = 750), free testosterone (fT, n = 718), dehydroepiandrosteronesulfate (DHEAS, n = 598) and cortisol (n = 538) were measured. RESULTS: In healthy men, LH was measured from 0.75-8.58 mIU/ml and ACTH from 10.59-121.7 pg/ml. Statistically, age was not correlated to LH (P = 0.573) and ACTH (P = 0.833) in healthy men. The secretion products T (P < 0.05), fT (P < 0.001), DHEAS (P < 0.001) and cortisol (P < 0.05) declined significantly with age in healthy persons. In patients with ED, a significant age dependent increase of LH (P < 0.05, n = 739), but not ACTH (P = 0.469, n = 480) was found. T (P < 0.001, n = 736), fT (P < 0.001, n = 718) and DHEAS (P < 0.001, n = 598), but not cortisol (P = 0.307, n = 538) declined in age dependent patients with ED. Age matching revealed a statistical significant elevation (P < 0.05) only for LH (n = 659) in comparison to healthy men (n = 94), all other hormones were not different in both groups. CONCLUSION: An LH-increase in patients with erectile dysfunction underlines the importance of Leydig cell degeneration in this disease, but age dependent decline of T secretion was comparable to healthy men, demonstrating a working hypophyseal-testicular-axis. Indication of androgen replacement is therefore limited to selected cases.     

The release of excitatory amino acids,dopamine, and potassium following transplantation of embryonic mesencephalic dopaminergic grafts to the rat striatum,and their effects on dopaminergic neuronal survival in vitro

A major limitation to the effectiveness of grafts of fetal ventral mesencephalic tissue for parkinsonism is that about 90-95% of grafted dopaminergic neurones die. In rats, many of the cells are dead within 1 day and most cell death is complete within 1 week. Our previous results suggest that a major cause of this cell death is the release of toxins from the injured CNS tissue surrounding the graft, and that many of these toxins have dissipated within 1 h of inserting the grafting cannula. In the present experiments we measured the change over time in the concentration of several potential toxins around an acutely implanted grafting cannula. We also measured the additional effect of injecting suspensions of embryonic mesencephalon, latex microspheres, or vehicle on these concentrations. Measurements of glutamate, aspartate, and dopamine by microdialysis showed elevated levels during the first 20-60 min, which then declined to baseline. In the first 20 min glutamate levels were 10.7 times, aspartate levels 5 times, and dopamine levels 24.3 times baseline. Potassium levels increased to a peak of 33 +/- 10.6 mM 4-5 min after cannula insertion, returning to baseline of <5 mM by 30 min. Injection of cell suspension, latex microspheres, or vehicle had no significant effect on these levels. We then assayed the effect of high concentrations of glutamate, aspartate, dopamine, and potassium on dopaminergic neuronal survival in E14 ventral mesencephalic cultures. In monolayer cultures only dopamine at 200 microM showed toxicity. In three-dimensional cultures only the combination of raised potassium, dopamine, glutamate, and aspartate together decreased dopaminergic neuronal survival. We conclude that toxins other than the ones measured are the main cause of dopaminergic cell death after transplantation, or the effects of the toxins measured are enhanced by anoxia and metabolic challenges affecting newly inserted grafts.     

Side effects of retroviral gene transfer into hematopoietic stem cells

Recent conceptual and technical improvements have resulted in clinically meaningful levels of gene transfer into repopulating hematopoietic stem cells. At the same time, evidence is accumulating that gene therapy may induce several kinds of unexpected side effects, based on preclinical and clinical data. To assess the therapeutic potential of genetic interventions in hematopoietic cells, it will be important to derive a classification of side effects, to obtain insights into their underlying mechanisms, and to use rigorous statistical approaches in comparing data. We here review side effects related to target cell manipulation; vector production; transgene insertion and expression; selection procedures for transgenic cells; and immune surveillance. We also address some inherent differences between hematopoiesis in the most commonly used animal model, the laboratory mouse, and in humans. It is our intention to emphasize the need for a critical and hypothesis-driven analysis of "transgene toxicology," in order to improve safety, efficiency, and prognosis for the yet small but expanding group of patients that could benefit from gene therapy.     

Comparison of two types of synthetic biodegradable barriers for GTR in interproximal infrabony defects: clinical and radiographic 24-month results

The aim of the present study was to compare the efficacy of guided tissue regeneration (GTR) using two different biodegradable barriers (polylactide acetyltributyl citrate; polydioxanon) in three- and two-walled infrabony defects. The polydioxanon barrier is an experimental GTR membrane that consists of a continuous occlusive barrier with a layer of slings on the side that is meant to face the mucoperiosteal flap. Fifteen patients provided 15 pairs of similar contralateral periodontal defects: 12 predominantly two-walled and 18 predominantly three-walled infrabony defects. Each defect was randomly assigned to treatment with polylactide acetyltributyl citrate (control) or polydioxanon (test) devices. At baseline, 6, 12, 18, and 24 months after surgery, clinical measurements were performed and standardized radiographs obtained (not at 18 months). Both treatments revealed a significant Gingival Index reduction, probing depth reduction, and vertical probing attachment level gain 24 months after surgery. Both treatments showed slight resorption of the crestal alveolar ridge after 24 months, which failed to reach statistical significance. A statistically significant bone gain within the infrabony pockets was measured for both treatment options 24 months postsurgical. Regarding Gingival Index and probing depth reduction as well as vertical probing attachment level and bone gain, there were neither statistically significant nor clinically relevant differences between test and control barriers. The use of both biodegradable barriers in GTR therapy may be recommended.     

Arterial switch operation with a single coronary artery

OBJECTIVE: Our purpose was to evaluate the impact of coronary pattern on survival and reintervention in patients who underwent the arterial switch operation with a single coronary artery. METHODS: We conducted a retrospective analysis of 53 patients with a single coronary artery who underwent the arterial switch operation between 1983 and 2000 at Children's Hospital Boston. Recent follow-up information was obtained for 40 of the 46 long-term survivors (mean follow-up 7.3 +/- 4.5 years). RESULTS: Thirty-five patients had a single right coronary artery, with the left coronary artery posterior to the pulmonary artery in 27. Eighteen patients had a single left coronary artery (16 with the right coronary artery anterior to the aorta). Six of 7 total patients who died had a single right coronary artery; all died before 1992. There were 5 early deaths, all with a single right coronary artery, with 4 deaths due to coronary malperfusion. Survivals for all patients were 91% at 6 months and 87% at 1, 5, and 10 years after the arterial switch operation. Survival figures were lower for patients having a single right ostium with the left main coronary artery posterior to the pulmonary artery compared with all other subtypes (P =.02, log-rank test). Seven patients had reintervention, 4 because of right ventricular outflow tract obstruction, 1 for heart transplantation, 1 for mitral valve repair and 1 for pacemaker implantation. Freedom from reintervention for all patients was 96% at 6 months, 92% at 1 year, 86% at 5 years, and 82% at 10 years after the arterial switch operation, with lower rates for patients having a single left ostium with the right coronary artery anterior to the aorta (P =.0003, log-rank test). CONCLUSIONS: In the current era, the arterial switch operation with a single coronary artery can be performed safely irrespective of the coronary anatomy. Risk of reintervention is higher in patients having a single left ostium with the right coronary artery anterior to the aorta.     

Hypertonic-hyperoncotic solutions reduce the release of cardiac troponin I and s-100 after successful cardiopulmonary resuscitation in pigs

In some patients, cardiopulmonary resuscitation (CPR) can revive spontaneous circulation (ROSC). However, neurological outcome often remains poor. Hypertonic-hyperoncotic solutions (HHS) have been shown to improve microvascular conductivity after regional and global ischemia. We investigated the effect of infusion of HHS in a porcine CPR model. Cardiac arrest was induced by ventricular fibrillation. Advanced cardiac life support was begun after 4 min of nonintervention and 1 min of basic life support. Upon ROSC, the animals randomly received 125 mL of either normal saline (placebo, n = 8) or 7.2% NaCl and 10% hydroxyethyl starch 200,000/0.5 (HHS, n = 7). Myocardial and cerebral damage were assessed by serum concentrations of cardiac troponin I and astroglial protein S-100, respectively, up to 240 min after ROSC. In all animals, the levels of cardiac troponin I and S-100 increased after ROSC (P < 0.01). This increase was significantly blunted in animals that received HHS instead of placebo. The use of HHS in the setting of CPR may provide a new option in reducing cell damage in postischemic myocardial and cerebral tissues. IMPLICATIONS: Infusion of hypertonic-hyperoncotic solutions (HHS) after successful cardiopulmonary resuscitation in pigs significantly reduced the release of cardiac troponin I and cerebral protein S-100, which are sensitive and specific markers of cell damage. Treatment with HHS may provide a new option to improve the outcome of cardiopulmonary resuscitation.     

Severe complex regional pain syndrome type II after radial artery harvesting

The radial artery is increasingly used as a coronary bypass graft. We report on a patient who developed a severe complex regional pain syndrome type II--also called causalgia--after radial artery harvesting. After an odyssey of diagnostic and presumed therapeutic procedures, she underwent surgical revision of the left forearm. Intraoperatively, a titanium clip in close neighborhood to the superficial radial nerve affecting the perineurium was found and removed, and more distally, a small neurinoma (3 by 4 mm) was resected. Despite presumed successful operation, symptoms did not improve. The patient presumably remains unable to use her left arm and hand.     

Improving results of the modified Fontan operation in patients with heterotaxy syndrome

BACKGROUND: Historically the Fontan operation in patients with single ventricle heterotaxy syndrome and atrial isomerism has been associated with high mortality. We studied whether recent modifications of the surgical technique have improved outcome. METHODS: A retrospective review of 135 patients with heterotaxy syndrome who underwent a Fontan operation between 1981 and 2000 was performed. RESULTS: There were 93 patients with right isomerism and 42 with left isomerism. Anomalies of venous return included 25 patients with extracardiac pulmonary venous connection (19%) and 37 patients with an interrupted inferior vena cava (27%). Thirty-six patients (27%) had at least moderate atrioventricular valve regurgitation. The type of Fontan procedure included 17 patients with an atriopulmonary Fontan connection, 67 with a lateral tunnel modification, 19 with an intraatrial tube graft, 25 with an extracardiac tubegraft, and 7 with an intra-extra atrial tube graft. A fenestration was placed in 93 patients (78%). Early mortality was 19% before 1991, 3% since 1991, and no patient has died early since 1993. Ten-year survivals were 70% for Fontan operations before 1990 and 93% for Fontan operations after 1990. Thirty-two patients (23%) had prolonged pleural effusions. Risk factors for death included anomalous pulmonary venous connection (p = 0.02) and higher preoperative pulmonary vascular resistance (p = 0.002). Sixty-two patients (47%) had some form of early postoperative arrhythmia. At 10 years, freedom from late bradyarrhythmia and late tachyarrhythmia were 78% and 70%, respectively. Preoperative arrhythmias, older age at operation, and anatomic features were each independent predictors of late arrhythmia. CONCLUSIONS: The Fontan operation can now be performed in patients with heterotaxy syndrome with excellent survival. However, morbidity in terms of postoperative arrhythmias and prolonged pleural effusions remains significant. Fontan staging, appropriate choice of Fontan modification, aggressive treatment of concomitant malformations, and use of a baffle fenestration contribute to improved outcome.