High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Cardiotoxicity in signal transduction therapeutics: erbB2 antibodies and the heart.

Cardiotoxicity is a common and potentially devastating side effect of antineoplastic drug therapy. This empiric observation is seen as paradoxical given that the cardiomyocyte is considered to be a terminally differentiated cell. Despite the fact that these cells do not divide after birth, adult cardiomyocytes may become "innocent bystander" targets of anticancer drugs designed to interfere with cell signaling pathways in rapidly proliferating cells. In breast cancer clinical trials, treatment with the erbB2 receptor antibody trastuzumab combined with anthracyclines has been associated with an increased risk for the development of cardiac pump failure. Trastuzumab/anthracycline cardiomyopathy may be the first clinically significant cardiotoxicity to emerge from signal transduction therapeutics. The erbB2 receptor tyrosine kinase is known to have a critical role in cardiac development. In addition, erbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes as part of a signaling network that involves neuregulins and the neuregulin receptor erbB4. However, erbB2 levels in the adult heart are low when compared with the levels found in erbB2-overexpressing breast cancer cells that are the intended targets of trastuzumab therapy. Thus, trastuzumab-associated cardiotoxicity must be explained by some alternative mechanism. After confirming that trastuzumab is capable of inducing tyrosine phosphorylation of the human cardiomyocyte erbB2 protein, a novel system for culturing human myocardium was developed in our laboratory. We used this system to study the effects of trastuzumab on human cardiomyocytes in vitro and observed trastuzumab-induced structural and functional changes in human cardiomyocytes that were at least partially reversible with the addition of recombinant neuregulins. The results obtained in these experiments support a direct action of trastuzumab on human cardiomyocytes. In addition, these data provide insight regarding potential molecular mechanisms. Most importantly, these data draw attention to the inherent risk of cardiotoxicity associated with a newly emerging class of antineoplastic drugs that interfere with signal transduction pathways.

A 9-year, single-institution, retrospective review of death rate and prognostic factors in adult respiratory distress syndrome.

OBJECTIVE: To evaluate, at a single institution, the adult respiratory distress syndrome (ARDS) death rate in critically ill ventilated surgical/trauma patients and to identify the factors predicting death in these patients. SUMMARY BACKGROUND DATA: The prognostic features affecting mortality at the onset of ARDS have not been clearly defined. Defining rare characteristics would be valuable because it would allow for better stratification of patients in clinical trials and more appropriate utilization of constrained resources in ICU environments. METHODS: A retrospective analysis of 980 ventilated surgical and trauma intensive care unit patients from January 1990 to December 1998 was performed at Rhode Island Hospital. One hundred eleven adult intensive care unit patients with ARDS were identified using the criteria of Lung Injury Score more than 2.50 and the definition from the American-European Consensus Conference. Slightly more than half were trauma patients, 57% were men, and the median age was 59 years. The overall death rate was 52%. Patients were segregated by admission date to the intensive care unit (before or after January 1, 1995). Severity of illness was measured by the Revised Trauma Score for trauma patients and the Acute Physiology and Chronic Health Evaluation III for surgical patients. The Multiple Organ Dysfunction Score was determined on the day of onset of ARDS for all patients. Other recorded variables were age, sex, intensive care unit length of stay, length and mode of ventilation, presence or absence of tracheostomy, ventilation variables of peak and mean airway pressures, lung injury scores, elective versus emergency surgery, and presence or absence of pneumonia. RESULTS: There was a significant decrease in the ARDS death rate from the period 1990 to 1994 to the period 1995 to 1998. The major reason for the decline was a reduction in the posttraumatic ARDS death rate. Lung-protective ventilation strategies were used more frequently in the second period than in the first, and the death rate was significantly decreased in trauma patients in the second period when lung-protective ventilation modes were used. Predictors of death at the onset of ARDS were advanced age, Multiple Organ Dysfunction Score of 8 or more, and Lung Injury Score of 2.76 or more. CONCLUSION: In this single-institution series, the death rate from ARDS declined from 1990 to 1998, primarily in posttraumatic patients, and the decrease is related to the use of lung-protective ventilation strategies. Based on this patient population, the authors developed a statistical model to evaluate important prognostic indicators (advanced age, organ system and pulmonary dysfunction measurements) at the onset of ARDS.

Effects of fluconazole administration in critically ill patients: analysis of bacterial and fungal resistance.

HYPOTHESIS: The administration of fluconazole in intensive care unit (ICU) patients leads to the emergence of bacterial and fungal resistance. DESIGN: Retrospective analysis of 2 patient cohorts: (1) critically ill patients treated in surgical, trauma, and medical ICUs between June 1997 and January 1999 who did and did not receive fluconazole; and (2) ICU patients with fungal infections and sensitivity testing results from June 1994 to December 1998. SETTING: University-affiliated tertiary care hospital. PATIENTS: The first cohort included 99 ICU patients with documented microorganism culture(s) who were treated with (n = 50) or without (n = 49) fluconazole; the second cohort included 38 patients with Candida species infection, identification, and antifungal susceptibility testing. RESULTS: Mortality (40% vs 20%; P = .03) and hospital length of stay (33.8 vs 25.6 days; P = .04) were higher in the patients treated with fluconazole compared with patients not treated with fluconazole. The ICU length of stay was also higher in patients treated with fluconazole (23.7 vs 15.1 days; P = .009). An increase in bacterial resistance occurred in patients after fluconazole treatment as opposed to bacterial resistance of patients who were treated for bacterial microorganism(s) without fluconazole (16% vs 4%; P = .049). Comparison of patient populations with Candida species identification before and after December 1997 showed an increase in Candida species resistance to fluconazole (11% vs 36%; P = .16), respectively. Fungal strains were dominated by a combination of Candida albicans and Candida glabrata in both populations (60% [before 1998] vs 82% [after 1998]), with an emergence of Candida non-albicans species tolerant to fluconazole. The amount of fluconazole administered and the number of patients receiving fluconazole treatment in the ICUs has also increased when comparing both periods. CONCLUSIONS: Comparison of critically ill patient populations with and without fluconazole treatment found increased mortality and longer hospital and ICU lengths of stay in the fluconazole-treated group. This group also had higher bacterial pathogen resistance to antibiotics after fluconazole administration compared with bacterial resistance of patients without fluconazole treatment. Our results warrant concern regarding worsening bacterial infections, increased mortality, and an increase in Candida resistance to fluconazole from increased use in ICU patients, with a shift in yeast infection that is more difficult to treat.

Demonstration of viable, stunned myocardium with technetium-99m-sestamibi.

Delayed improvement of left ventricular contractile function in the setting of acute ischemia followed by reperfusion ("stunned myocardium") has been observed in a number of clinical scenarios, and may have important clinical implications. At present, there are no widely accepted techniques available to demonstrate its presence. We report a case in which a rest 99mTc-sestamibi scan performed 12 hr after thrombolytic therapy in the setting of acute myocardial infarction demonstrated viable myocardium in a region that was akinetic by contrast ventriculography. After surgical revascularization, follow-up 99mTc-sestamibi images showed normal perfusion and radionuclide ventriculography demonstrated normal left ventricular function. Demonstration of preserved 99mTc-sestamibi myocardial uptake in the infarct zone despite an extensive region of akinesis by contrast ventriculography predicted the recovery of left ventricular function after revascularization in this case. This suggests that perfusion imaging with 99mTc-sestamibi early after myocardial reperfusion can detect stunned myocardium and thus facilitate the decision-making process regarding management of such patients.

Technetium-99m isonitrile myocardial uptake at rest. II. Relation to clinical markers of potential viability.

To determine the utility of rest-injected technetium-99m methoxybutyl isonitrile (Tc-99m isonitrile) uptake as a marker of myocardial viability, the regional uptake of this agent was compared with regional wall motion by equilibrium gated blood pool scan in 26 patients with previous myocardial infarction and with postrevascularization uptake in 8 patients after coronary bypass surgery. Rest left ventricular Tc-99m isonitrile uptake was assessed qualitatively in three coronary vascular territories as grade 0 (markedly reduced) to grade 2 (normal), and quantitatively by circumferential profile analysis. Wall motion was scored qualitatively in corresponding vascular territories as normal, hypokinetic or akinetic/dyskinetic. There was an overall relation between qualitative Tc-99m isonitrile uptake and wall motion. Abnormal wall motion occurred in 74% of vascular territories with perfusion grade 0, in 61% of those with grade 1 and in 30% of those with grade 2; however, 26% of territories with grade 0 uptake had normal wall motion. In the territories visually assigned perfusion grade 0, quantitative isonitrile uptake (mean value +/- SD) was higher when corresponding wall motion was normal or hypokinetic (62 +/- 15%) than when akinesia was detected by gated blood pool scan (39 +/- 16%, p less than 0.02). Qualitative Tc-99m isonitrile uptake improved after coronary bypass surgery in 12 of 13 territories with reduced uptake preoperatively; this included all 5 territories with a preoperative Tc-99m isonitrile score of 0. Quantitative uptake in these regions increased from 55 +/- 18% to 73 +/- 21% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)