Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR

Atypical lipomatous tumor/well-differentiated liposarcomas and dedifferentiated liposarcomas are characterized by the amplification of MDM2 and CDK4 genes. To evaluate the accuracy of fluorescence in situ hybridization (FISH) analysis in the differential diagnosis of adipose tissue tumors, we investigated MDM2-CDK4 status by FISH, real-time polymerase chain reaction (PCR) [quantitative PCR (Q-PCR)] and immunohistochemistry (IHC) in a series of 200 adipose tumors. First, we evaluated MDM2-CDK4 amplification and expression in a series of 94 well-defined adipose tissue tumors. Results showed that FISH was interpretable in 45 of 50 cases (90%), and was more specific and sensitive than Q-PCR and IHC. We then used the same techniques as complementary diagnostic tools in a series of 106 adipose and soft tissue tumors of unclear diagnosis to distinguish between (i) lipomas and atypical lipomatous tumor/well-differentiated liposarcomas, (ii) malignant undifferentiated tumors and dedifferentiated liposarcomas, and (iii) a variety of benign tumors and liposarcomas. Our results indicate that although helpful, IHC alone is often insufficient to solve diagnostic problems. FISH and Q-PCR methods gave concordant results and were equally informative in most cases. However, the proportion of noninterpretable cases was slightly higher with FISH than with Q-PCR. When tumor cells represented a minor component of the tumor tissue, such as with inflammatory tumors, FISH was more powerful than Q-PCR by allowing visualization of individual cells. In conclusion, we recommend that the evaluation of MDM2-CDK4 amplification using FISH or Q-PCR be used to supplement IHC analysis when diagnosis of adipose tissue tumors is not possible based on clinical and histologic information alone.     

Thrombotic microangiopathy and anti-VEGF agents.

Sir, We report the occurrence of thrombotic microangiopathy (TMA)that may be directly related to vascular endothelial growthfactor (VEGF) Trap treatment, a fully humanized recombinantfusion protein containing extracellular portions of the extracellulardomains of two different VEGF receptors, VEGFR-1 and VEGFR-2.VEGF Trap is currently under evaluation in combination withLV5FU2-CPT11 in a     

Catalase Overexpression Prevents Nuclear Factor Erythroid 2–Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression,Hypertension, and Kidney Injury in Diabetic Mice

This study investigated the impact of catalase (Cat) overexpression in renal proximal tubule cells (RPTCs) on nuclear factor erythroid 2–related factor 2 (Nrf2) stimulation of angiotensinogen (Agt) gene expression and the development of hypertension and renal injury in diabetic Akita transgenic mice. Additionally, adult male mice were treated with the Nrf2 activator oltipraz with or without the inhibitor trigonelline. Rat RPTCs, stably transfected with plasmid containing either rat Agt or Nrf2 gene promoter, were also studied. Cat overexpression normalized systolic BP, attenuated renal injury, and inhibited RPTC Nrf2, Agt, and heme oxygenase-1 (HO-1) gene expression in Akita Cat transgenic mice compared with Akita mice. In vitro, high glucose level, hydrogen peroxide, and oltipraz stimulated Nrf2 and Agt gene expression; these changes were blocked by trigonelline, small interfering RNAs of Nrf2, antioxidants, or pharmacological inhibitors of nuclear factor-κB and p38 mitogen-activated protein kinase. The deletion of Nrf2-responsive elements in the rat Agt gene promoter abolished the stimulatory effect of oltipraz. Oltipraz administration also augmented Agt, HO-1, and Nrf2 gene expression in mouse RPTCs and was reversed by trigonelline. These data identify a novel mechanism, Nrf2-mediated stimulation of intrarenal Agt gene expression and activation of the renin-angiotensin system, by which hyperglycemia induces hypertension and renal injury in diabetic mice.     

Cost of Contralateral Prophylactic Mastectomy

Purpose

To compare the healthcare costs of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) with those of women who did not.

Methods

We conducted a retrospective study of 904 women treated for stage I–III breast cancer with or without CPM. Women were matched according to age, year at diagnosis, stage, and receipt of chemotherapy. We included healthcare costs starting from the date of surgery to 24 months. We identified whether care was immediate or delayed (CPM within 6 months or 6–24 months after initial surgery, respectively). Costs were converted to approximate Medicare reimbursement values and adjusted for inflation. Multivariable regression analysis was performed to evaluate the effect of CPM on total breast cancer care costs adjusting for patient characteristics and accounting for matched pairs.

Results

The mean difference between the CPM and no-CPM matched groups was $3,573 (standard error [SE] $455) for professional costs, $4,176 (SE $1,724) for technical costs, and $7,749 (SE $2,069) for total costs. For immediate and delayed CPM, the mean difference for total costs was $6,528 (SE $2,243) and $16,744 (SE $5,017), respectively. In multivariable analysis, the CPM group had a statistically significant increase of 16.9 % in mean total costs compared with the no-CPM group (p < 0.0001). Human epidermal growth factor receptor 2/neu-positive status, receipt of radiation, and reconstruction were associated with increases in total costs.

Conclusions

CPM significantly increases short-term healthcare costs for women with unilateral breast cancer. These patient-level cost results can be used for future studies that evaluate the influence of costs of CPM on decision making.     

Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis

BackgroundThe prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis (CF) patients has increased and MRSA seems to be associated with a poorer prognosis. The aim of this study was to assess the prevalence and clinical consequences of MRSA and methicillin-susceptible Staphylococcus aureus (MSSA), associated or not associated with Pseudomonas aeruginosa (PA).MethodsIn a retrospective study on 419 sputum producer patients (293 adults and 126 children > 7 years of age), we recorded patient characteristics, lung function, nutritional status, IV antibiotics and hospitalisations, the presence of SA and/or PA and FEV1 decline over 2 years.ResultsSA was found in 72% of the patients: MSSA in 68.2% of children and 48.8% of adults; MRSA in 17.5% of children and 17.8% of adults. Sixty percent of MRSA patients and 60.4% of MSSA patients also harboured PA. The rate of deterioration of clinical status of the various groups, as assessed from respiratory function, IV antibiotic courses and hospitalisations, increased in the order: no SA/no PA, MSSA alone, MRSA alone, MSSA/PA, MRSA/PA, and PA alone. Nutritional status did not differ between groups. Results were roughly similar for children and adults. The yearly FEV1 decline was significantly higher only for MRSA/PA patients (p = 0.03) compared to no SA/no PA patients.ConclusionClinical condition of CF patients with MSSA only or MRSA only appeared similar, whereas MRSA/PA patients had more severe respiratory function than MSSA/PA patients. In CF patients, MRSA might be more deleterious than MSSA only when associated with PA.     

Breast conservation surgery using nipple-areolar resection for central breast cancers

HYPOTHESIS: Resection of the nipple-areolar complex (NAC) for central breast cancers that involve the nipple or areola, with postoperative radiation therapy, adheres to the oncologic principles established for breast conservation surgery of other breast cancers. Good or excellent cosmetic results can be achieved. The rate of ipsilateral breast recurrence will be similar to that seen with peripheral breast cancers. The indications for breast conservation surgery can be safely extended to include patients with breast cancers that involve the NAC. DESIGN: Retrospective medical record review; follow-up patient questionnaire. SETTING: Community teaching hospital. PATIENTS: Fifteen patients, aged 46 to 88 years, whose central breast cancers involved the NAC precluding preservation of the NAC. INTERVENTIONS: Nipple-areolar complex resection, postoperative radiation therapy. MAIN OUTCOME MEASURES: Ipsilateral breast recurrence, survival, cosmesis. RESULTS: Ten patients had subareolar cancers that directly involved the nipple or areola; 5 patients had Paget disease of the nipple. Average tumor size was 1.6 cm (range, 0.2-3.5 cm). With a mean follow-up of 32 months (range, 4-109 months), there has been only 1 recurrence (7%), which was treated successfully by modified radical mastectomy. All 15 patients are alive and free of disease. Cosmetic results are satisfactory to excellent, as judged by both the patients and the surgeons. CONCLUSIONS: Nipple-areolar complex resection for central subareolar cancers that directly involve the NAC, as well as for Paget disease of the nipple, extends the indications for breast conservation in other areas of the breast, and with acceptable cosmesis.     

Diagnostic criteria for testing for BRCA1 and BRCA2: the experience of the Department of Defense Familial Breast/Ovarian Cancer Research Project

The Department of Defense Familial Breast/Ovarian Cancer Research Project has offered genetic counseling and testing for BRCA1 and BRCA2 on a research basis to patients meeting specific diagnostic criteria, with risk for BRCA1 and BRCA2 mutations calculated based on the Couch model. In 2.5 years, 250 patients were evaluated and 101 patients met criteria requirements, including 33 who met criteria in more than one category. Ninety patients elected to undergo DNA testing. In this group of 90 patients, 14 mutations (15.5%) and 16 unclassified variants (17.7%) were identified. The most common inclusion criteria were onset of breast/ovarian cancer before age 45 years (n = 32) and onset of breast/ovarian cancer before age 45 years with strong family history (n = 21). However, when number of mutations and unclassified variants found were compared separately across all diagnostic criteria (including those of more than one capacity) using the chi 2 statistic, no significant differences were seen among the categories to suggest that one criterion was more predictive of mutations or variants than another. Couch risk values for patients with mutations showed a mean of 14% and ranged from 3.2 to 43.5% (range for all patients, 1.2-69.7%). These findings emphasize the importance of using multiple diagnostic criteria and suggest that a Couch risk value of > 3% may be useful in selecting patients for testing. The data also underscore the necessity of genetic counseling in the testing process, particularly given the large number of unclassified variants diagnosed and their uncertain status for disease predisposition.     

Risk of pulmonary embolism after a negative spiral CT angiogram in patients with pulmonary disease: 1-year clinical follow-up study

PURPOSE: To evaluate the effect of pulmonary disease on diagnostic utility of spiral computed tomographic (CT) angiography in clinical practice. MATERIALS AND METHODS: Three hundred thirty-four patients, including 215 patients with pulmonary disease (group 1) and 119 patients with no history of respiratory disorder (group 2), were referred for thin-collimation CT angiography of the pulmonary circulation as the first-line diagnostic test. Patients with negative angiograms who had not received anticoagulation therapy and who could be clinically followed up at 3 months, 6 months, and 1 year were considered in the final study groups (n = 185); 135 patients had lung disease (group 3), and 50 patients had no history of a respiratory disorder (group 4). RESULTS: Between groups 3 and 4, no significant differences were found in the referral location, age, and risk factors. Confident evaluation of pulmonary arteries down to the subsegmental level was performed in 31 (23%) patients in group 3 and in 15 (30%) in group 4 (P =.5). Three episodes of acute pulmonary embolism (PE), all fatal, were diagnosed in group 3 patients; two cases occurred 14 days and one case occurred 6 months after the negative spiral CT scan. The negative predictive value of spiral CT angiography was 98% (175 of 178) in the study group in which follow-up was performed, with no significant difference between the values in groups 3 (98% [132 of 135]) and 4 (100% [50 of 50]). CONCLUSION: Underlying respiratory disease does not affect the negative predictive value of thin-collimation CT angiography, which appears to be a reliable tool in the work-up in this subgroup of patients with acute PE.     

Clinical sedation and bispectral index in burn children receiving gamma-hydroxybutyrate

Background: Gamma‐hydroxybutyrate (GHB) may be an interesting hypnotic agent in burn patients because of its good respiratory or hemodynamic tolerance. However, its clinical and electroencephalographic (EEG) sedative effects are not yet described in children. The aim of this prospective and randomized study was to assess clinical and EEG effects of increasing intravenous (IV) doses of GHB in burn children requiring sedation for burn wound cares. Methods: Thirty six children hospitalized in a burn care unit were included and randomly assigned into three groups (G) according to the single IV dose of GHB they received before burn wound care: 10 mg·kg^?1 in G10, 25 mg·kg^?1 in G25, or 50 mg·kg^?1 in G50. All patients received oral premedication (morphine and hydroxyzine) 30 min before GHB injection. Respiratory rate, heart rate, pulse oximetry, and bispectral index (BIS) were continuously monitored. Depth of sedation was clinically assessed using Observer’s Assessment of Alertness and Sedation (OAAS) Score, every 2 min until recovery (i.e., OAAS = 4). Results: Median age was 17.5 [12–34] months. Whatever the dose, BIS decreased after IV GHB. Nadir value of BIS was significantly lower in G25 and G50 than in G10, as was for OAAS score. Nadir values were reached after same delays in G25 and G50. Duration of sedation was dose‐dependant. Conclusion: Bispectral index decreased after GHB injection and was correlated with OAAS score. Deep sedation can be safely achieved with IV doses of 25 or 50 mg·kg^?1, but the last dose was associated with prolonged duration of clinical sedation.     

Prospective, Multicenter, 3-Year Trial of Laparoscopic Adjustable Gastric Banding with the MIDBAND?

Background

Although laparoscopic adjustable gastric banding (LAGB) is a popular metabolic/bariatric procedure, few prospective studies have assessed its outcomes. This study aimed to prospectively assess LAGB safety and effectiveness outcomes using the MIDBAND? (MID, Dardilly, France).

Methods

Between May 2005 and September 2006, 262 morbidly obese patients underwent primary gastric banding with pars flaccida technique in 13 French medical centers. Excess weight loss and change in body mass index (BMI, kilogram per square meter), percentage of patients with comorbidities, and obesity-related complications were recorded. Patients were followed at 6-month intervals for 3?years. A multivariable individual growth model was used to analyze weight change over time and determine potential predictors of weight loss.

Results

The majority of patients were female (n?=?233, 89%), with mean age of 36.4?±?9.7?years. At 3?years, LAGB with MIDBAND resulted in significant decrease in mean BMI from 41.8?±?4.2 to 30.7?±?5.8 (p?p?Conclusion Prospective outcomes demonstrate the safety and efficacy of gastric banding over time using the MIDBAND. Individual growth modeling demonstrated that postoperative weight loss is strongly related to the frequency and consistency of follow-up visits.