Comparative Ventricular Electrophysiologic Effect of Racemic Bupivacaine, Levobupivacaine, and Ropivacaine on the Isolated Rabbit Heart

Background: Numerous local anesthetics have an asymmetric tetrahedron carbon, which confers stereoselective differences between the isomers. The authors attempted to quantify the depressant effect of racemic bupivacaine, levobupivacaine, and ropivacaine on myocardial ventricular conduction and on myocardial contractility.

Methods: The authors studied the pharmacokinetics (outflow concentration) and pharmacodynamics (QRS widening) of the three drugs infused in an isolated rabbit heart preparation. All data were fitted simultaneously with use of mixed-effect modeling, thus allowing precise statistical comparison between the three drug parameters. The rate dependence of QRS widening was fitted separately.

Results: Racemic bupivacaine, levobupivacaine, and ropivacaine induced a calculated maximum increase in QRS duration in the ratio 1:0.4:0.3. Css50, the dose which caused half the maximum increase in QRS duration at steady state, was similar for all three drugs (22 [mu]m free concentration). A rate dependence of QRS widening was observed, which was in the ratio 1:0.5:0.25 for racemic bupivacaine, levobupivacaine, and ropivacaine, respectively.     

Cardiac Troponin I and Myocardial Contusion in the Rabbit

Background: Patients with cardiac contusion have a high risk of cardiac complications during emergency anesthesia. Despite the progress in cardiac imaging, a biologic marker of myocardial damage such as cardiac troponin I remains useful and has been proposed in clinical practice. The relationship among histologic injury, left-ventricular function, and release of cardiac enzymes and cardiac troponin I has been investigated after a controlled myocardial contusion in a rabbit model.

Methods: A global trauma (two levels of energy: 250 and 350 mJ) was produced on an isolated preparation of rabbit's heart, of which the temperature, perfusion flow, beating rate, and left-ventricular volume were kept constant. Left-ventricular pressure and its first derivative as a function of time were measured during a 60-min period after the blow; a timed collection of the effluent was made to assess creatine kinase, lactate dehydrogenase, and cardiac troponin I. At the end of the period, an anatomic score of the contusion was calculated by histologic examination of the hearts.

Results: Compared with a control group, the two levels of cardiac trauma resulted in a proportional anatomic injury significantly correlated with left-ventricular dysfunction ([DELTA]%dP/dtmax = -16 +/- 12 and -36 +/- 20% at 3 min, mean +/- SD). Transient releases in cardiac markers after the lesser amount of trauma contrasted with a prolonged and biphasic release of cardiac troponin I after the greater amount. Peak cardiac troponin I level was correlated with anatomic injury ([rho] = 0.596, P = 0.001) and negatively correlated with left-ventricular dysfunction (r = -0.375, P = 0.04).     

KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome.

Recent biological studies have classified breast carcinomas into HER2-overexpressing, estrogen receptor-positive/luminal, basal- and normal-like groups. According to this new biological classification, the objectives of our study were to assess the clinical, morphologic and immunophenotypic characteristics of adenoid cystic carcinoma of the breast in order to classify this subtype of breast carcinoma. A total of 18 cases of adenoid cystic carcinoma were identified from the Institut Curie files. Clinical information was available for 16 patients with a median follow-up of 6.5 years. Morphologically, all tumors were graded according to the system defined by Kleer and Oberman (histologic and nuclear grade). Immunophenotype was assessed with anti-ER, PR, HER-2, KIT, basal (CK5/6) and luminal cytokeratins (CK8/18) and p63 antibodies. One out of 18 tumors was nuclear grade 1 (16%), nine were nuclear grade 2 (50%) and eight were nuclear grade 3 (44%). All cases were estrogen receptor, progesterone receptor and HER-2 negative. Epithelial cells were strongly positive around glandular lumina with one or both cytokeratins, identifying the coexistence of CK5/6+ cells, CK5/6 and CK8/18+ cells, CK8/18+ cells and p63+ cells. All cases (100%) were also KIT positive. In all, 15 patients were treated by surgery. Nine of them received adjuvant radiotherapy. Follow-up was available for 16 patients. In all, 14 patients were alive. Two of them, initially treated by surgery only, presented a local recurrence. Two patients died (one of them treated by radiation therapy only died from her disease). Our study shows that adenoid cystic carcinoma of the breast is a special, estrogen receptor, progesterone receptor, HER-2 negative and highly KIT-positive, basal-like breast carcinoma, associated with an excellent prognosis. This highly specific immunophenotype could be useful to differentiate adenoid cystic carcinoma of the breast from other subtypes of breast carcinoma such as cribriform carcinoma.     

New Therapeutic Approaches for Waldenstrom Macroglobulinemia

Waldenstrom Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is an incurable disease, with an overall medial survival of only 5-6 years. First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g. chlorambucil or cyclophasphamide), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab. Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine. The range of the ORR to these agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM.     

Imatinib plus low‐dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high‐dose imatinib

BACKGROUND:

In KIT‐expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1‐2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high‐dose imatinib therapy.

METHODS:

Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15‐20 mg/m²/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18‐fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin.

RESULTS:

Twenty‐six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for ≥6 months). Median progression‐free survival (PFS) was 100 days (95% confidence interval [CI], 62‐138), and median survival was 390 days (95% CI, 264‐516). Interestingly, PFS was 211 days (95% CI, 52‐370) in patients with wild type (WT) KIT and 82 days (95% CI, 53‐111) in non‐WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination.

CONCLUSIONS:

Low‐dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT‐KIT genotype. Cancer 2010. © 2010 American Cancer Society.     

La integración de la cirugía y el tratamiento quimioterápico en el cáncer de vejiga infiltrante

IntroductionTreating patients with invasive transitional cell carcinoma of the bladder remains difficult due to the multiple biological behaviour patterns found in this disease. There is still controversy regarding the use of systemic treatment in invasive bladder carcinoma and the ideal moment for launching perioperative chemotherapy. We present an overview of current trends for systemic treatment of invasive bladder carcinoma.Material and methodsUsing MEDLINE, we reviewed relevant English and Spanish language literature published during the last five years, with “chemotherapy in bladder cancer” as keywords. We selected randomized trials, meta-analyses and clinical trials.ResultsWe obtained a total of 241 articles. Thirty-one of them referred to neoadjuvant and adjuvant chemotherapy in invasive bladder cancer. We classified the articles in three different groups neoadjuvant, adjuvant and neoadjuvant plus chemotherapy. All of that information is displayed in the tables within the text.ConclusionsA multidisciplinary approach to the treatment of invasive bladder cancer is essential to guarantee adequate oncological control. A detailed evaluation and proper selection of each patient is fundamental in determining the best moment to start chemotherapy.     

MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD

Background  

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised.