mTOR as a target of everolimus in refractory/relapsed Hodgkin lymphoma.

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

Ischemic mitral valve reconstruction and replacement: comparison of long-term survival and complications.

OBJECTIVE: This study reviews the 223 consecutive mitral valve operations for ischemic mitral insufficiency performed at New York University Medical Center between January 1976 and January 1996. The results for mitral valve reconstruction are compared with those for prosthetic mitral valve replacement. METHODS: From January 1976 to January 1996, 223 patients with ischemic mitral insufficiency underwent mitral valve reconstruction (n = 152) or prosthetic mitral valve replacement (n = 71). Coronary artery bypass grafting was performed in 89% of cases of mitral reconstruction and 80% of cases of prosthetic replacement. In the group undergoing reconstruction, 77% had valvuloplasty with a ring annuloplasty and 23% had valvuloplasty with suture annuloplasty. In the group undergoing prosthetic replacement, 82% of patients received bioprostheses and 18% received mechanical prostheses. RESULTS: Follow-up was 93% complete (median 14.6 mo, range 0-219 mo). Thirty-day mortality was 10% for mitral reconstruction and 20% for prosthetic replacement. The short-term mortality was higher among patients in New York Heart Association functional class IV than among those in classes I to III (odds ratio 5.75, confidence interval 1.25-26.5) and was reduced among patients with angina relative to those without angina (odds ratio 0.26, confidence interval 0.05-1.2). The 30-day death or complication rate was similarly elevated among patients in functional class IV (odds ratio 5.53; confidence interval 1.23-25.04). Patients with mitral valve reconstruction had lower short-term complication or death rates than did patients with prosthetic valve replacement (odds ratio 0.43, confidence interval 0.20-0.90). Eighty-two percent of patients with mitral valve reconstruction had no insufficiency or only trace insufficiency during the long-term follow-up period. Five-year complication-free survivals were 64% (confidence interval 54%-74%) for patients undergoing mitral valve reconstruction and 47% (confidence interval 33%-60%) for patients undergoing prosthetic valve replacement. Results of a series of statistical analyses suggest that outcome was linked primarily to preoperative New York Heart Association functional class. CONCLUSIONS: Initial mortalities were similar among patients undergoing prosthetic replacement and valve reconstruction. Poor outcome was primarily related to preexisting comorbidities. Patients undergoing valve reconstruction had fewer valve-related complications. Valve reconstruction resulted in excellent durability and freedom from complications. These findings suggest that mitral valve reconstruction should be considered for appropriate patients with ischemic mitral insufficiency.

Minimally invasive versus sternotomy approaches for mitral reconstruction: comparison of intermediate-term results.

BACKGROUND: This study compares intermediate-term outcomes of mitral valve reconstruction after either the standard sternotomy approach or the new minimally invasive approach. Although minimally invasive mitral valve operations appear to offer certain advantages, such as reduced postoperative discomfort and decreased postoperative recovery time, the intermediate-term functional and echocardiographic efficacy has not yet been documented. METHODS: From May 1996 to February 1999, 100 consecutive patients underwent primary mitral reconstruction through a minimally invasive right anterior thoracotomy and peripheral cardiopulmonary bypass and Port-Access technology (Heartport, Inc, Redwood City, Calif). Outcomes were compared with those for our previous 100 patients undergoing primary mitral repair who were operated on with the standard sternotomy approach. RESULTS: Although patients were similar in age, the patients undergoing the minimally invasive approach had a lower preoperative New York Heart Association classification (2.1 +/- 0.5 vs 2.6 +/- 0.6, P <.001). There was one (1.0%) hospital mortality with the sternotomy approach and no such case with the minimally invasive approach. Follow-up revealed that residual mitral insufficiency was similar between the minimally invasive and sternotomy approaches (0.79 +/- 0.06 vs 0.77 +/- 0.06, P =.89, 0- to 3-point scale); likewise, the cumulative freedom from reoperation was not significantly different (94.4% vs 96.8%, P =.38). Follow-up New York Heart Association functional class was significantly better in the patients undergoing the minimally invasive approach (1.5 +/- 0.05 vs 1.2 +/- 0.05, P <.01). CONCLUSIONS: These findings demonstrate comparable 1-year follow-up results after minimally invasive mitral valve reconstruction. Both echocardiographic results and New York Heart Association functional improvements were compatible with results achieved with the standard sternotomy approach. The minimally invasive approach for mitral valve reconstruction provides equally durable results with marked advantages for the patient and should be more widely adopted.

Beating-heart coronary artery bypass grafting for left ventricular failure assisted by the Abiomed BVS 5000.

Two cases of postmyocardial infarction cardiogenic shock were treated with left ventricular assist device (LVAD) implantation. With the left ventricular function bypassed, beating-heart coronary artery bypass grafting (CABG) was performed. This technique may be useful in the setting of acute myocardial dysfunction where limited coronary revascularization is required.

Late results of isolated mitral annuloplasty for "functional" ischemic mitral insufficiency.

BACKGROUND: Repair of functional ischemic mitral regurgitation (MR) due to annular deformity and leaflet restriction remains a challenge for the surgeon and lacks well-documented outcomes. We investigated outcomes in the treatment of functional ischemic MR corrected by annuloplasty techniques alone. METHODS: From May 1980 to July 1999, 174 patients underwent repair for functional ischemic mitral insufficiency with annuloplasty alone (128 ring annuloplasty; 46 suture annuloplasty). Acute insufficiency was present in 25 (14.4%). Concomitant procedures included CABG (n = 152; 87.4%). Patients were studied longitudinally with annual follow-up and echocardiograms. RESULTS: Overall hospital mortality was 17.8% and was increased by NYHA Class 4 (23.8% vs. 8.7%; p = 0.011), diabetes (25.0% vs. 13.6%; p = 0.059), and chronic mitral insufficiency (16.4% vs. 8.0%; p = 0.070). Multivariate analysis revealed age (beta = 0.099; p = 0.049) and ejection fraction < 30% (beta = 1.260; p = 0.097) as significant predictors of hospital death. Mean postoperative mitral insufficiency was 0.84 +/- 0.86 (scale of 0-4). NYHA Class 4 (beta = 2.33; p = 0.034) and simple suture annuloplasty (beta = 2.08; p = 0.07) were associated with increased risk of late cardiac death. Cumulative incidence of mitral reoperation was 7.7% at 5 years. At follow-up, 89.7% of patients were in NYHA Class 1 or 2 with 83.4% having none or only mild mitral insufficiency. CONCLUSIONS: Ring annuloplasty is associated with a survival benefit when compared to simple suture repair in ischemic patients who require annuloplasty alone to correct the MR. Mitral reconstruction with a ring annuloplasty offers durable results in this homogeneous subset of functional ischemic MR patients. Ischemic mitral insufficiency is associated with significant late mortality.

Minimal access reoperative mitral and aortic valve surgery.

Minimally invasive cardiac surgery has allowed surgeons to perform valve procedures with a morbidity and mortality comparable with conventional resternotomy approaches while reducing postoperative ventilatory and intensive care unit requirements and overall hospital length of stay. Additionally, patient satisfaction with rapid recovery, earlier return to work, and improved cosmetic results has pushed the pendulum of reoperative valve surgery towards minimally invasive techniques. We reviewed our institutional data consisting of 129 patients requiring reoperative valve surgery over the past 4 years, which was accomplished using these minimally invasive approaches.

Assisted venous drainage presents the risk of undetected air microembolism.

OBJECTIVES: The proliferation of minimally invasive cardiac surgery has increased dependence on augmented venous return techniques for cardiopulmonary bypass. Such augmented techniques have the potential to introduce venous air emboli, which can pass to the patient. We examined the potential for the transmission of air emboli with different augmented venous return techniques. METHODS: In vitro bypass systems with augmented venous drainage were created with either kinetically augmented or vacuum-augmented venous return. Roller or centrifugal pumps were used for arterial perfusion in combination with a hollow fiber oxygenator and a 40-micrometer arterial filter. Air was introduced into the venous line via an open 25-gauge needle. Test conditions involved varying the amount of negative venous pressure, the augmented venous return technique, and the arterial pump type. Measurements were recorded at the following sites: pre-arterial pump, post-arterial pump, post-oxygenator, and patient side. RESULTS: Kinetically augmented venous return quickly filled the centrifugal venous pump with macrobubbles requiring continuous manual clearing; a steady state to test for air embolism could not be achieved. Vacuum-augmented venous return handled the air leakage satisfactorily and microbubbles per minute were measured. Higher vacuum pressures resulted in delivery of significantly more microbubbles to the "patient" (P <.001). The use of an arterial centrifugal pump was associated with fewer microbubbles (P =.02). CONCLUSIONS: Some augmented venous return configurations permit a significant quantity of microbubbles to reach the patient despite filtration. A centrifugal pump has air-handling disadvantages when used for kinetic venous drainage, but when used as an arterial pump in combination with vacuum-assisted venous drainage it aids in clearing air emboli.

Robotic-assisted instruments enhance minimally invasive mitral valve surgery.

BACKGROUND: The potential for totally endoscopic mitral valve surgery has been advanced by the development of minimally invasive techniques. Recently surgical robots have offered instrument access through small ports, obviating the need for a significant thoracotomy. This study tested the hypothesis that a microsurgical robot with 5 degrees of freedom is capable of performing an endoscopic mitral valve replacement (MVR). METHODS: Dogs (n = 6) were placed on peripheral cardiopulmonary bypass; aortic occlusion was achieved with endoaortic clamping and transesophageal echocardiographic control. A small left seventh interspace "service entrance" incision was used to insert sutures, retractor blade, and valve prosthesis. Robotically controlled instruments included a thoracoscope and 5-mm needle holders. MVR was performed using an interrupted suture technique. RESULTS: Excellent visualization was achieved with the thoracoscope. Instrument setup required 25.8 minutes (range 12 to 37); valve replacement required 69.3+/-5.39 minutes (range 48 to 78). MVR was accomplished with normal prosthetic valve function and without misplaced sutures or inadvertent injuries. CONCLUSIONS: This study demonstrates the feasibility of adjunctive use of robotic instrumentation for minimally invasive MVR. Clinical trials are indicated.

Evaluation of trisomy 12 by fluorescence in situ hybridization in peripheral blood, bone marrow and lymph nodes of patients with B-cell chronic lymphocytic leukemia.

BACKGROUND AND OBJECTIVE: Trisomy 12 is the most common numerical chromosomal aberration in patients with B-cell chronic lymphocytic leukemia (B-CLL). Fluorescence in situ hybridization (FISH) has improved the detection of this cytogenetic abnormality and has made detection possible in all phases of the cell cycle. The presence of the trisomy 12 positive (+12) cell population has generally been investigated in leukemic cells obtained from the peripheral blood of CLL patients. To ascertain whether trisomy 12 is expressed homogeneously in cells of different hemopoietic tissues, we applied FISH to lymph node, peripheral blood and bone marrow samples obtained simultaneously from 23 untreated B-CLL patients. DESIGN AND METHODS: Twenty-three newly diagnosed patients with B-CLL, 15 in stage B and 8 in stage C, were included in the present study. Peripheral blood smears, bone marrow aspirate smears and lymph node touch imprints were collected from each patient at diagnosis. Cytologic preparations were examined by light microscopy in order to assess the lymphocyte morphology. Immunophenotyping was performed by cytofluorimetric analysis of the peripheral blood, bone marrow and lymph node mononuclear cell suspensions. The diagnosis was supported in all cases by histologic findings in bone marrow biopsy and lymph node biopsy specimens. Fluorescence in situ hybridization was performed on smears of blood and aspirated bone-marrow and lymph node touch imprints obtained by fresh tissue apposition. RESULTS: In 6 of the 23 cases (26%) trisomy 12 was clearly present in all tissues examined. A comparative analysis of the three different hemopoietic tissues was performed. A higher percentage of leukemic CD5+CD23+ cells was detected in lymph nodes than in peripheral blood and bone marrow. A significantly higher proportion of trisomic cells was observed in lymph nodes samples than in peripheral blood or bone marrow smears of trisomy 12 positive CLL patients. INTERPRETATION AND CONCLUSIONS: Several previous reports show that only a proportion of malignant B-CLL cells carry trisomy 12 when analyzed by interphase FISH. The higher proportion of +12 cells in lymph nodes than in peripheral blood or bone marrow of CLL patients with trisomy 12 could reflect different cell distributions in different tissues, or lymph node specific tropism, or proliferative advantage in selected tissue. At present, the role of trisomy 12 in the pathogenesis of lymphoproliferative disorders is unclear.

Time-dependent effect of glutaraldehyde on the tendency to calcify of both autografts and xenografts.

To determine mechanisms responsible for the reduced calcification in short-term glutaraldehyde (Glu)-treated autologous pericardial bioprostheses, we studied the time effect of Glu on subsequent calcification and differences in calcification of autograft and xenograft implants in a rat subcutaneous implantation model. In experiment 1, four groups of bovine pericardial pieces (1 cm2) were prepared: (A) fresh bovine pericardium without Glu, (B) with 15-minute Glu, (C) with 60-minute Glu, and (D) with 120-minute Glu. Seven young male Sprague-Dawley rats were used; each received four bovine pericardial pieces from group A, B, C, or D for subcutaneous implantation. Calcium content of the implants (microgram/mg dry weight) 45 days later was 4.8 +/- 2.9, 29.8 +/- 13.6, 106.3 +/- 13.7, and 176.3 +/- 85.5 in groups A, B, C, and D, respectively (p < 0.05 between any two groups). Experiment 2 used 8 young male Sprague-Dawley rats from different mothers. Each received five subcutaneous skin implants. The five skin implants were prepared as follows: (1) fresh self skin, (2) self skin with 30-minute Glu, (3) self skin with 48-hour Glu, (4) fresh skin of others, and (5) skin of others with 48-hour Glu. After 45 days of implantation, the calcium content of the implants was 1.4 +/- 1.1, 57.9 +/- 35.4, 142.7 +/- 61.4, 1.5 +/- 1.1, and 94.9 +/- 24.1 micrograms/mg dry weight in groups 1, 2, 3, 4, and 5, respectively (p < 0.05 for 1 versus 2, 3, or 5; 2 versus 3, 4, or 5; 3 versus 4; and 4 versus 5).(ABSTRACT TRUNCATED AT 250 WORDS)