Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.

Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population.

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.

Trials of 9-amino-20(S)-camptothecin in Boston.

9-Amino-20(S)-camptothecin (9-AC) is an analog of camptothecin with limited water solubility which has shown significant preclinical activity in a variety of human solid tumor xenografts. A Phase I trial using a soluble formulation of 9-AC, given as a 72-hour continuous infusion, has been completed. Thirty-one patients with resistant cancers received 5-60 micrograms/M2/h at three week intervals. The Maximum Tolerated Dose (MTD) was 45 micrograms/M2/hour. Neutropenia was the dose limiting toxicity, with few significant non-myelosuppressive toxicities. Minor responses were seen in 3/31 patients. Pharmacokinetic studies of 9-AC lactone (closed ring) showed substantial interpatient variability with a predicted half-life of 36 hours. A phase I/II trial of the same formulation of 9-AC is ongoing in refractory leukemia. Stomatitis and diarrhea are the non-myelosuppressive dose limiting toxicities. Evidence of antineoplastic activity has been seen in 3/15 patients. A Phase II trial in previously untreated metastatic breast cancer is also underway. A Phase I trial of a colloidal dispersion formulation, not yet completed, is better tolerated with a MTD > 45 micrograms/M2/h as a 72-hour continuous infusion. Evidence of antineoplastic activity has also been demonstrated.

Aortic valve endocarditis. Determinants of early survival and late morbidity.

BACKGROUND: Aortic valve surgery for endocarditis remains a high-risk procedure. The objective of this study was to analyze the interaction between the various subsets of endocarditis (native, prosthetic, healed, and active), timing of surgery, and their influence on early and late outcomes. METHODS AND RESULTS: During a 20-year period starting January 1972, 200 patients underwent aortic valve replacement for infective endocarditis (age range, 13 to 88 years; median, 53 years). There were 51 (26%) females, and 109 (55%) were in New York Heart Association functional class IV before surgery. Native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE) were present in 132 (66%) and 68 (34%) patients, respectively. Surgery was required in 120 (60%) during the active phase (AE) and 80 (40%) during the healed phase (HE) of endocarditis. The main indication for surgery in the healed group was progressive congestive heart failure. The indications for the active group were congestive heart failure (68%), continuing active sepsis (70%), echocardiographic vegetation (28%), peripheral emboli (30%), and arrhythmias (13%). Streptococcal infections predominated in NVE, staphylococcal in PVE and AE; culture-negative endocarditis predominated in the healed group. Isolated aortic valve surgery was performed in 68% of the patients, and concomitant procedures (32%) included mitral valve and coronary bypass procedures. The overall operative mortality (OM) was 12.5%. The OM was 7.5% and 22% for NVE and PVE, respectively (P = .004), and 7% for HE versus 15% for AE (P = .06). The OM for early PVE was 33% versus 18% for late PVE (P < .05). Multivariate logistic regression analysis identified PVE and New York Heart Association functional class IV to be independent predictors for early death. Recurrent endocarditis occurred 26 times in 24 patients (11 early, 13 late), with three operative deaths in the early group, all due to residual staphylococcal infections. Freedom from recurrent endocarditis was significantly different between HE (96 +/- 3% and 86 +/- 6% at 5 and 10 years, respectively) and AE (89 +/- 3% and 83 +/- 4%, respectively (P = .02). Long-term survival for discharged patients was 81 +/- 3% and 63 +/- 5% at 5 and 10 years, respectively, with no significant difference between NVE, PVE, AE, and HE. CONCLUSIONS: These data suggest that for active endocarditis, surgery should be delayed to achieve a healed status provided there is no pressing need for immediate surgery. Patients with staphylococcal endocarditis, particularly on a prosthesis, should be operated on sooner and should be covered with antibiotics for an extended period to prevent recurrent PVE. This study stresses the need for aggressive antibiotic prophylaxis, particularly in the presence of a prosthesis.

Rapid noninvasive diagnosis and surgical repair of acute ascending aortic dissection. Improved survival with less angiography.

Angiography has been considered the gold standard for the diagnosis of acute dissection of the ascending aorta, but it may increase mortality by imposing an unnecessary delay before surgical repair. In addition, coronary angiography has often been considered essential as well. From 1988 to 1993, 37 patients (median age 61 years, 30 men and 7 women) had acute dissection of the ascending aorta. All of the initial 15 patients (group I) had angiography, even through the diagnosis of aortic dissection had already been made noninvasively in 14; six (40%) of 15 died, three of aortic rupture and none of complications of coronary artery disease. Among the next 22 patients (group II), 21 had a noninvasive diagnosis of acute dissection of the ascending aorta (eight by echocardiography; 13 by computed tomography), and 19 (86%) were operated on without angiography; two died (9%, p = 0.03 versus group I) and neither death was due to aortic rupture or coronary artery disease. Overall, either root or selective coronary angiography was attempted in 18 of 37 patients, but it documented coronary artery disease in only two patients (11%). Coronary artery disease was found in four other patents at autopsy; three of them, including two that died of aortic rupture, had angiography that failed to reveal the coronary artery disease. Noninvasive diagnosis of acute dissection of the ascending aorta is reliable and avoids the risks and delays inherent in invasive angiography. Rapid noninvasive diagnosis of aortic dissection and avoidance of routine angiography appear to improve survival by expediting surgical intervention and thus decreasing the risk of aortic rupture.

Single-clamp technique: an important adjunct to myocardial and cerebral protection in coronary operations.

To determine the myocardial and cerebral protective properties of the single cross-clamp (group I; n = 160) versus the partial occluding clamp (group II; n = 150) technique for construction of the proximal anastomoses, a retrospective analysis of 310 patients operated on by the same surgeon was performed. Group I patients were older (median age, 70 versus 64 years; p < or = 0.0001), with 83 (52%), versus 41 (27%) in group II, 70 years and older (p < or = 0.0001). More group I patients were in New York Heart Association functional class IV (42 [26%] versus 22 [15%]; p = 0.008); more required preoperative balloon counterpulsation (35 [22%] versus 16 [11%]; p = 0.006); and more required emergent operation (20 [13%] versus 3 [2%]; p < or = 0.0001). Antegrade crystalloid cardioplegia was used in both groups. The median cross-clamp time was 58 minutes for group I versus 44 minutes for group II (p < or = 0.0001). However, there was no significant difference between the two groups in terms of the number of bypass grafts, the use of the mammary artery, or the bypass time. The operative mortality was 2.5% (n = 4) for group I versus 5.3% (n = 8) for group II (p = 0.16), and the perioperative myocardial infarction/low cardiac output state was seen in 6 patients (3.8%) in group I versus 18 patients (12%) in group II (p = 0.006). The median creatine kinase MB release was 13 U/L for group I versus 19 U/L for group II (p = 0.0029).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term results of mitral valve reconstruction for regurgitation of the myxomatous mitral valve.

The myxomatous, degenerated, prolapsed or "floppy" mitral valve is the most common cause of mitral regurgitation in North America. Mitral valve reconstruction for mitral regurgitation was carried out in 219 consecutive patients with a myxomatous mitral valve from 1984 to 1993. Of the 139 men and 80 women, 23 to 84 years of age (mean 63 years), 36% of patients were 70 years of age or older, 77% were in New York Heart Association functional class III or IV, and 29% had coronary artery disease necessitating coronary bypass. The most common operation was posterior leaflet resection (161 patients [73%]). The anterior leaflet was resected in 14 patients, and both the anterior and posterior leaflets were resected in 15 patients. A variety of other techniques were used, including commissuroplasty and use of annuloplasty rings. A flexible Duran ring was used in 111 patients (51%), a Carpentier-Edwards ring in 44 patients (20%), and no ring was used in 64 patients (29%). Five operative deaths occurred (2.3%); four of the five deaths occurred in patients 70 years of age or older (5.1%); and one in 141 patients (0.7%) was younger than 70 years of age. In the late postoperative period (mean follow-up 2 years), 90% of patients had no symptoms, two had endocarditis, and seven patients had thromboemboli (transient in four, permanent in three). Structural valve degeneration requiring reoperation occurred late in 12 patients; eight were in posterior leaflet resection and two in anterior or anterior and posterior; six of 12 had no annuloplasty ring. The incidence of structural valve degeneration was less than 5% from 1990 to 1993. No systolic anterior motion of the mitral valve was seen with postoperative echocardiography before discharge. Actuarial analysis at 5 years for overall survival was 86% +/- 5%, freedom from infectious valve degeneration 97% +/- 2%, and freedom from thromboembolism 94% +/- 3%. Freedom from structural valve degeneration overall was 83% +/- 4%, with a flexible ring it was 89% +/- 6%, with a rigid ring it was 88% +/- 6%, and with no ring it was 67% +/- 12% (p = 0.03). Mitral valve reconstruction for complicated myxomatous disease of the mitral valve, regardless of leaflet involvement, is feasible and offers excellent early and late results.

Aortic valve replacement in the elderly. Effect of gender and coronary artery disease on operative mortality.

BACKGROUND: Aortic valve replacement remains the treatment of choice for aortic valve disease, even in the extreme elderly who may present with advanced symptoms. Defining risk factors for short-term survival was the object of this study. METHODS AND RESULTS: This was a retrospective analysis of 717 patients at least 70 years of age who underwent aortic valve replacement alone or with coronary artery bypass graft between 1980 and 1992. Age range was 70 to 95 years, and mean age was 77 years; there were 529 septuagenarians (74%); 188 were octogenarians (26%); 326 were women (45%); and 386 patients (54%) had aortic valve replacement and coronary artery bypass graft. Atrial fibrillation/flutter or heart block was present in 16%, and 34% of patients were in New York Heart Association (NYHA) functional class IV. Aortic stenosis was present in 88%, and mechanical prostheses were used in 22% of patients. There were 47 deaths, giving an overall operative mortality of 6.6%, with 4.2% for aortic valve replacement and 8.8% for aortic valve replacement and coronary artery bypass graft (P = .01). The operative mortality for aortic valve replacement was 2.9% versus 10.3% for aortic valve replacement and coronary artery bypass graft in women (P = .006). The corresponding values for men were 5.6% and 7.4% (P = .31). Multivariate logistic regression showed coronary artery bypass graft and NYHA class IV to be significant predictors of operative mortality in women. The significant predictors in men were NYHA class IV, atrial fibrillation/flutter or heart block rhythm, and the use of mechanical prosthesis. Age was not a predictor of operative mortality in either sex. CONCLUSIONS: Aortic valve replacement carries an acceptable mortality rate in elderly patients. Female gender was a significant predictor of operative mortality in the concomitant coronary artery bypass graft group; however, gender was not a predictor of operative mortality in the isolated aortic valve replacement group. Advance stage of the disease process represented by NYHA class IV was a significant predictor of mortality for the whole group, stressing the need for earlier referral for surgery.

Decrease in operative risk of reoperative valve surgery.

We analyzed the risk of valve re-replacement in 640 patients reoperated on between 1980 and 1992. This represented 17% of total valve operations (640/3,764) during that period. A univariate and logistic multivariate analysis was carried out for four sequential periods for the 640 re-replacement patients to determine if changing methods of perfusion and myocardial protection affected recent results. There were 323 female and 317 male patients with a mean age of 58 years (range, 17 to 84 years). Ninety-seven (15%) had coronary artery bypass grafting, 135 (21%) were 70 years old or older, 377 (59%) were in New York Heart Association functional class III or less, and 263 (41%) were in functional class IV. The aortic valve was re-replaced in 245, the mitral valve in 289, and both aortic and mitral synchronously in 106. Four periods were analyzed: 1980 through 1982, 1983 through 1985, 1986 through 1988, and 1989 through 1992. The overall operative mortality was 65 of 640 patients (10%), falling from 12/73 (16%) in 1980 through 1982 to 23/268 (8%) in 1989 through 1992 (p = 0.05). Univariate and multivariate logistic analysis documented that New York Heart Association functional class was highly significant for operative mortality; operative mortality was 4% for functional classes I through III, and 19% for functional class IV (p < or = 0.001). The requirement for coronary bypass was of borderline significance (p = 0.05), and year of operation was also significant. Mortality for re-replacement of aortic valve fell from 15% to 10%, double valve from 20% to 9%, and mitral valve from 16% to 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute bacterial endocarditis. Optimizing surgical results.

BACKGROUND: Acute bacterial endocarditis continues to be a condition with high morbidity. Although the majority of patients are treated by high-dose antibiotics, a high-risk patient group requires surgical intervention, which is the subject of this article. METHODS AND RESULTS: From 1972 to 1991, 3,820 patients underwent heart valve replacement at the Brigham and Women's Hospital, Boston. Of this group, 158 patients underwent surgery for acute bacterial endocarditis: 109 had native valve endocarditis (NVE), and 49 had prosthetic valve endocarditis (PVE). There were 108 men and 50 women with a mean age of 49 years (range, 16-79 years); 64% were New York Heart Association functional class IV before surgery, and 12% of the group had a history of intravenous drug abuse. In both NVE and PVE groups, Streptococcus was the predominant infecting agent. Uncontrolled sepsis, progressive congestive failure, peripheral emboli, and echocardiographically demonstrated vegetations were the most common indications for surgery. Eighty-five percent of patients had a single-valve procedure, 15% had a multivalve procedure, and 34 patients had other associated major cardiac procedures. The operative mortality was 6% in NVE and 22% in PVE. Long-term survival at 10 years was 66% for NVE and 29% for PVE. Freedom from recurrent endocarditis at 10 years was 85% for NVE and 82% for PVE. The main factors associated with decreased survival overall were PVE and nonstreptococcal infection. CONCLUSIONS: The morbidity and mortality after surgical treatment of acute endocarditis depend on the site, the severity, and the subject infected. Early aggressive surgical intervention is indicated to optimize surgical results, especially in patients with nonstreptococcal infection or PVE.

The long-term follow-up of the Hancock Modified Orifice porcine bioprosthetic valve.

The Hancock Modified Orifice valve is a specially fabricated, trileaflet porcine valve, which has been in clinical use at the Brigham and Women's Hospital since 1976. Three hundred seventy-nine aortic valve replacements with this device were implanted from 1976 to 1985; 305 were isolated aortic valve replacements and 74 were in association with a mitral valve bioprosthesis. The 305 patients undergoing isolated aortic valve replacement, a Food and Drug Administration patient group, are the subject of this article. The mean valve size was 22.5 mm, with 115 21-mm valves used. The mean functional preoperative class was 3.2; 99 of 305 patients (32.5%) underwent concomitant coronary artery bypass grafting. There were six operative deaths (2%). Patients were followed from 6-14 years (mean 7.4 years), and analysis was completed in early 1991. The 10-year actuarial calculation of survival freedom from reoperation, thromboembolism, structural valve degeneration, perivalvular leak, infectious valve degeneration, and total morbidity and mortality are presented.

Decreased operative risk of surgical treatment of mitral regurgitation with or without coronary artery disease.

The consecutive 2 year experience with patients undergoing first-time surgery for mitral regurgitation with and without coronary artery disease was reviewed. From January 1988 to January 1990, 127 patients with pure mitral regurgitation undergoing first-time operation were surgically treated. No other valve lesion, no reoperation and no congenital defects were included. The mean patient age was 62 years with 26% of the patients greater than 70 years. Twenty-six percent of the entire group was in functional class IV. Seventy-five patients received mitral valve repair and 52 underwent mitral valve replacement with a St. Jude or Hancock valve. In patients undergoing mitral valve repair, there was a higher incidence of those greater than 70 years old and of coronary artery disease and in patients undergoing mitral valve replacement there was a higher incidence of functional class IV. The operative mortality rate was 2.3% (3 of 127 patients). No patient failed to be discontinued from cardiopulmonary bypass and all three deaths occurred after mitral valve replacement, with one from complications of chronic renal failure and dialysis. There was no significant difference in patients who either did or did not have a concomitant coronary artery bypass graft and there was no difference related to age or functional class. Postoperative complications occurred in five patients in the valve repair group, including recurrent mitral regurgitation in two necessitating reoperation, and in three patients in the valve replacement group. With newer operative and postoperative management techniques, especially preservation of the papillary muscle annular continuity, the risk of mitral valve surgery, particularly of valve repair, is considerably lower than in previous years.