A randomised Phase II trial to evaluate the toxicity of high-dose rifampicin to treat pulmonary tuberculosis.

SETTING: Randomised Phase IIB clinical trial. OBJECTIVES: To assess whether increasing the dose of rifampicin (RMP) from 10 mg/kg to 15 or 20 mg/kg results in an increase in grade 3 or 4 hepatic adverse events and/or serious adverse events (SAE). METHODS: Three hundred human immunodeficiency virus negative patients with newly diagnosed microscopy-positive pulmonary tuberculosis (TB) were randomly assigned to one of three regimens: 1) the control regimen (R10), comprising daily ethambutol (EMB), isoniazid (INH), RMP and pyrazinamide for 8 weeks, followed by INH and RMP daily for 18 weeks; 2) Study Regimen 1 (R15), as above, with the RMP dose increased to 15 mg/kg body weight daily for the first 16 weeks; and 3) Study Regimen 2 (R20), as above, with RMP increased to 20 mg/kg. Serum alanine transferase (ALT) levels were measured at regular intervals. RESULTS: There were seven grade 3 increases in ALT levels, 1/100 (1%) among R10 arm patients, 2/100 (2%) in the R15 arm and 4/100 (4%) in the R20 arm (trend test P = 0.15). One (R15) patient developed jaundice, requiring treatment modification. There were no grade 4 ALT increases. There was a non-significant increase in culture negativity at 8 weeks with increasing RMP dosage: 75% (69/92) in R10, 82.5% (66/80) in R15 and 83.1% (76/91) R20 patients (P = 0.16). CONCLUSIONS: No significant increase in adverse events occurred when the RMP dose was increased from 10 mg/kg to 15 mg/kg or 20 mg/kg.

Results at 30 months of a randomised trial of FDCs and separate drugs for the treatment of tuberculosis.

Study C was an open-label, non-inferiority, randomised controlled trial of fixed-dose combination (FDC) or separate drugs given during the intensive phase of treatment to 1585 patients with smear-positive pulmonary tuberculosis conducted at 11 sites in Africa, Asia and Latin America. Thirty months post-randomisation, the failure/relapse rates in the per protocol population were 7.4% of 591 patients on FDCs and 6.5% of 587 patients on separate drugs; the site-adjusted difference was 0.3% (90%CI -1.8 to 2.3). In the modified intention-to-treat analysis, the corresponding results were respectively 17.9% of 683 and 16.1% of 671; the site-adjusted difference was 2.0% (90%CI -1.2 to 5.2).

Results at 30 months of a randomised trial of two 8-month regimens for the treatment of tuberculosis.

SETTING: An 8-month isoniazid (INH, H) and ethambutol (EMB, E) based regimen recommended by the World Health Organization (WHO) had never been evaluated in a randomised controlled multicentre trial. OBJECTIVE: To compare, in a non-inferiority study design, two 8-month INH+EMB-based regimens with a standard INH and rifampicin (RMP, R) based regimen. DESIGN: A total of 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly allocated to receive 1) daily EMB, INH, RMP and pyrazinamide (PZA, Z) for 2 months, followed by EMB+INH for 6 months (2EHRZ/6HE); 2) the same drugs in the intensive phase but given three times weekly, followed by the same continuation phase of daily EMB+INH (2(EHRZ)(3)/6HE); or 3) a control regimen with the same intensive phase as in regimen 1, followed by 4 months of daily RMP+INH (2EHRZ/4HR). All patients were to be seen and sputum examinations for microscopy and culture carried out at regular intervals up to 30 months after randomisation. RESULTS: At 30 months, failure/relapse rates were 11.7% of 281 2EHRZ/6HE, 15.3% of 301 2(EHRZ)(3)/6HE and 6.0% of 282 2EHRZ/4HR patients (χ(2), 2 degrees of freedom = 12.8, P = 0.002). CONCLUSION: These results confirm earlier findings demonstrating the inferiority of the INH+EMB-based regimens to the standard 6-month regimen. The WHO has withdrawn its recommendation of these regimens.

Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial.

BACKGROUND: A WHO-recommended 8-month regimen based on ethambutol and isoniazid was evaluated in a randomised clinical trial against a 6-month standard regimen. METHODS: 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly assigned one of three regimens: daily ethambutol, isoniazid, rifampicin, and pyrazinamide for 2 months, followed by ethambutol and isoniazid for 6 months (2EHRZ/6HE); the same drugs but given three times weekly in the initial intensive phase (2[EHRZ]3/6HE); or the same initial intensive phase as the first regimen, followed by 4 months of daily rifampicin and isoniazid (2EHRZ/4HR). Follow-up was to 30 months after the start of chemotherapy. Sputum was regularly examined by microscopy and culture. Unfavourable outcome was defined as failure during treatment or relapse afterwards. Analyses were by intention to treat. FINDINGS: At 2 months, a significantly higher proportion of patients assigned the daily intensive phase than of those assigned the three-times-weekly regimen were culture negative (700/828 [85%] vs 333/433 [77%], p=0.001). 12 months after the end of chemotherapy, the proportions of unfavourable outcomes were 36 of 346 (10%) with 2EHRZ/6HE, 48 of 351 (14%) with 2(EHRZ)3/6HE, and 17 of 347 (5%) with 2EHRZ/4HR. Both 8-month regimens were significantly inferior to the control 6-month standard regimen (difference between control and 2EHRZ/6HE 5.5% [95% CI 1.6 to 9.4]; between control and 2(EHRZ)3/6HE 8.8% [4.5 to 13.0]). Adverse effects leading to interruption of treatment for 7 days or longer occurred in 28 patients (12 2EHRZ/6HE, five 2[EHRZ]3/6HE, 11 2EHRZ/4HR). INTERPRETATION: The results of this study must be taken into account in recommendations on management of new cases of smear-positive tuberculosis.

Carpentier-Edwards pericardial bioprosthesis in aortic position: long-term follow-up 1980 to 1994.

Aortic valve replacement with Carpentier-Edwards pericardial bioprosthesis was associated with excellent midterm clinical results. Long-term evaluation, however, remained to be determined. We reviewed the first 124 patients who underwent aortic valve replacement with a Carpentier-Edwards bioprosthesis at the Hôpital Broussais between 1980 and 1985. There were 67 males (54%) and 57 females (46%). The mean age at operation was 65 years (range, 18-83 years). The operative mortality (30 days) was 4%. All but 2 patients were followed up for an average of 7.7 years and a total of 973 patient years. There were 45 late deaths (4.7%/patient-year) of which 16 were valve-related (1.7%/patient-year). The actuarial survival rate was 49.9% at 12 years. The actuarial rate for freedom from valve-related mortality was 78.3% at 12 years. There were 7 thromboembolic events in 5 patients and 3 anticoagulation-related hemorrhages. Freedom from structural valve deterioration was 100% at 12 years and 83.3% at 13 years. We conclude that implantation of Carpentier-Edwards pericardial bioprosthesis in aortic position is associated with an excellent long-term clinical outcome. It is believed that the improved results of this valve result from the following original features: fully flexible stent, distensible struts, infrastent tissue mounting, optimal tissue orientation, and improved preservation.

Postoperative cardiac surgical care: an alternative approach .

Combined appropriate anaesthetic and surgical techniques have allowed increasing numbers of patients to be successfully managed in a general surgical recovery ward after cardiac surgery rather than in an intensive care unit. From 1983 to 1989, 933 of 1542 patients undergoing open heart surgery were transferred to the general surgical recovery ward in the immediate postoperative period. Of these, 718 (77%) had undergone coronary artery bypass grafts, sometimes combined with other procedures and 168 (18%) had had cardiac valve replacements with or without other procedures. The remaining 47 (5%) had had miscellaneous cardiac operations. Significant cardiac complications occurred in 29 (3%) patients. The 24 hour chest radiograph was reported as abnormal (mainly atelectasis and effusion) in 63% of patients. Most resolved spontaneously or with physiotherapy. Twenty nine (3%) patients were re-explored to achieve haemostasis. There were no deaths in the general surgical recovery ward. Thirty seven (4%) patients had to be transferred to the intensive care unit for various reasons. The remaining 896 patients were transferred to the general ward after one night (871 patients) or two nights (25 patients) in the general surgical recovery ward. The average duration of stay in hospital for these patients was 9.3 days. Because of the overall success of such management and the low rate of complications over 80% of patients are now managed in the general surgical recovery ward after open heart surgery. The resulting savings in capital expenditure of equipment, medical, nursing, and technical personnel are substantial, and there are major implications for the planning of new cardiothoracic units.

Long-term evaluation of the Carpentier-Edwards pericardial valve in the aortic position.

From July 1980 to December 1985, 124 patients underwent isolated aortic valve replacement with the Carpentier-Edwards pericardial bioprosthesis. The mean age of the patients was 64.9 +/- 13.1 years. All patients but one (0.7%) were followed for an average of 5.52 +/- 0.21 years after the operation and follow-up totaled to 677 patient-years. There were six early deaths (30-day mortality of 4.8%) and 25 late deaths (3.7% +/- 0.7% patient-year). After 9 years the actuarial survival rate was 64% +/- 14%. Six patients died of valve-related deaths (three anticoagulant-related hemorrhage, one endocarditis, one thromboembolic complication, and one sudden death) for an actuarial rate of 95% +/- 5% patients free of valve-related death at 9 years. Valve-related complications included five thromboembolic episodes (0.7% +/- 0.3% patient-year), eight anticoagulant-related hemorrhagic complications (1.2% +/- 0.4% patient-year), and two reoperations (0.3% +/- 0.2% patient-year). After 9 years, freedom from thromboembolic events was 96% +/- 4%, that from anticoagulant-related hemorrhage was 93% +/- 5%, and that from reoperation was 98% +/- 2%. There was no structural deterioration of the valve. We conclude that the Carpentier-Edwards pericardial prosthesis has a low incidence of valve-related complication and mortality within the 9-year time frame of this study.

Paraprosthetic leak: a complication of cardiac valve replacement.

Paraprosthetic leak (PPL) is a rare but potentially serious complication of cardiac valve replacement. Between 1974 and 1988, 1175 prosthetic valves were implanted in 1026 patients by one cardiac surgeon at St. Thomas' Hospital, London. Of these 539 (52.5%) were aortic (AVR), 334 (32.6%) mitral (MVR), 7 (0.7%) tricuspid, and 144 (14%) AV and MV double valve replacements (DVR). There were only 2 triple valve replacements. The prosthetic valves implanted were the Starr-Edwards (7%), Bjork Shiley (11.8%), Lillehei-Kaster (23%), Carpentier-Edwards bioprosthesis (35.2%), Duromedics bileaflet (16.4%) and a variety of other mechanical and bioprosthetic valves (6.6%). Over the 15 year period there were a total of 82 (7%) valve failures of which PPL was diagnosed in 29 (2.5%) valves in 24 patients. Presenting features included cardiac decompensation in 72%, bacterial endocarditis in 12% and haemolytic anaemia in 12%. One patient (4%) had no symptoms. Nineteen patients underwent re-operation. Median time to re-operation was 15 months (range 1-65 months) with a re-operative mortality of 22%. Clinical evidence of prosthetic valve infection was found in 79% of MVR and 67% of AVR. A heavily calcified aortic annulus, found in 47% of patients, may also have contributed to PPL after AVR.

Results of a conservative treatment combining induction (neoadjuvant) and consolidation chemotherapy, hormonotherapy, and external and interstitial irradiation in 98 patients with locally advanced breast cancer (IIIA-IIIB).

Ninety-eight patients with locally advanced breast cancer (Stage IIIA-IIIB) were entered into a pilot study combining intensive induction (neoadjuvant) chemotherapy (VTMFAP) with or without hormonochemotherapy, external and interstitial radiotherapy, and consolidation chemotherapy with or without hormonochemotherapy. Tumor regression over 50% was observed in 91% patients after chemotherapy, and complete clinical remission occurred in 100% patients after irradiation. The rate of local relapse is 13%. The 3-year disease-free survival is 62% and 3-year global survival is 77%. Initial chemotherapeutic tumor regression greater than 75% is the main predictive factor for disease-free survival.

Appraisal of the World Health Organization classification of lung tumours.

The 1967 World Health Organization (WHO) classification of the histologic types of lung tumours has been examined in relation to 303 tumours of patients admitted to a national trial of the treatment of lung cancer. In 63 instances (20%) there was disagreement between the diagnoses of the local pathologist and the reference pathologist. The slides for these 63 tumours were reviewed by two other pathologists, and the slides for 60 tumours for which there was agreement between the local and reference pathologists were reviewed by one of the other pathologists. The main disagreement was in the diagnosis of epidermoid (squamous) tumours. It is apparent that many pathologists do not adhere to the strict criterion of the presence of keratinization or intercellular prickles or both for the diagnosis of epidermoid carcinoma. In addition, there was substantial variation in the use of subtypes within the WHO classification. Use of the revised classification proposed by the WHO would have removed a small amount of the variation from these findings but would not have affected the main discrepancy. Stricter attention to the definition of types is required for a uniform approach to the histologic classification of lung tumours.

Oral administration of BCG as an adjuvant to surgical treatment of carcinoma of the bronchus.

A controlled clinical trial of the value of bacille Calmette--Guérin (BCG) vaccine given orally to patients with resectable carcinoma of the lung was conducted in 18 centres across Canada. A total of 308 patients were included in the analysis, 155 in the BCG group and 153 in the control group. The two groups were similar at the time of admission to the trial. BCG (120 mg) was given orally at weekly intervals for 1 month, every 2 weeks up to 3 months and then every 3 months until the total duration of therapy was 18 months. Over a 3- to 5-year follow-up period after the operation there was no difference in survival between the two groups, the proportion alive at 2 years being 61% in the BCG group and 58% in the control group. There was also no evidence of differences in the time to the detection of recurrent or metastatic disease or in the distribution of such disease. An analysis of prognostic factors confirmed the poor survival associated with histologically confirmed lymph node involvement. It may be concluded that no favourable effect from the oral administration of BCG was demonstrated.