Evolving concepts in the adjuvant systemic therapy of operable breast cancer.
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Biomedical subjects
Publications and source records attributed to L Norton.
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Thirty-four patients with suspected common bile duct stones were randomized to undergo endoscopic cholangiography and stone removal prior to open cholecystectomy or to have open cholecystectomy, operative cholangiography, and common bile duct exploration. Sixteen underwent the first protocol, and 18 the second. Analysis of the ability to clear stones from the common bile duct, morbidity, mortality, hospital stay, length of operation, and hospital cost showed no difference in outcome between patients treated by either method. These data suggest there is neither an advantage nor a disadvantage to treating patients with suspected duct stones by precholecystectomy endoscopic cholangiography and stone removal.
In 1978, Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985, 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP, 28%; CHOP-B, 26%, P = 0.81), or from the use of different doses of methotrexate (5-year FFS: high-dose, 34%; standard-dose, 33%, P = 0.51). Patients with follicular large cell lymphoma, with or without diffuse areas, had a better FFS (5-year FFS, 47%) than patients with DLCL (5-year FFS, 27%), while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS, 16%).
Parameters of cell-mediated and humoral-mediated immunity were measured in ten infection-free, insulin-dependent, controlled diabetic patients and in ten similar but nondiabetic patients awaiting elective operations. Tests performed included total and differential leukocyte counts, neutrophil reduction of nitroblue tetrazolium, mitogen response of lymphocyte to phytohemagglutinin, ratio of thymus-derived to bone marrow-derived lymphocytes, serum immunoglobulins IgA, IgG, and IgM, macrophage inhibition factor, serum zinc, and reaction to skin test antigens. Diabetics had a significantly (P less than .05) decreased mean response response to phytoheagglutinin stimulation and a lowered ratio of thymus-derived to bone marrow-derived lymphocytes. These findings support the concept of depressed cell-mediated immunity in the controlled, adult diabetic and might explain the propensity of the uncontrolled diabetic to increased frequency and severity of bacterial infection.
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Methotrexate (MTX) followed by citrovorum factor (CVF) rescue was evaluated for its effectiveness in reducing graft-versus-host disease (GVHD) in lethally irradiated dogs transplanted with bone marrow from unrelated histoincompatible donors. Animals were given no immunosuppressive therapy (group A) or a combined regimen of MTX and CVF (group AMC). These two groups were compared with a group of animals transplanted earlier given MTX alone (group AM). Ainmals in the AMC group lived significantly longer than the A group (p less than 0.05). Engraftment rate, hematopoietic recovery and incidence of GVHD were similar in all three groups. Incidence of early deaths was significant in the AM group (p less than 0.05). It is concluded that MTX combined with CVF increases survival and is an effective posttransplantation immunosuppressive regimen with minimal toxicity.
Thirty-four cases of duodenal trauma, 23 caused by gunshot wounds, are reviewed. All but three patients had associated major organ injuries, a total of 97 injuries. Postoperative mortality was 14% for injuries into the duodenal lumen. Techniques for operative repair included simple primary closure, use of omental or serosal patches, controlled fistula with a duodenostomy tube, decompressive and feeding ostomies, "diverticulization", segmental duodenal resection and anastomosis, and total duodenectomy and pancreatectomy. It is emphasized that the surgeon finding duodenal injury must be familiar with all of these techniques, each of which has its indications. Treatment of duodenal injuries perhaps more than any other bowel trauma must be individualized.
Three new diagnostic techniques, gray-scale ultrasonography, gallium-67 scanning (67Ga), and computed tomography (CT) were used in combination to detect intraperitoneal abscess in 30 patients. All 30 had sonography, 24 were scanned for 67Ga, and 15 underwent CT. Nine had three tests and 21 had two. Accuracy of results was evaluated by subsequent laparotomy in 16 and by clinical impression in the remainder. Ultrasound was accurate (true positive and true negative) in 12 of 16 (75%) operated patients, with 12% false-positive and 12% false-negative results. Gallium correctly diagnosed nine of 14 (64%) operated patients having 22% false-positive and 14% false-negative diagnoses. CT was accurate in five of seven (71%) patients evaluated by operation, with 14% false positives and 14% false negatives. Overall accuracies for both operated and clinical groups was ultrasound 57%, gallium 54%, and CT 67%, not significantly different results. Three tests agreed in only two of nine patients (22%), with no single test more accurate than another. Two tests agreed in 57%, with no test superior to another. It is concluded that ultrasonography, 67Ga scanning, and CT each have significant limits in diagnosing intra-abdominal pus. No single test is better than another. Disagreement among test results in the same patient obviates use of more than one technique in most instances.
In vivo studies were performed in mice bearing L1210 ascites tumor to examine the interaction of vincristine (VCR) at doses of 0.15 and 1.5 mg/kg with methotrexate (MTX) at doses of 0.5, 5, 50, and 350 mg/kg. The combination was administered on Days 2, 6, and 10 after tumor inoculation. VCR was given either concurrently with MTX or preceding it by 30, 60, or 120 minutes. VCR administered at a dose of 0.15 mg/kg achieved a peak peritoneal fluid concentration of 1.4 micron declining with a half-life (T1/2) of 33.5 minutes and produced no in vivo augmentation of MTX uptake. VCR administered at a dose of 1.5 mg/kg achieved a peak peritoneal fluid concentration of 16.5 micron declining with a T1/2 of 24.9 minutes and produced significant in vivo augmentation of MTX uptake when given concurrently with the MTX and 30 minutes prior to MTX at a dose of 350 mg/kg. No other interval was associated with augmented MTX uptake. When animal survival was evaluated, no therapeutic synergism was observed at any dose level of either drug in any schedule. In fact, VCR (0.15 and 1.5 mg/kg) and MTX at doses of greater than or equal to 50 mg/kg produced toxic synergism which adversely affected survival. Since the drug doses studied are comparable with those used in "high-dose" clinical protocols, individual tumor evaluation is indicated to support the use of these drugs in combination.
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Because it has long been recognized that the growth of most untreated tumors is well described by Gompertzian or exponential growth curves but that the growth of treated tumors has never been well characterized mathematically, we developed and applied an equation that, while not dependent on restrictive assumptions or unmeasurable variables, was nevertheless capable of describing perturbed as well as unperturbed growth. For the 3964A rat hepatoma, a functional relationship between dose level of radiotherapy and growth-curve response was derived and used for predictive purposes. An implied relationship between tumor size and sensitivity to therapy and some clinical implications were examined.
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Although granulocyte transfusion therapy has been shown to be effective in infected granulocytopenic animals and humans, the relative effectiveness of granulocytes (PMN) harvested by continuous flow centrifugation (CFC) or by continuous flow filtration leukapheresis (FL) remains uncertain. Studies in vitro of morphology and granulocyte functions have suggested cells collected by FL may be damaged. To compare the function in vivo of granulocytes collected by different methods, dogs were made granulocytopenic with cyclophosphamide (CYT) and then transfused with granulocytes collected by CFC or FL. The local neutrophil mobilization (LNM) through a standard skin abrasion into a chamber containing a strong chemoattractant, autologous serum, was measured. Greater LNM was found after transfusions of CFC PMN than after transfusions of the same number of FL PMN (p less than 0.0003). This difference persisted even when the dose of FL PMNs was four times greater than that of CFC mn and when the FL donor was pretreated with steroids (p less than 0.001). These results suggest that during filtration leukapheresis, granulocytes are functionally altered and that their function in vivo may be compromised.
Forty-two postoperative patients, each with demonstrable failure of two or more vital organ systems, have been studied as they define a syndrome of multiple organ failure. They typify the emerging clinical entity of patients kept alive solely by reason of specific mechanical and pharmacologic support. Trauma initiated hospitalization in 40 per cent and major bleeding, in 11 per cent. Sepsis was judged to be of etiologic significance in 69 per cent. Complications in clinical management were, in retrospect, thought to be of contributory etiologic significance in 57 per cent. Twenty-nine of 42 patients died; a mortality of 69 per cent. Mean duration of multiple organ failure was 30.5 days. Hospital cost, omitting the physician's fees, was conservatively estimated at $700 per day. Scientific, social, moral, ethical and legal factors emphasize the need to establish a statistically valid large data base concerning this new man-made syndrome which has both important scientific and social implications. This study is a first step in this direction.
Hepatic support by whole liver, liver slice, or hepatocyte perfusion is unsatisfactory. A new concept of support with circulating hepatocytes on one side of a cuprophan membrane and blood from an anhepatic pig on the other was evaluated in 19 dialysis experiments. Levels of pyruvate metabolism and oxygen utilization were similar to those obtained when liver cells in a centrifuge are perfused with oxygenated plasma. Of six anhepatic pigs given late hepatic support, five showed neurologic improvement. One had concomitant improvement in electroencephalographic results. A membrane hemodiolysis unit in which hepatocytes circulate against blood from an anhepatic animal is the most suitable extracorporeal liver support unit described so far. Its simplicity allows repeated and prolonged use.