Relationship between response and survival in patients with advanced ovarian cancer.
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Female↗
Biomedical subjects
R Simon
Publications and source records attributed to R Simon.
[An aortopulmonary shunt after a knife wound].
An extensive hemopneumothorax developed in a 23-year-old man after having been knifed in the region of the left nipple. After general surgical care a Bülau suction drain was inserted. Cardiological examination became necessary a week later when a chest X-ray film demonstrated an enlarged cardiac silhouette. Echocardiography revealed pericardial effusion (about 600 ml) which was removed by pericardial aspiration. Cross-sectional and colour Doppler echocardiography showed a shunt between the aorta and right ventricular outflow tract at the origin of the pulmonary artery. At surgery a fistula between the root of the aorta and the pulmonary artery was identified (the posterior sinus near the anulus was nearly completely detached). The fistula was closed and the pulmonary valve reconstructed. The early and late postoperative course was unremarkable.
Adult↗
[Colonic complications of acute necrotizing pancreatitis].
Among 126 patients operated upon for acute necrotizing pancreatitis in our department over a 10-year period starting in November 1979, 17 had a colonic resection. Colectomy was made mandatory by a necrotic or ischaemic appearance (12 cases, including 3 bowel perforations), an isolated perforation (2 cases) or extensive fat necrosis of the pericolonic atmosphere (3 cases). The hospital mortality was 5 out of the 17 cases. In 6 patients, the pathological results suggested that colonic resection was unnecessary. Since May 1988, a diverting loop ileostomy has been performed whenever colonic viability was found to be dubious at laparotomy. After this policy was introduced no case of secondary colonic complication was encountered. Nevertheless, there still are "abusive" colectomies unjustified by the pathology. Their number should be reduced by a more cautious indication of colonic resection in acute necrotizing pancreatitis.
Acute Disease↗
Statistical model to determine the relationship of response and survival in patients with advanced ovarian cancer treated with chemotherapy.
BACKGROUND: A statistically appropriate analysis of the association between survival and response measures in patients with ovarian cancer could help to define the role of response rate in planning, monitoring, and interpreting the results of clinical trials. PURPOSE: This study was designed to investigate the relationship between antitumor response determined by clinical or pathological means and survival in patients with advanced ovarian cancer with no previous treatment. We focused on avoiding the limitations of the usual approach of comparing durations of survival for patients responding to therapy with those for nonresponders. METHODS: A new meta-analytic statistical model we developed was used to analyze data from 26 randomized clinical trials published between 1975 and 1989. Our model incorporates intra-study and inter-study sources of variability in the estimates of response and survival. The study also addresses the methodological problems of evaluating response as a surrogate end point and the relevance of this association to clinical decision making and the design of clinical trials. RESULTS: For 13 studies in which response was pathologically assessed, an improvement in surgically documented complete response rate was associated with an increase in median survival. A similar but apparently smaller effect was found for the association between objective clinical response and median survival in the 25 studies reporting these data. CONCLUSIONS: These results suggest that therapeutic measures must produce large improvements in clinical response rates to achieve meaningful effects on median survival. Improvement in surgically documented complete response rate appears to be more strongly associated with increased median survival and, hence, might be used for interim monitoring in clinical trials, but the role of second-look procedures in clinical management is controversial.
Antineoplastic Combined Chemotherapy Protocols↗
Bayesian subset analysis in a colorectal cancer clinical trial.
Subset analysis is the examination of treatment comparisons within groups of patients with restricted levels of patient characteristics. Such analyses are vulnerable to multiplicity effects. We examine the problem in the context of a proportional hazards model with terms for treatment, each of several dichotomous covariates representing the patient characteristics of interest, and treatment-by-covariate interaction effects. Parametrically, a subset-specific treatment effect is equal to the treatment effect term plus a linear combination of the interaction terms. We present Bayesian point and interval estimates under the assumption that the interaction terms are exchangeable and the prior distributions for the other regression parameters are locally uniform. This produces a shrinking of the estimated interaction effects towards zero, thereby discounting them and dealing in a natural way with multiplicity. We illustrate the method using results of a recent North Central Cancer Treatment Group/Mayo Clinic study in advanced colorectal cancer.
Antineoplastic Combined Chemotherapy Protocols↗
Selecting dose-intense drug combinations: metastatic breast cancer.
A mathematical model previously described is applied to the problem of selecting drug combinations for metastatic breast cancer. The model accounts for the differing single-agent activities of the drugs as well as their differing profiles of toxicity. With no bone marrow protection, combinations with cisplatin offer a small improvement in total equivalent dose over therapy with the more active single-agents. Restricting consideration to the four most commonly used agents, single-agent doxorubicin has the greatest equivalent dose. With protection for leukopenia or willingness to accept a higher incidence of severe leukopenia, a combination with large doses of cyclophosphamide, doxorubicin, and fluorouracil, and a small dose of cisplatin has greatest equivalent dose. The doublets cyclophosphamide/fluorouracil or fluorouracil/cisplatin at higher doses are almost as good. With protection for leukopenia and thrombocytopenia, a cyclophosphamide/thiotepa combination at very high doses maximizes total equivalent dose. This approach can be used to identify regimens worthy of prospective evaluation.
Alkaloids↗
Percutaneous tracheostomy after trauma and critical illness.
A method of percutaneous tracheostomy (PT) using a tracheostome, which permits insertion of a full-sized cuffed tracheostomy tube, was evaluated in 61 critically ill or injured patients (89% had trauma). Of the 54 trauma patients, 65% had brain injuries, 14% had injuries to the cervical spinal cord, 33% had face or jaw injuries, and 15% had lung injuries. The indications for PT were coma (46%), acute airway obstruction (5%), face or jaw injury (20%), pneumonitis (39%), adult respiratory distress syndrome (12%), and sepsis (21%). Tracheostomy was done in 51% of all cases specifically for managing pulmonary secretions, in 37% for prolonged intubation, and in 25% for neurologic lesions. The tracheostomy was done as an emergency in 5%, as urgent in 28%, and electively in 77%. Percutaneous tracheostomy was successful in 90% of the cases, and in 8% it was converted to a surgical tracheostomy after an initial percutaneous attempt. In 46% it was performed at the bedside, in 46% in the operating room, and in 7% in the emergency suite. A full-sized tracheostomy tube (#6 to #8) was used in all cases and was considered optimal or larger than needed in 87% of cases. With three exceptions the complications of PT were minor, but 30% of the patients died of their primary disease. In one case death occurred because of bronchospasm and cardiac arrest during the PT, but appeared to be independent of the type of tracheostomy. Healing after in-hospital removal (37%) was excellent in 95% of cases and 97% of physicians indicated that they would use the device again.
Adult↗
Translational control by poly(A) elongation during Xenopus development: differential repression and enhancement by a novel cytoplasmic polyadenylation element.
One characteristic of oocyte maturation and embryogenesis in Xenopus laevis is the activation of translationally repressed (masked) maternal mRNAs by cytoplasmic poly(A) elongation. At maturation, poly(A) elongation is controlled by two cis-acting elements in the 3'-untranslated regions (UTRs) of responsive mRNAs, the hexanucleotide AAUAAA and the cytoplasmic polyadenylation element (CPE), consisting of UUUUUAU or other similar sequences. To investigate poly(A) elongation and translational activation during embryogenesis, we have focused on Cl2 RNA, a representative transcript that undergoes these processes. By injecting radiolabeled Cl2 RNA into fertilized eggs and allowing development to proceed, we found that maximal polyadenylation of this RNA is reached by the 4000-cell blastula stage and that it requires two cis-acting elements, the hexanucleotide AAUAAA and a novel CPE, which is dodecauridine. Interestingly, a shortening of the distance between the two elements changes the timing of maximal polyadenylation to the four-cell stage. The injection of a chloramphenicol acetyl transferase (CAT)-Cl2 chimeric RNA into fertilized eggs not only results in embryonic polyadenylation of the transcript but also 5- to 15-fold more CAT activity compared with eggs injected with CAT RNA or CAT-Cl2 chimeric RNA that is prevented from undergoing poly(A) elongation by a mutation in the polyadenylation hexanucleotide. However, eggs injected with a CAT-Cl2 chimeric RNA that is preadenylated but that cannot undergo further poly(A) elongation contain no more CAT activity than eggs injected with the same RNA without a poly(A) tail, suggesting that the process of poly(A) elongation, and not poly(A) tail length, is important for translation. Finally, we show that precocious poly(A) elongation of Cl2 RNA during oocyte maturation is prevented by a large "masking" element that includes the dodecauridine CPE. The dual role of the CPE in both repression and activation of poly(A) elongation is discussed.
Animals↗
Genetics of xanthan production in Xanthomonas campestris: the xanA and xanB genes are involved in UDP-glucose and GDP-mannose biosynthesis.
The nucleotide sequence of a 3.4-kb EcoRI-PstI DNA fragment of Xanthomonas campestris pv. campestris revealed two open reading frames, which were designated xanA and xanB. The genes xanA and xanB encode proteins of 448 amino acids (molecular weight of 48,919) and 466 amino acids (molecular weight of 50,873), respectively. These genes were identified by analyzing insertion mutants which were known to be involved in xanthan production. Specific tests for the activities of enzymes involved in the biosynthesis of UDP-glucose and GDP-mannose indicated that the xanA gene product was involved in the biosynthesis of both glucose 1-phosphate and mannose 1-phosphate. The deduced amino acid sequence of xanB showed a significant degree of homology (59%) to the phosphomannose isomerase of Pseudomonas aeruginosa, a key enzyme in the biosynthesis of alginate. Moreover, biochemical analysis and complementation experiments with the Escherichia coli manA fragment revealed that xanB encoded a bifunctional enzyme, phosphomannose isomerase-GDP-mannose pyrophosphorylase.
Amino Acid Sequence↗
Phase II trials of small-cell lung cancer.
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Carcinoma, Small Cell↗
Performance of a stentless xenograft aortic bioprosthesis up to four years after implantation.
Conventional biologic and mechanical prostheses have important limitations with regard to their hemodynamic characteristics and long-term durability. We evaluated the hemodynamic function of a stentless porcine aortic prosthesis in 10 patients by invasive pressure measurements and angiography with videodensitometry 8 +/- 4 days after operation, as well as by Doppler echocardiography 35 +/- 15 months after valve replacement. The early postoperative invasive study revealed a mean gradient of 8 +/- 6 mm Hg across the prosthesis, no regurgitation in eight patients, and mild regurgitation, defined as less than 20% regurgitant fraction, in the remaining two patients. The late postoperative Doppler echocardiographic study revealed a mean gradient across the aortic prosthesis of 6 +/- 3 mm Hg, mean Doppler-derived valve orifice area of 1.8 +/- 0.6 cm2, and color Doppler flow velocity mapping suggested no regurgitation in eight patients and mild regurgitation in two patients corresponding to early postoperative angiography. None of the 10 patients received anticoagulation therapy. The clinical course of all patients was without incident. This stentless aortic bioprosthesis may offer hemodynamic advantage; however, further studies are needed to allow comparison with conventional mechanical and biologic prostheses.
Adult↗
[Additive effects of milrinone and dobutamine in severe heart failure].
The hemodynamic effects of dobutamine, milrinone, and a combination of both drugs were compared intra-individually in 14 patients with severe heart failure (NYHA III: n = 9; NYHA IV: n = 5). Dobutamine (maximum dose: 9 micrograms/kg/min) and milrinone (0.5 micrograms/kg/min) each induced a comparable increase in stroke volume index (21 to 29 resp. 21 to 30 ml/m2; mean values; p less than 0.001) and reduction in pulmonary capillary wedge pressure (29 to 22 resp. 28 to 21 mm Hg; p less than 0.001), as well as in systemic (1846 to 1218 resp. 1858 to 1276 dyn s/cm5; p less than 0.001) and pulmonary vascular (301 to 195 resp. 293 to 216 dyn s/cm5; p less than 0.001) resistances. The heart rate rose significantly after dobutamine (92 to 107 min-1; p less than 0.05), but did not change after milrinone (94 to 95 min-1; ns). Neither drug had a significant effect on systemic arterial pressures. The combination of milrinone and dobutamine induced a further significant rise in stroke volume index (37 ml/m2; p less than 0.01) when compared to either drug alone. The combination also caused an additional fall in pulmonary capillary wedge pressure (14 mm Hg; p less than 0.01), as well as in systemic (799 dyn s/cm5; p less than 0.001) and pulmonary (133 dyn s/cm5; p less than 0.001) vascular resistances. When compared to dobutamine alone, the combined therapy did not significantly change the heart rate and systemic arterial pressures. The combined administration of a beta-adrenergic agonist and a phosphodiesterase inhibitor induces beneficial hemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma.
The goal of this study was to use dose-intensity analyses of published Ewing's sarcoma and osteogenic sarcoma trials to determine which agents were most closely associated with a favorable response. The percentage of patients with more than 90% tumor necrosis following neoadjuvant chemotherapy was the end point for analysis of osteogenic sarcoma trials, and disease-free survival and percentage of patients with distant-only relapse were the end points for analysis of Ewing's sarcoma trials. The data were analyzed using logistic regression analysis to circumvent the distortion of univariate analysis resulting from the correlation between doxorubicin dose intensity and the dose intensity of other agents. Our analysis suggests that doxorubicin dose intensity is an important determinant of favorable outcome for both Ewing's sarcoma and osteogenic sarcoma and that the dose intensities of other agents do not contribute as significantly to outcome as does doxorubicin dose intensity. Increasing dactinomycin dose intensity was associated with a poorer outcome in treatment of osteogenic sarcoma and Ewing's sarcoma, most likely resulting from regimens with a higher dactinomycin dose intensity having a lower doxorubicin dose intensity. While our analysis of osteogenic sarcoma trials is consistent with significant activity for cisplatin and high-dose methotrexate (and likely ifosfamide), a rank ordering of the efficacy of these agents when given with doxorubicin in multiagent regimens is not possible. Our analysis illustrates the importance of analyzing the contributions of individual agents to combination chemotherapy regimens. In the design of future clinical trials for osteogenic sarcoma and Ewing's sarcoma, careful attention should be given to optimizing doxorubicin dose intensity in regimens to be tested.
Dose-Response Relationship, Drug↗
A decade of progress in statistical methodology for clinical trials.
Clinical trials played a dominant and expanding role in the evaluation of new treatments during the decade of the 1980s. There were major improvements in the quality of clinical trials in many medical fields. There were also important developments in the methodology of designing, monitoring, conducting, analysing, reporting and interpreting clinical trials. This paper attempts to review some of these developments. A comprehensive review is beyond the abilities of any one individual. Consequently, this paper attempts to offer a broad stroke description of this area and to highlight specific topics of importance based on my particular experience. An extensive, but non-comprehensive bibliography is included to provide entry points to the literature of methodologic developments for clinical trials in the 1980s.
Clinical Trials as Topic↗
Selecting combinations of chemotherapeutic drugs to maximize dose intensity.
A mathematical model is described for selecting combinations of chemotherapeutic drugs in order to maximize antitumor dose intensity subject to constraints on toxicity to normal organ systems. Determination of which drugs to combine and in what proportions to combine them offers combinatorially huge numbers of possibilities. The method described here offers one approach to identifying combinations worthy of evaluation in prospective comparative clinical trials.
Antineoplastic Combined Chemotherapy Protocols↗
Quaternary ammonium compounds as structural probes of single batrachotoxin-activated Na+ channels.
Quaternary ammonium (QA) blockers are well-known structural probes for studying the permeation pathway of voltage-gated K+ channels. In this study we have examined the effects of a series of n-alkyl-trimethylammonium compounds (Cn-QA) on batrachotoxin (BTX)-activated Na+ channels from skeletal muscle incorporated into planar lipid bilayers. We found that these amphipathic QA compounds (Cn-QA where n = 10-18) block single Na+ channels preferentially from the internal side with equilibrium dissociation constants (KD) in the submicromolar to micromolar range. External application of amphipathic QA compounds is far less effective, by a factor of greater than 200. The block can be described by a QA molecule binding to a single site in the Na+ channel permeation pathway. QA binding affinity is dependent on transmembrane voltage with an effective valence (delta) of approximately 0.5. QA dwell times (given as mean closed times, tau c) increase as a function of n-alkyl chain length, ranging from approximately 13 ms for C10-QA to 500 ms for C18-QA at +50 mV. The results imply that there is a large hydrophobic region within the Na+ channel pore which accepts up to 18 methylene groups of the Cn-QA cation. This hydrophobic domain may be of clinical significance since it also interacts with local anesthetics such as cocaine and mepivacaine. Finally, like BTX-activated Na+ channels in bilayers, unmodified Na+ channels in GH3 cells are also susceptible to QA block. Amphipathic QA cations elicit both tonic and use-dependent inhibitions of normal Na+ currents in a manner similar to that of local anesthetic cocaine. We conclude that amphipathic QA compounds are valuable structural probes to study the permeation pathway of both normal and BTX-activated Na+ channels.
Animals↗
Management of transperitoneal gunshot wounds of the spine.
To evaluate the results of a conservative approach to gunshot wounds of the spine with a transperitoneal trajectory, we analyzed our 4-year experience with 21 patients. The management protocol consisted of standard treatment of the intra-abdominal injuries, vigorous irrigation of the missile track, and a 48-hour course of antibiotic therapy. The lumbar spine was involved in 14 patients (67%) and the thoracic spine was injured in seven (33%). Eleven patients (52%) were paraplegic on admission and ten patients (48%) had a fixed partial neurologic deficit. One patient with an ISS of 75 died intraoperatively from exsanguination (mortality, 5%). Early morbidity correlated with ISS greater than 40 and spinal AIS greater than 3. Late nonneurologic morbidity was independent of ISS and spinal AIS. One patient required reoperation for a retroperitoneal abscess secondary to a leak from a repaired ureter. Another patient had a retroperitoneal collection on a CT scan which resolved spontaneously. There were no spinal or paraspinal infectious complications in the presence (five cases) or absence of a colonic injury. No change in neurologic status was observed in any patient during a mean follow-up period of 3 months. This preliminary experience suggests that a conservative approach consisting of irrigation of the missile track and short-term antibiotic therapy without laminectomy or removal of fragments from the spinal canal yields optimal results without increasing infectious complications of the spine.
Abdominal Injuries↗
Isolation and characterization of insertion sequence elements from gram-negative bacteria by using new broad-host-range, positive selection vectors.
On the basis of an RSF1010-derived broad-host-range vector, three different systems which enable positive detection and isolation of insertion sequence (IS) elements from gram-negative bacteria were constructed. Vectors pSUP104-pheS, pSUP104-rpsL, and pSUP104-sac were used successfully in a number of Rhizobium strains and in Xanthomonas campestris. More than 20 different IS elements were isolated and characterized. The 16 IS elements from Rhizobium meliloti were further used to characterize various R. meliloti strains by hybridization. The resulting hybridization patterns were different for every strain and gave a clear and definite IS fingerprint of each strain. These IS fingerprints can be used to identify and characterize R. meliloti strains rapidly and unequivocally, as they proved to be relatively stable. Some of the IS elements were found to be identical when the IS fingerprints from a given strain were compared. This method of IS fingerprinting can also establish whether IS elements are the same, related, or different.
Blotting, Southern↗