Post-poliomyelitis syndrome: evidence of ongoing denervation in symptomatic and asymptomatic patients.
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Biopsy↗
Biomedical subjects
R Simon
Publications and source records attributed to R Simon.
Why predictive indexes perform less well in validation studies. Is it magic or methods?
When prognostic indexes have been tested in a second population, they have often performed less well. Since this is believed to be inevitable, methodologic differences that may explain the discrepancies have been overlooked. Data from a prospective study of 232 patients undergoing noncardiac surgery were used to examine the effect of methodologic differences in assembly of population, postoperative surveillance, and the criteria for cardiac complications on the performance of Goldman's cardiac risk index. Our prospective population was used to simulate the methods used in Goldman's study and in three other studies using the risk index to demonstrate the potential impact of differences in population, surveillance, and outcome criteria for cardiac complications. If Goldman's detection and outcome criteria were employed and only the eligibility criteria used for assembly of the populations differed, the overall complication rates would be between 5.2% and 6.9%; and the complication rates for the different Goldman classes were similar. When both different detection strategies and different outcome criteria were used, however, important discrepancies in cardiac complication rates emerged. For example, complication rates in class 2 varied from 2% to 23%. In conclusion, important discrepancies in performance of prognostic indexes may arise from differences in surveillance strategies and definitions of outcome. With sufficient attention to methodologic consistency, the performance of predictive indexes may not inevitably deteriorate in subsequent studies.
Adult↗
Overviews of randomized clinical trials.
Therapeutic decisions should obviously be based on all available relevant evidence. Research reviews are important for bringing together and critically assessing such evidence. The conclusions of individuals who perform research reviews are subjective, however, because the determination of what evidence is relevant and how the pieces of evidence should be fitted together is generally not straightforward. Although the findings of studies often do not fit together neatly, discrepancies sometimes provide an opportunity to better understand the factors that influence treatment effectiveness. Consequently, although reviews are not substitutes for well-done clinical trials, individual clinical trials are also not substitutes for well-done reviews.
Clinical Trials as Topic↗
Clinical drug development: an analysis of phase II trials, 1970-1985.
We examined the activity reported in phase II trials for all cytotoxic drugs introduced into clinical trial by the National Cancer Institute (NCI) since 1970. For each drug in each tested tumor type we derived a response rate from the pooled data of all trials reported either in the literature or to the NCI. We rated a drug active if the lower 80% confidence bound of the response rate was greater than 10%. Of the 83 drugs developed and introduced by the NCI, there are 47 which we considered evaluable. Of these drugs, 24 were rated active in at least one cancer type, of which ten were analogs of drugs in wide clinical use. Diseases most commonly responsive include lymphoma (74% of the tested drugs rated active), leukemia (35%), urothelial cancer (29%), small cell lung cancer (29%), ovarian cancer (22%), cervical cancer (22%), and breast cancer (18%). For colon cancer and melanoma, only one of 42 and two of 30 tested drugs rated active, respectively. We also examined the completeness of clinical testing: among the 47 drugs there were 20 tested in greater than or equal to 14 patients with leukemia, 23 tested in patients with lymphoma, and 18 tested in patients with small cell lung cancer; whereas 34 drugs for breast cancer, 42 for colon cancer, and 33 for non-small cell lung cancer were more completely evaluated. Considering the "clinical panel" of seven cancer types (breast, non-small cell lung, small cell lung, colon, melanoma, leukemia, and lymphoma), drugs were tested in greater than or equal to 30 patients in a median of four tumor types. Testing in this panel failed to detect activity in only one drug found active in another tumor, although testing in diseases other than this clinical panel was even less complete. Phase II testing should emphasize completion of minimum accrual goals, testing in patient populations with minimum prior therapy, and evaluation in a minimum set of tumor types.
Acute Disease↗
Diagnosis of schizophrenia. Prediction of short-term outcome.
Seven systems for the diagnosis of schizophrenia were compared in their ability to predict short-term outcome at follow-up: with each other, with selected specific symptoms, and with a simple additive composite symptom score. None of the systems nor the symptoms predicted strongly, but DSM-III and Schneiderian First Rank Symptoms and the composite score performed somewhat better than the other predictors.
Female↗
Plasmid vectors for the genetic analysis and manipulation of rhizobia and other gram-negative bacteria.
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Bacteriophage lambda↗
Identification of Rhizobium plasmid sequences involved in recognition of Psophocarpus, Vigna, and other legumes.
Symbiotic DNA sequences involved in nodulation by Rhizobium must include genes responsible for recognizing homologous hosts. We sought these genes by mobilizing the symbiotic plasmid of a broad host-range Rhizobium MPIK3030 (= NGR234) that can nodulate Glycine max, Psophocarpus tetragonolobus, Vigna unguiculata, etc., into two Nod- Rhizobium mutants as well as into Agrobacterium tumefaciens. Subsequently, cosmid clones of pMPIK3030a were mobilized into Nod+ Rhizobium that cannot nodulate the chosen hosts. Nodule development was monitored by examining the ultrastructure of nodules formed by the transconjugants. pMPIK3030a could complement Nod- and Nif- deletions in R. leguminosarum and R. meliloti as well as enable A. tumefaciens to nodulate. Three non-overlapping sets of cosmids were found that conferred upon a slow-growing Rhizobium species, as well as on R. loti and R. meliloti, the ability to nodulate Psophocarpus and Vigna, thus pointing to the existence of three sets of host-specificity genes. Recipients harboring these hsn regions had truly broadened host-range since they could nodulate both their original hosts as well as MPIK3030 hosts.
Base Sequence↗
A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes.
We reviewed 53 publications reporting 751 patients with hematologic malignancies treated with low doses (5 to 20 mg/m2/d) of cytosine arabinoside (LoDAC). Of 507 patients evaluable for response, complete remission (CR) rates varied from 32% for patients with primary acute non-lymphoblastic leukemia (1 degree ANLL) to 16% for patients with hematologic malignancies secondary to previous chemotherapy or following a myelodysplastic syndrome (MDS) (2 degrees ANLL), and 16% for MDS. Median duration of CR was 9.5 months for 1 degree ANLL, and 10.5 months for both 2 degrees ANLL and MDS. Based on limited available survival data, overall median survival for these groups was 9 months, 3 months, and 15 months, respectively. Only three CRs were reported of 31 evaluable patients treated for a variety of other hematologic malignancies. CR rates for patients with 1 degree ANLL greater than or equal to 50 years old was 56%, compared with 29% less than 50 years old (P = .10). While prior chemotherapy was more common in 1 degree ANLL patients less than 50 years of age (86% v 21%; P less than .001), it did not influence response rates in those greater than 50 years of age, suggesting other biases. Hematologic toxicity was mentioned in only 33 of 53 publications, affecting 254 of 289 patients (88%), with at least 15% treatment-related deaths. LoDAC hypothetically acts as a differentiating agent; however, correlative laboratory studies were rarely performed. Cytogenetic data were available for only 15%, and in vitro studies for 10% of all patients with marked discrepancies in the interpretation of results. LoDAC is clearly cytotoxic for both malignant and normal hematopoietic cells. While large numbers of patients have been reported, the lack of well-designed clinical trials prohibits definitive conclusions as to its role as a differentiating agent. Future LoDAC studies should determine optimal dose and schedule, with clinical laboratory correlates to assess differentiation. Trials in ANLL comparing LoDAC with conventional chemotherapy, and in MDS with supportive care alone, may help identify the role of LoDAC. Until appropriate indications can be identified, LoDAC should not be routinely used in clinical practice.
Acute Disease↗
Confidence intervals for reporting results of clinical trials.
Tests of statistical significance are often used by investigators in reporting the results of clinical research. Although such tests are useful tools, the significance levels are not appropriate indices of the size or importance of differences in outcome between treatments. Lack of "statistical significance" can be misinterpreted in small studies as evidence that no important difference exists. Confidence intervals are important but underused supplements to tests of significance for reporting the results of clinical investigations. Their usefulness is discussed here, and formulas are presented for calculating confidence intervals with types of data commonly found in clinical trials.
Clinical Trials as Topic↗
Some thoughts on the future of clinical trials in cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
[Acute effect of the cardioselective beta-1-partial agonist, Corwin, on ventricular function and myocardial oxygen consumption in patients with dilated cardiomyopathy].
The effects on left ventricular function and myocardial metabolism of Corwin (ICI 118,587), a selective beta-1 partial agonist, were evaluated in 12 patients with dilated cardiomyopathy. All patients were in sinus rhythm at the time of cardiac catheterization. Immediately before and 20 minutes after intravenous administration of 0.2 mg/kg Corwin over 2 minutes, high-fidelity left ventricular pressures and thermodilution coronary sinus blood flow were recorded along with ventriculograms in the 30 degrees right anterior oblique projection. In 11 patients, Corwin resulted in no change in heart rate, a fall in left ventricular end-diastolic pressure, a rise in left ventricular systolic pressure and an increase in cardiac index. There was a rise in both peak positive and peak negative dP/dt. End-diastolic and end-systolic volume indices fell, and ejection fraction rose. There was an increase in coronary sinus blood flow and a small rise in myocardial oxygen consumption. In contrast to these results in the group as a whole, in one patient Corwin produced depression of both systolic and diastolic left ventricular function. We conclude that, in many patients with dilated cardiomyopathy, Corwin produces an improvement in systolic and diastolic left ventricular function while at the same time only slightly increasing myocardial oxygen demand. In some patients, however, Corwin may result in a significant worsening of left ventricular performance due to its antagonistic effects.
Adrenergic beta-Agonists↗
The effect of thyrotropin and cAMP on DNA synthesis and cell growth of human thyrocytes in monolayer culture.
Monolayer cultures of human thyrocytes from normal tissue (n = 10), and adenomas (n = 7), differentiated (n = 4), poorly differentiated (n = 2), and undifferentiated (n = 3) thyroid cancers were established to assess the significance of thyrotropin (TSH) and cAMP (adenosine 3',5'-cyclic monophosphate) on cell growth and DNA (deoxyribonucleic acid) synthesis. Cell growth of thyrocytes from normal and adenomatous tissues increased more rapidly (p less than 0.01) after TSH (0.1 IU/ml) was added but was unaffected by cAMP (10(-4) mol/L). In these cells, TSH also enhanced DNA synthesis twofold to twelvefold (p less than 0.01). The adenylate cyclase (AC) inhibitor, 2',3' dideoxyadenosine (ddA), increased DNA synthesis 1.3 to 6 times at a concentration of 2 X 10(-4) mol, whereas the membrane/passable cAMP analogue, dibutyryl-cAMP, and the AC stimulator, forskolin, failed to show any effect on DNA synthesis up to a concentration of 10(-5) mol/L (p less than NS). When administered simultaneously, TSH (1/2 maximum) and ddA (20 mumol) had no cumulative effect on DNA synthesis (p = NS). TSH stimulation in cancerous thyroid tissue (n = 11) demonstrated a lack of TSH response in seven of 11 monolayer cultures with no apparent correlation to cancer differentiation, patient age, or sex. Thus TSH was demonstrated to stimulate DNA synthesis and cell growth of human thyrocytes in monolayer cultures independent of the AC system. However, the TSH effect on cell growth and DNA synthesis was unpredictable in thyrocytes from cancerous tissues.
Adenoma↗
Disseminated intravascular coagulation (DIC) induced by liquoid (polyanetholsulfonate) in the rat. V. Effects on circulating fibronectin.
Levels of plasma fibronectin (Fn) were 63% lower than normal 15 min after the intravenous injection of liquoid (P less than 0.01); 3 h later they were still low but rebounded to 35% above normal (P less than 0.01) by 24 h. Concurrently microthrombi containing fibrinogen, Fn and Factor VIII related-antigens (VIII:Ag) were detected in the kidneys and lungs by immunohistopathological studies. Ultrastructurally, thrombi were composed of dense granular and occasional fibrillar non-striated material. In liquoid-injected rats 125I-fibrinogen mainly localized in kidneys and lungs, especially in the latter (P less than 0.01), and the lungs had a higher wet-to-dry weight ratios than did controls (P less than 0.01). It is concluded that the polyanion (liquoid)-induced intravascular coagulation-like reaction sequestered Fn concomitantly with the precipitation of fibrinogen and VII:Ag in the microclots. The reduced concentration of plasma Fn may have impaired the disposal of coagulation products thus enhancing the expression of the coagulopathy-mediated renal and pulmonary histopathology. It is suggested that the liquoid-related coagulopathy may have resulted in enzymatic lysis of Fn.
Animals↗
Role of hexamethylmelamine in the treatment of ovarian cancer: where is the needle in the haystack?
Hexamethylmelamine (HMM) was selected for development as an antineoplastic agent because it demonstrated activity in a variety of preclinical tumor models. Its mechanism of action is unknown. It has been used in clinical trials since 1964. The clinical toxic effects have consisted of signs and symptoms involving the following systems: gastrointestinal (nausea, vomiting, anorexia), hematologic (leukopenia, mild anemia), and neurologic (critical depression, hallucinations, peripheral motor and sensory deficits). Antitumor activity against advanced ovarian cancer was demonstrated in phase I trials and the drug was quickly incorporated into trials which utilized drug combinations. The majority of these have consisted of phase II trials without an identified control population. As might be predicted, all of the HMM-containing combinations are active. However, the contribution of HMM to the antitumor activity of the combination remains conjectural. Thus, in spite of greater than 15 years of clinical trials with a drug that has single-agent activity, the questions regarding the role of HMM in the treatment of ovarian cancer remain unanswered.
Altretamine↗
Characterization of the enkephalin-degrading aminopeptidase of neuroblastoma (N1E-115) cell membranes.
A membrane-bound enkephalin (ENK) -hydrolyzing amino-peptidase (AP) was partially purified from neuroblastoma (clone N1E-115) cell membranes; enzyme activity was assayed by determination of the leu-enkephalin (LENK) degradation product, tyrosine (Tyr), with HPLC. The enzyme was extracted with Triton X-100, resolved by anion-exchange chromatography and further purified by gel filtration. The overall purification was about 100-fold with a yield of 43%. The apparent Mr value of the AP by gel filtration in the presence of 0.3% Triton X-100 was approx. 400 kDa. In the absence of detergent the apparent Mr value was about 305 kDa. In the elution buffers, where Triton X-100 was omitted, the peptidase activity was lost. The enzyme had a Km of 0.13 mM and a Vmax of 450 nmoles per mg protein per min at 25 degrees C for LENK and exhibited little sensitivity to bestatin (IC50: 200 microM) and puromycin (IC50: 500 microM), but it was strongly inhibited by amastatin (IC50: 8 microM). The enzyme is an amphiphilic membrane protein; the native primary structure is preserved only in the 'detergent form'. It seems to be AP N (EC 3.4.11.2) with an optimum of pH 7.2 to 7.4. We assume that this AP plays the important role in inactivating ENKs on the neuronal level. The ENK-degrading AP, partially purified from primary rat brain astrocyte cell membranes, exhibited a smaller apparent Mr value (130 kDa) and a higher sensitivity to amastatin (IC50: 0.4 microM), bestatin (IC50: 90 nM) and puromycin (IC50: 5 microM) than did the N1E-115 enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The Norton-Simon hypothesis revisited.
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Animals↗
Resection of the liver for colorectal carcinoma metastases: a multi-institutional study of patterns of recurrence.
The Registry of Hepatic Metastases has collected data on consecutive patients from 24 institutions who have undergone hepatic resection for colorectal carcinoma metastases. Patterns of recurrence were examined in a subgroup of 607 patients who had undergone curative resection of isolated hepatic metastases. Forty-three percent of these patient have had recurrences in the liver and 31% have had recurrences in the lung (either alone or in combination with other organs). A multivariate analysis showed that patients with positive pathologic margins or bilobar metastases were at an increased risk of having a recurrence in the liver (68% and 64%, respectively). We conclude that: hepatic resection effectively controls hepatic tumor in a substantial number of patients, adjuvant therapy after hepatic resection should be directed at both the lung and liver to significantly increase survival, and patients with positive pathologic margins or bilobar metastases are at an increased risk for hepatic recurrence.
Clinical Trials as Topic↗
Therapeutic response in phase I trials of antineoplastic agents.
We analyzed the therapeutic effect reported in 187 phase I trials of 54 anticancer drugs introduced into National Cancer Institute-sponsored clinical trial from 1974 to 1982. An additional 12 drugs entering clinical trial prior to 1974 were also examined. Objective responses (partial and complete) were reported in 271 of the 6447 patients (4.2%). Thirty-nine percent of the patients were treated at an initial dose level greater than or equal to the dose ultimately recommended for phase II trials. Patients in phase I trials generally had adequate performance status (Karnofsky scale greater than 80% or Eastern Cooperative Oncology Group 0, 1, or 2). More than 90% of the patients had received prior chemotherapy. We next examined the therapeutic effect observed in phase II trials for each of the drugs. Thirty-eight of the 54 drugs had completed at least one phase II trial. Twenty-one drugs were rated active, and nine were rated inactive. For the drugs entering clinical trial since 1974, the median phase I response rate for those active in phase II was 4.3%, compared to 2.7% for the drugs not found active in phase II. This difference was not statistically significant. The tabulated response rate in phase I trials reported here should be interpreted cautiously. There are many factors which may contribute to significant variability in the reported response rates, including the heterogeneity of patient population with respect to prior therapy and tumor type, lack of requirement for measurable/evaluable disease on entry into many studies, and variations in the rigor with which tumor sites are followed for response. These factors may lead to either an overestimate or underestimate of the true response rate in phase I. Although little therapeutic effect is produced in phase I, we discuss several measures which might increase patient benefit during these trials.
Antineoplastic Agents↗