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Biomedical subjects

H Stern

Publications and source records attributed to H Stern.

At least 37 records · Page 2Linked to original sources
PubMed1995

Problems of delivery of monoclonal antibodies. Pharmaceutical and pharmacokinetic solutions.

Monoclonal antibodies to tumour-associated antigens have great theoretical potential for the specific targeting of radioactivity and anti-neoplastic agents to tumours. The clinical success of monoclonal antibody-based cancer diagnosis and therapy depends, however, on solving a number of pharmacokinetic delivery problems. These include: (i) slow elimination of monoclonal antibodies from the blood and poor vascular permeability; (ii) low and heterogeneous tumour uptake; (iii) cross-reactivity with normal tissues; (iv) metabolism of monoclonal antibody conjugates; and (v) immunogenicity of murine forms in humans. As a result of extensive pharmaceutical and pharmacokinetic research conducted over the past 10 to 15 years, several potential solutions to these delivery problems have been identified. Blood concentrations of antibody conjugates may be reduced through regional administration, the use of antibody fragments, interventional strategies and various pre-targeting techniques. Tumour uptake may be increased through administration of higher doses, or the use of agents to increase tumour vascular permeability. Tumour retention of antibody conjugates may be improved by inhibition of metabolism, by using more stable linkage chemistry. Alternatively, normal tissue retention may be decreased through the use of metabolisable chemical linkages inserted between the antibody and conjugated moiety. Very small antigen-binding fragments and peptides that exhibit improved tumour penetration and more rapid elimination from the blood and normal tissues have been prepared by genetic engineering techniques. Chimeric (mouse/human) and human monoclonal antibodies have been developed to circumvent the problem of immunogenicity. Future research will continue to be focused on improvements in the design of monoclonal antibodies for tumour targeting, with the ultimate goal of finally uncovering the 'magic bullet' envisioned by Paul Ehrlich almost a century ago.

Animals↗
PubMed1994

Characterization of two novel adenomatous polyposis coli (APC) gene mutations in patients with familial adenomatous polyposis (FAP).

Patients with Familial Adenomatous Polyposis (FAP) manifest numerous colorectal adenomas as well as benign and malignant extra-colonic lesions. Adenomatous polyposis coli (APC) gene mutations are the underlying genetic defect in FAP. We analyzed germline DNA of 81 unrelated FAP patients and evaluated correlation of APC mutation genotype and clinical phenotype. Germline APC mutations were identified in 18 FAP patients including two novel 2 bp deletions at APC codons 1067 and 1259. FAP patients were screened for hypertrophic ocular fundus lesions, desmoids and peri-ampullary adenomas. As reported previously (Olshwang et al 1993b), a positive correlation for the frequency of retinal lesions and germline APC mutation was observed among all FAP patients except one. No significant correlation was observed for APC mutation genotype and the occurrence of desmoids and peri-ampullary adenomas. Genetic factors contributing to familial segregation of these lesions need further investigation.

Adenomatous Polyposis Coli↗
PubMed1994

Colorectal tumourigenesis.

Colorectal cancer is significant because of its lethality and high incidence in the Western world. Furthermore, it is a particularly suitable model for studying the events involved in the progression from normal tissue to invasive cancer. There is a great deal of epidemiological and histopathologic evidence to implicate the adenomatous polyp as the precursor to colorectal cancer. Moreover in recent years investigators have uncovered some of the molecular genetic events that underlie the progression from normal epithelium to polyp to cancer. It is hoped that an increased understanding of the molecular changes will afford opportunities for new diagnostic, prognostic and therapeutic strategies in the management of this disease.

Adenoma↗
PubMed1994

Immunoscintigraphy of human colon cancer xenografts in nude mice using a second-generation TAG-72 monoclonal antibody labelled with 99Tcm.

Monoclonal antibody CC83 is a second-generation high-affinity antibody directed against the TAG-72 antigen in colorectal cancer. Our objectives were to evaluate the biodistribution, pharmacokinetics and imaging properties of CC83 labelled with 99Tcm via a modified Schwartz technique. The immunological integrity of 99Tcm-CC83 was evaluated by size-exclusion FPLC and by determining the immunoreactive fraction in vitro against bovine submaxillary mucin. The biodistribution of 99Tcm-CC83 up to 24 h postinjection was evaluated in nude mice bearing subcutaneous LS174T human colon cancer xenografts. Blood radioactivity data was fitted to a one-compartment pharmacokinetic model. Images of tumour-bearing mice were obtained at 17-24 h postinjection with 99Tcm-CC83. 99Tcm-CC83 was eluted as intact immunoglobulin by FPLC analysis and the mean immunoreactive fraction was 0.49 +/- 0.15. Tumour uptake at 24 h postinjection was 11.2 +/- 4.1% i.d.g-1. Radioactivity in the blood was eliminated rapidly with a half-life of 8 h and tumour:blood ratios were > 2:1 at 24 h postinjection. LS174T tumours were successfully imaged in 3/3 mice. In vitro studies showed instability of 99Tcm-CC83 when challenged with cysteine and glutathione but not metallothionein, suggesting a metabolic route for the 99Tcm antibody in vivo. We conclude that CC83 labelled directly with 99Tcm retains its immunological integrity and capability specifically to target subcutaneous LS174T human colon cancer tumours hosted in nude mice. These results further suggest that 99Tcm-CC83 may have potential for imaging colorectal cancer in humans.

Animals↗
PubMed1994

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

Adolescent↗
PubMed1993

Local excision and post-operative radiation therapy for rectal carcinoma.

PURPOSE: To assess the patterns of failure and outcome following conservative surgery and post-operative radiation therapy for rectal cancer. METHODS AND MATERIALS: Twenty-five patients underwent post-operative radiation therapy (50 Gy in 20 fractions over 4 weeks) following local excision or electrocoagulation for carcinoma of the rectum. None of the patients had palpable residual disease following surgery. Selection factors for post-operative radiation therapy were refusal of a permanent colostomy, excessive operative risk of an abdominal perineal resection and concern regarding local control with conservative surgery alone. RESULTS: Six of 25 patients developed failure at the primary site. There was no lymph node failure. All five patients with primary failure alone underwent abdominal perineal resection and 2 remained free of recurrence. With a median follow-up of 6 years, 20 of 25 patients remained alive and free of disease. There was no apparent influence of age, sex, type of surgery, tumor size, distance of tumor from anal verge, tumor configuration, resection margins, integrity of the resected tissue, depth of invasion, differentiation, presence of lymphatic or vascular channel invasion, radiation dose or field size on local control and survival. One of 15 patients failed locally when the overall treatment time was 30 days or less, whereas 5 of 10 patients developed local failure when the overall treatment time exceeded 30 days. Sixteen of 20 patients in whom cancer did not recur retained normal anorectal function. All four patients with grade 3 early morbidity and the only patient with Grade 3 late morbidity were amongst the group of 13 patients treated with large AP-PA fields (mean: 15 x 19 cm2). CONCLUSION: In selected patients who are at high risk of local recurrence following local excision alone, and who refuse a colostomy or are at high operative risk from radical surgery, post-operative radiation therapy is an alternative to radical surgery.

Aged↗
PubMed1993

Treatment of peripheral bronchopleural fistulas with endobronchial occlusion coils.

Persistent peripheral bronchopleural fistulas can be difficult to manage. Endoscopic plugging of involved bronchi has been accomplished in a number of ways. We have devised a method of permanently blocking small peripheral airways using Gianturco vascular occlusion coils placed endobronchially by modified angiographic techniques. This procedure has been applied in 5 cases of complicated parenchymal air leaks. Complete or substantial partial control was achieved in all cases. There were no complications.

Adult↗
PubMed1993

The apolipoprotein E gene and the serum low-density lipoprotein cholesterol response to dietary fiber.

Our goal was to determine whether differences in apolipoprotein E (apo E) influenced the response to dietary changes aimed at reducing serum cholesterol levels, especially increases in fiber. Apo E phenotype and genotype were determined in 43 men and 24 women who had previously taken part in parallel 2-week metabolic dietary studies involving either wheat bran or oat bran supplementation at a level of 6.8 g fiber/1,000 kcal. Fasting blood lipid measurements had been made at the beginning and end of the 2-week metabolic period. Reductions in low-density lipoprotein (LDL) cholesterol levels across both oat and wheat bran diets were significantly different depending on the E allele (P = .048). The LDL cholesterol level reduction for E2 carriers (0.60 +/- 0.14 mmol/L, n = 13) was greater than that for E3 homozygotes (0.21 +/- 0.07 mmol/L, n = 38; P = .014) and E4 carriers (0.28 +/- 0.12 mmol/L, n = 16; P = .09). Only the change in dietary fiber on the oat bran diet was related significantly to the decrease in LDL cholesterol levels (r = -.47, P = .007; n = 32). No such relationship was seen on the wheat bran diet (r = -.010, P = .59; n = 33). Carriers of the E2 allele appear to be more responsive than noncarriers to a dietary change involving increased fiber intake. The data also support a lipid-lowering advantage of oat bran over wheat bran. Current dietary recommendations to reduce serum lipid levels may vary in effectiveness depending on distribution of apo E alleles in the different populations studied.

Adult↗
PubMed1993

Genetic variation associated with differences in the response of plasma apolipoprotein B levels to dietary fibre.

1. We hypothesized that differences within genes whose protein products are involved in apolipoprotein B metabolism could influence the response of plasma apolipoprotein B-containing lipoprotein concentrations to increases in dietary fibre. 2. We studied 67 subjects (43 men and 24 women) who had taken part in parallel 2 week metabolic dietary studies involving either wheat bran or oat bran supplementation. Fasting blood lipid, lipoprotein and apolipoprotein concentrations were measured at the start and end of the 2 week metabolic period. Genotypes were determined using DNA markers for the low-density lipoprotein receptor, apolipoprotein B, apolipoprotein CIII and hepatic lipase gene loci. 3. Reductions in plasma concentrations of apolipoprotein B were significantly different depending on genotype determined with a low-density lipoprotein receptor DNA marker (P = 0.03). There was no significant variation in the reduction of plasma total cholesterol, low-density lipoprotein cholesterol or apolipoprotein B concentrations for alleles of other genes tested. 4. Thus, genetic variability is associated with interindividual differences in the fibre-related reduction in plasma apolipoprotein B and apolipoprotein B-containing lipoprotein concentrations. Implementation of current dietary recommendations to reduce plasma lipoprotein levels with fibre may have variable effects in different individuals in part because of structural differences in candidate genes whose products are involved in lipoprotein metabolism.

Apolipoproteins B↗
PubMed1993

The use of lasers in colorectal cancer.

The potential addition of lasers to the armamentarium of physicians treating advanced colorectal cancer is welcome because of the morbidity associated with the disease and because of the limitations of standard treatments for some of the problems related to this common disease. However, laser treatment cannot be regarded yet as a standard modality. Questions still remain regarding the efficacy of these treatments in relieving the most troublesome symptoms of tenesmus and urgency, although bleeding and mucous discharge appear to be well controlled. Additional questions remain regarding expense and the relative benefits of lasers versus electrocoagulation (much cheaper) for rectal cancers. Other concerns relate to the learning curve involved with lasers, particularly for decompression of colonic obstructions, and efficacy compared to pneumatic dilatation.

Colorectal Neoplasms↗
PubMed1993

Radioimmunodetection of colorectal cancer metastases with 131I-labeled monoclonal antibody B72.3: a pilot study to determine efficacy of detection and pharmacokinetics.

We performed radioimmunoscintigraphy (RIS) and/or pharmacokinetic (PCK) studies in 12 patients with primary or metastatic colorectal carcinoma, utilizing an intravenous administration of 1-4 mCi (1 mg) of 131I-B72.3 monoclonal antibody. Metastatic lesions were correctly identified in 4/8 patients by RIS. Two patients with small lesions (> 2 cm diameter) had a false-negative RIS scan. Two patients had a true-negative RIS scan. Optimal images were obtained at 1 week postinjection. PCK studies showed that the plasma clearance of 131I-B72.3 was biexponential with an alpha-phase half-life ranging from 0.5 to 7.1 hr and a beta-phase half-life ranging from 47.5 to 85.3 hr. Systemic and renal clearance data indicated that 131I-B72.3 was cleared very slowly and almost entirely by deiodination. This pilot study was conducted to gain an understanding of the pharmacokinetics of this radiolabeled antibody. On the basis of these data, we are now studying second-generation antibodies as part of our long-range objectives to incorporate them in early detection and treatment protocols.

Adult↗
PubMed1993

Left ventricular function assessed with echocardiography and myocardial perfusion assessed with scintigraphy under dipyridamole stress in pediatric patients after repair for anomalous origin of the left coronary artery from the pulmonary artery.

Twenty-three patients who underwent operation for anomalous origin of the left coronary artery from the pulmonary artery were reexamined with two-dimensional echocardiography and thallium 201 perfusion imaging. Follow-up studies were performed 0.6 to 16.2 years (median 2.9 years) after operation. In 22 of 23 patients, a two coronary artery system had been established by implantation of the left coronary artery into the aorta (n = 8) or by anastomosis of the left subclavian artery with the left coronary artery (n = 14). The left coronary artery had been ligated in only one patient. For stress testing, 0.8 mg dipyridamole per kilogram body weight was infused in a 10-minute period in 20 of the 23 patients. High-dose dipyridamole infusion increased mean heart rate (98.1 +/- 27.1 to 122.3 +/- 19.2 beats/min, p < 0.001) and mean left ventricular ejection fraction (54.8% +/- 11.8% to 61.3% +/- 12.5%, p < 0.05) and decreased left ventricular end-diastolic volume index (38.8 +/- 26.7 to 29.9 +/- 8.3 ml/m2, p < 0.005). At rest, left ventricular dimensions were abnormal in only one patient, in whom the anastomosis with the left coronary artery proved to be occluded, as seen with subsequent angiography. Left ventricular function seen with two-dimensional echocardiography was normal in 19 patients and was compromised in 3 (all of whom had major structural anomalies of the left ventricle, such as left ventricular aneurysm, occlusion of the anastomosis, or mitral valve prosthesis). Patients with R-wave loss as seen with preoperative electrocardiography tended to have larger left ventricular volumes at follow-up (69.2 +/- 56.5 ml/m2 versus 32.4 +/- 9.6 ml/m2, p < 0.07). Ten of 20 patients had normal thallium 201-perfusion scans. In 9 of 20 patients defects revealed by permanent thallium 201-perfusion were observed and determined to be myocardial scars. Transient perfusion defects under dipyridamole stress with redistribution at rest occurred in three children, two of whom also had permanent thallium 201 defects. None of the three patients had angina-like symptoms or S-T segment changes during dipyridamole stress. Left ventricular ejection fraction, however, decreased severely during dipyridamole infusion in the single patient with ligature of the left coronary artery. The two remaining patients had normal echocardiographic left ventricular function under stress, and the diagnosis of myocardial ischemia as seen with scintigraphy must be questioned.(ABSTRACT TRUNCATED AT 400 WORDS)

Child, Preschool↗
PubMed1992

Giant cell carcinoma of the lung.

BACKGROUND: Giant cell carcinoma of the lung has been described as an aggressive tumor characterized by extensive local and distant disease and extremely short survival. In 1981, the World Health Organization defined giant cell carcinoma as a variant of large cell carcinoma. Before then giant cell lung cancer was a descriptive term, but it was not considered a separate entity. METHODS: The authors retrospectively studied 16 cases of giant cell carcinoma of the lung. RESULTS: These cases had a prognosis that was not appreciably different from that for lung cancer of other non-small cell histologic types. Of those patients with pathologic Stage I or II at resection, five of nine are alive and disease-free from 20 to 116 months and one has died without evidence of disease at 15 months. CONCLUSIONS: Based on this series and a review of the literature, there appears to be an increased incidence of both clinical and subclinical gastrointestinal tract involvement in patients with this histology, compared with patients with other non-small cell histologic types. The authors conclude that patients with giant cell carcinoma of the lung have a prognosis similar to that of patients with other non-small cell histologic types, and that clinicians should be aware of the increased incidence of gastrointestinal tract involvement in this disease.

Adult↗
PubMed1992

Comparison of magnetic resonance imaging with cross-sectional echocardiography in the assessment of left ventricular mass in children without heart disease and in aortic isthmic coarctation.

Although left ventricular (LV) mass may be important to judge effects of left-sided cardiac obstruction or hypertension, reproducible noninvasively determined normal data in the pediatric age group are scarce. To validate cross-sectional echocardiographic LV mass determination, our data were compared with LV mass assessed by magnetic resonance imaging (MRI). MRI was considered to be a good reference method because there is usually no problem in defining endo- and epicardial borders with MRI. LV mass was assessed in 14 children aged 5.3 years (10 days to 14.7 years) with a mean body surface area of 0.78 m2 (range 0.25 to 1.61). With cross-sectional echocardiography the epicardial and endocardial volumes were calculated using a Simpsons rule algorithm in the apical 2- and 4-chamber view. The difference between epi- and endocardial volumes was multiplied by 1.05 to yield the mass. Mass was assessed with MRI using a multislice technique; the area of each myocardial slice was calculated and multiplied with the slice thickness, and the resultant slice volumes were added to obtain the myocardial volume. On cross-sectional echocardiography, the mass was 55 g (range 12 to 126) or 64 g/m2 (range 46 to 79); on MRI it was 60 g (range 33 to 87) or 69 g/m2 (range 46 to 89). Regression analysis yielded an r value of 0.98 with a standard error of the estimate of 5.7 g or a 10% difference. In older children, LV mass determined by MRI was bigger than the one derived by echocardiography. It is concluded that cross-sectional echocardiography can reliably assess LV myocardial mass in pediatric patients.

Adolescent↗
PubMed1992

Urinary gonadotropin fragment measurements in patients with lung and esophageal disease.

Urinary gonadotropin fragment (UGF), a small glycoprotein and an intracellular processing product of human chorionic gonadotropin, has been demonstrated in trophoblast tissue and in nontrophoblastic cancers. Levels of UGF were assayed in 107 patients with malignant and benign pulmonary and esophageal lesions to determine if elevated levels were associated with the presence or progression of malignancy. There were 64 patients with primary bronchogenic carcinoma, 9 with metastatic pulmonary malignancies, 7 with lymphoma, 2 with mesothelioma, 9 with esophageal carcinoma, 1 patient each with metastatic cancer to chest wall and carcinoid, and 14 patients with benign pulmonary and esophageal lesions. Sensitivity was only 24% for urine samples from patients with demonstrable cancer. False-positive rates were 6% and 12% for urine samples from patients with benign lesions and those without evidence of residual cancer following treatment, respectively. Although elevated levels of UGF are present in some patients with pulmonary and esophageal cancer it is neither sensitive nor specific enough for use as a tumor marker.

Adult↗
PubMed1992

Prenatal diagnosis of Pallister-Killian syndrome: resolution of cytogenetic ambiguity by use of fluorescent in situ hybridization.

We report a case of Pallister-Killian syndrome initially diagnosed prenatally as tetrasomy 21. A 33-year-old primiparous woman was noted at 24 weeks' gestation to have moderate polyhydramnios. Ultrasonography showed diminished fetal stomach filling, hydronephrosis, and prominence of the cisterna magna. Cytogenetic analysis of cultured amniocytes was initially interpreted as mosaic tetrasomy 21: 46,XX/47,XX,+i(21q). The patient was then referred to our centre for genetic counselling. At 34 weeks' gestation, a dysmorphic infant was delivered and died within 30 min. Physical features were consistent with the Pallister-Killian syndrome. Renal, gastrointestinal, and central nervous system anomalies were found at post-mortem examination. Analysis of peripheral lymphocytes revealed 5 per cent of cells with a marker chromosome, while 92 per cent of cultured fibroblasts had this same marker. Fluorescent in situ hybridization (FISH) using an alpha-satellite probe for chromosomes 13 and 21 failed to hybridize to the marker, while a chromosome 12 centromeric probe unequivocally identified it as an i(12p). Use of FISH can provide rapid, specific prenatal diagnosis of ambiguous marker chromosomes and improve prenatal counselling.

Abnormalities, Multiple↗