Biomedical subjects

P Choyke

Publications and source records attributed to P Choyke.

At least 19 recordsLinked to original sources

PubMed2002

Impaired renal function in progressive multiple sclerosis.

The authors analyzed renal function in 25 patients with progressive MS. The mean glomerular filtration rate (GFR) was 92 mL/min/1.73 m(2), compared to the predicted GFR of 110 (p < 0.001). Nine of the 25 (36%) patients had abnormally low GFR (<90). The mean serum creatinine for patients with MS was lower than predicted normal values and poorly estimated GFR using standard equations. These data document impaired renal function in patients with progressive MS and have implications for treatment of these patients with potentially nephrotoxic drugs.

Adult↗

PubMed2001

A Phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar).

BACKGROUND: PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion. METHODS: Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study. RESULTS: The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response. CONCLUSIONS: PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833.

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. CONCLUSION: PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A prospective study of 2-[18F] fluoro-2-deoxy-D-glucose/positron emission tomography scan, 99mTc-labeled arcitumomab (CEA-scan), and blind second-look laparotomy for detecting colon cancer recurrence in patients with increasing carcinoembryonic antigen levels.

BACKGROUND: An increasing carcinoembryonic antigen (CEA) level in the absence of disease on imaging studies can present a diagnostic challenge. We evaluated 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography (FDG-PET) scan and CEA scan before second-look laparotomy as a means of localizing recurrent colorectal cancer. METHODS: Patients underwent computed tomography scan, bone scan, colonoscopy, and magnetic resonance imaging, and those without evidence of disease or resectable disease in the abdomen had FDG-PET and CEA scans. At second-look laparotomy, a surgeon blinded to the results of the FDG-PET and CEA scans performed an exploration and mapped findings. A second surgeon, with knowledge of the FDG-PET and CEA scans, then explored the patient; all lesions were biopsied or resected for pathology. RESULTS: In 28 patients explored, disease was found at operation in 26 (94%). Ten had unresectable disease. FDG-PET scans predicted unresectable disease in 90% of patients. CEA scans failed to predict unresectable disease in any patient. In 16 patients found to have resectable disease or disease that could be treated with regional therapy, FDG-PET scan predicted this in 81% and CEA scan in 13%. CONCLUSIONS: FDG-PET scan can predict those patients who would likely benefit from a laparotomy. If the FDG-PET scan indicates resectable disease, laparotomy can be considered. However, if the findings predict unresectable disease or the absence of disease, the patient should pursue systemic therapy or continued observation.

Adult↗

PubMed2001

Dynamic contrast-enhanced magnetic resonance imaging in oncology.

Dynamic contrast-enhanced MRI (DCE-MRI) is the acquisition of sequential images during the passage of a contrast agent within a tissue of interest. The current gadolinium chelate agents enable visualization of lesion vasculature and, due to their small size, can be used to assess vascular permeability. Recent studies demonstrated that the temporal evolution of gadolinium-induced signal intensity changes within a tumor reflects the angiogenic properties of the tumor. These can be quantified and are related to vascular density and other angiogenic characteristics of lesions, such as the level of vascular endothelial growth factor. DCE-MRI provides noninvasive characterization of antiangiogenic response of tumor during therapeutic intervention to monitor and predict response. This article reviews the fundamental pathophysiological basis of DCE-MRI and the technical aspects necessary for successful implementation DCE-MRI. The role of DCE-MRI in tumor detection, characterization, and therapy monitoring is reviewed.

Contrast Media↗

PubMed2000

Imaging of urea using chemical exchange-dependent saturation transfer at 1.5T.

The purpose of this study was to screen for slow proton chemical exchange between water and kidney metabolites using a standard clinical 1.5-T scanner. Imaging was performed using a fast spin-echo sequence with a magnetization transfer (MT) preparation pulse train. Off-resonance saturation ranging from +/-50 to +/-1000 Hz was used on urea and urine phantoms and normal human subjects imaged through the kidneys. The positive frequency was used as the control for each frequency pair. Results of frequency sweeps show an asymmetric MT effect peaking at approximately 100 Hz ( thick similar1 ppm) for urea, urine, and renal parenchyma. Varying differences (5%-25%) occurred with different human subjects. Few differences were observed from phantom water or subject muscle tissue. Chemical exchange is detectable in the kidney near 1 ppm at 1.5 T, attributable to urea. This technique was used to produce in vivo distribution maps of this metabolite in vivo.

Biological Transport↗

PubMed1999

Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype.

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.

Adenoma↗

PubMed1999

Novel gastrointestinal tract manifestations in juvenile dermatomyositis.

We report a case of juvenile dermatomyositis in which a dilated atonic esophagus was associated with delayed gastric emptying and intestinal mucosal thickening, resulting in a radiographic "stacked coin" appearance. These findings, which can also occur in infectious, neoplastic, or other immune-mediated diseases, broaden the spectrum of gastrointestinal tract manifestations in juvenile dermatomyositis. Physicians should be alert for these treatable manifestations in children with myositis who present with unexplained gastrointestinal symptoms, which are reversible with immunosuppressive therapy.

Anti-Inflammatory Agents↗

PubMed1999

Three-dimensional changes in the upper airway during neuromuscular stimulation of laryngeal muscles.

During swallowing, airway protection depends upon adequate glottal closure and laryngeal elevation to prevent the entry of substances into the airway. Three-dimensional changes in the upper airway during laryngeal muscle stimulation in a canine model were quantified in animals implanted with Peterson type stimulating electrodes in the inferior and superior portions of the thyroarytenoid muscle, together with a reference electrode. Computer tomography scanning was performed on an IMATRON scanner with a 3 mm slice thickness advanced at overlapping 1 mm increments. Stimulation of the thyroarytenoid muscle produced adductions of the vocal fold towards the midline and changes in the supraglottic region as well as the glottis; the glottic wall was compressed medially above and below the glottis. These results suggest that chronic neuromuscular stimulation can effect glottic protection by reducing the glottal opening and may be beneficial for patients with central control disorders affecting airway protection during swallowing.

Animals↗

PubMed1998

Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia.

Proteus syndrome is a rare and highly variable hamartomatous syndrome that can affect multiple organ systems. It is characterized by hyperplastic lesions of connective tissue, vascular malformations, linear verrucous epidermal nevi, and hyperostoses. The cause of the disorder is unknown, but the current working hypothesis is that it is caused by a mosaic alteration that leads to a highly variable phenotype, equal sex ratio, sporadic occurrence, and discordant monozygotic twins. Herein we describe our experience with 18 patients with a referring diagnosis of Proteus syndrome. It was found that imaging studies are very useful for the characterization of the syndrome. One finding was that splenic hyperplasia can be a manifestation of Proteus syndrome. Analysis of the clinical data shows that Proteus syndrome is frequently confused with "hemihyperplasia." A distinct subtype of hemihyperplasia is defined that includes static or mildly progressive hemihyperplasia and multiple lipomata.

Adolescent↗

PubMed1998

Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene.

Hereditary papillary renal carcinoma (HPRC) is a newly recognized inherited disorder characterized by a predisposition to develop multiple bilateral papillary renal carcinomas. Individuals affected with HPRC have been shown to have germ-line mutations in the tyrosine kinase domain of the MET proto-oncogene. We identified a novel mutation in exon 16 of the MET gene in two large North American HPRC families. The H1112R MET mutation segregated with the disease, was not present in 320 normal chromosomes, and caused malignant transformation of NIH 3T3 cells. By examining individuals with the H1112R mutation, we determined the age-dependent penetrance of this mutation and identified additional nonrenal malignancies that occurred in mutation carriers. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a founder effect. The identification of the H1112R mutation will facilitate predictive testing in HPRC and guide future studies of the MET gene in human neoplasia.

3T3 Cells↗

PubMed1998

Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.

von Hippel-Lindau disease (VHL) is an inherited neoplastic disorder characterized by the development of tumors in the eyes, brain, spinal cord, inner ear, adrenal gland, pancreas, kidney, and epididymis. The VHL tumor suppressor gene was identified in 1993. Initial studies reported the detection of germline mutations in the VHL gene in 39-75% of VHL families. We used tests that detect different types of mutations to improve the frequency of detection of germline mutations in VHL families. The methods included quantitative Southern blotting to detect deletions of the entire VHL gene, Southern blotting to detect gene rearrangements, fluorescence in situ hybridization (FISH) to confirm deletions, and complete sequencing of the gene. Here we report that we have detected germline mutations in the VHL gene in 100% (93/93) of VHL families tested. In addition, we describe 13 novel intragenic VHL germline mutations. With the methodology described in this article, it is now possible to identify germline mutations in virtually all families with VHL.

Blotting, Southern↗

PubMed1998

Familial renal oncocytoma: clinicopathological study of 5 families.

PURPOSE: We analyzed familial renal oncocytoma to provide a foundation for studies aimed at defining genes involved in the pathogenesis of renal oncocytoma. MATERIALS AND METHODS: We describe 5 families with multiple members affected with renal oncocytoma. Tumors were analyzed pathologically, and affected and nonaffected members were screened clinically and genetically. RESULTS: We identified 12 affected male and 3 affected female (ratio 4:1) individuals in the 5 families. In affected family members renal oncocytomas were often multiple and bilateral. No metastatic disease was observed. Most renal oncocytomas were detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal oncocytoma families. One identical twin pair was affected with bilateral multiple renal oncocytomas. CONCLUSIONS: Renal oncocytoma may be inherited in some families.

Adenoma, Oxyphilic↗

PubMed1997

Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Adult↗

PubMed1995

Hereditary papillary renal cell carcinoma: clinical studies in 10 families.

We recently described a 3-generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Possibly family 150 is an isolated occurrence, a reflection of some as yet unknown environmental factor. Alternatively, family 150 may represent a distinct class of inherited cancer. To distinguish between these 2 possibilities we sought additional families with papillary renal cell carcinoma and we identified 9 with members affected with papillary renal cell carcinoma. There were 29 affected male and 12 affected female subjects (ratio 2.41:1), including affected members of family 150. Papillary renal cell carcinomas were often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of renal cell carcinoma families. The penetrance, the proportion of obligate gene carriers that showed clinical evidence of the disease, was reduced. The median survival of affected individuals was 52 years. The results support the concept that the predisposition to develop papillary renal cell carcinomas may be inherited and that hereditary papillary renal cell carcinoma constitutes a distinct class of inherited cancer.

Adolescent↗

PubMed1994

Hereditary papillary renal cell carcinoma.

We describe a 3 generation family with members affected with papillary renal cell carcinoma, an uncommon histological type of renal cell carcinoma. Multiple tumors of varying size were present in both kidneys of affected family members. The disorder was not linked to polymorphic markers on chromosome 3p and there was no loss of heterozygosity at loci on 3p in renal tumors. The results suggest the presence of a renal cell carcinoma gene not located on 3p that predisposes to renal cell carcinoma with a distinct histological appearance. The inherited disorder in this family appears to be different from recognized hereditary cancer syndromes.

Adolescent↗

PubMed1992

Screening for von Hippel-Lindau disease by DNA polymorphism analysis.

OBJECTIVE: Von Hippel-Lindau (VHL) disease is a rare, inherited multisystem neoplastic disorder. There is no biochemical test available to distinguish VHL disease gene carriers from their healthy siblings. We evaluated DNA polymorphism analysis as a method for identifying disease gene carriers. DESIGN: Prospective comparison of the results of DNA analysis with a comprehensive clinical screening examination. SETTING: The Clinical Center of the National Institutes of Health. PATIENTS: Blood was collected from 182 members of 16 families with VHL disease. Forty-eight asymptomatic individuals, at risk of developing this hereditary illness (with an affected parent or sibling), were examined for occult disease at the Clinical Center of the National Institutes of Health and tested by DNA polymorphism analysis. RESULTS: DNA polymorphism analysis predicted nine disease gene carriers and 33 individuals with the wild-type (normal) allele among the 48 individuals at risk of developing VHL disease; the test was not informative in six individuals. All nine individuals predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 individuals predicted to carry the wild-type allele. CONCLUSIONS: DNA polymorphism analysis can identify individuals likely to carry the VHL disease gene among asymptomatic members of disease families. This technique serves to focus attention on those individuals who require periodic medical examination and may help to alleviate the morbidity and mortality associated with this disease.

DNA↗

PubMed1992

The urological manifestations of chronic granulomatous disease.

Chronic granulomatous disease is a rare disorder of phagocytic cell oxidative metabolism. Patients have recurrent infections with catalase positive organisms and granulomatous lesions throughout the body. The genitourinary tract can be an occult site of involvement. We reviewed the prevalence of urological abnormalities in 60 patients with chronic granulomatous disease. Chart review revealed that 23 of the 60 patients (38%) had urological manifestations. Seven patients had 10 ureteral strictures. Treatment of the granulomatous strictures with steroids caused at least a temporary decrease in size or a resolution of the granulomas and strictures with steroids caused at least a temporary decrease in size or a resolution of the granulomas and relief of the obstruction. Three patients had bladder granulomas and 1 had a urethral stricture. A total of 12 patients had urinary tract infections and 7 had altered renal function. Ten patients had other manifestations of genitourinary disease. Abnormalities in the urinary tract are relatively frequent. Risk factors include X-linked disease and low percentile weight. Genitourinary manifestations can cause significant morbidity in chronic granulomatous disease patients. A variety of therapies, including judicious use of steroids and gamma-interferon, are proving to be useful in the treatment of this disorder and in some cases they may offer a nonoperative alternative for relief of chronic granulomatous obstructive disease in these patients.

Female↗