Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma.

PURPOSE: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel-Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. MATERIALS AND METHODS: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, representing 80% of von Hippel-Lindau families, and register B, 62% living patients, to identify von Hippel-Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. RESULTS: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p < 0.001 each). In von Hippel-Lindau disease metastases occurred only in tumors larger than 7 cm. CONCLUSIONS: von Hippel-Lindau differs from sporadic renal cell carcinoma in morphology and biology. Our data provide arguments for planning surgery for von Hippel-Lindau renal cell carcinoma and should stimulate future investigations.

Review of the 1995 Food and Drug Administration/National Institutes of Health Public Forum on informed consent in clinical research conducted in emergency circumstances.

We describe some of the deliberations and questions raised by the recent Food and Drug Administration/National Institutes of Health Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances. Consent will have to be waived in emergency medical research if such research is to be conducted, because it is virtually impossible to obtain meaningful informed consent in emergency circumstances. There is clearly a conflict between research subject autonomy and society's perceived need for answers about emergency medical care. Who will resolve this dilemma and how it will be resolved are important questions for modern medicine.

Modeling intensive care unit census.

A mathematical model revealing the relationships between bed capacity, average patient admission rate, average patient length of stay, utilization rate, and overfill rate in intensive care units is developed and explained. Mathematical model predictions are compared to predictions of two kinds of discrete event intensive care unit simulations and to data from a variety of real intensive care units. This methodology applies to any intensive care unit or hospital ward. There is no significant (p < 0.05) difference between measured utilization and overfill rates assessed in actual intensive care units, the rates obtained by discrete event simulations, and the rates predicted by the intensive care unit model. The intensive care unit census model can enhance rational determination of intensive care unit bed and staff requirements.

Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma.

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation analyses and studied its expression in normal and tumor tissue. We identified germline mutations in 39% of VHL disease families. Moreover, 33% of sporadic RCCs and all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3' end of the known open reading frame.

Research for graduate medical education.

Several important questions are addressed herein. What is graduate medical education (GME), and what is research? What is the history of the association between GME and research? Why is research required for GME? What research is required for GME? How will health care reform affect GME and biomedical research? How much research is done in the United States? How can the value of research be assessed? What can we expect for the future with respect to GME and research?

Computer auditing of surgical operative reports written in English.

We developed a script-based scheme for automated auditing of natural language surgical operative reports. Suitable operations (appendectomy and breast biopsy) were selected, then audit criteria and operation scripts conforming with our audit criteria were developed. Our LISP parser was context and expectation sensitive. Parsed sentences were represented by semigraph structures and placed in a textual database to improve efficiency. Sentence ambiguities were resolved by matching the narrative textual database to the script textual database and employing the Uniform Medical Language System (UMLS) Knowledge Sources. All audit criteria questions were successfully answered for typical operative reports by matching parsed audit questions to the textual database.

Arterial-venous carbon dioxide tension difference during severe hemorrhage and resuscitation.

PURPOSE: To define clinically useful markers for determining the adequacy of resuscitation after hemorrhage. DESIGN: Prospective study of 20 Yorkshire swine, using an established model for hemorrhagic shock in swine. BACKGROUND AND METHODS: Clinically useful markers for assessing the adequacy of resuscitation after hemorrhage do not exist. We assess variables, such as BP and arterial blood pH. However, these variables do not correlate well with restoration of organ perfusion. In this study, 14 anesthetized swine were hemorrhaged to a mean arterial pressure of less than 25 mm Hg. After 30 mins without interventions, each animal was resuscitated with whole blood, hydroxyethyl starch, or normal saline. At baseline and during shock and resuscitation, hemodynamic variables, arterial and mixed venous blood gases, and arterial lactate concentrations were measured to determine which variables correlated most closely with the restoration of blood flow. RESULTS: The correlation between cardiac index and arterial or mixed venous pH and the correlations with arterial lactate values were poor. The correlation between cardiac index and mixed venous hemoglobin saturation also was weak (r2 = .28). Cardiac index correlated best with the arterial-venous PCO2 difference (r2 = .67) and the arterial-venous pH difference (r2 = .38). Using multiple regression, a linear correlation was established between the cardiac index and the arterial-venous pH and PCO2 differences throughout shock and resuscitation (r2 = .91). CONCLUSION: These findings suggest that the adequacy of resuscitation after hemorrhage can be assessed using paired arterial and mixed venous pH and PCO2 values.

Cerebral electrophysiologic effects of resuscitation with hypertonic saline-dextran after hemorrhage.

When brain injury accompanies hemorrhage, resuscitation with hypertonic saline (HS) improves intracranial pressure (ICP) and elastance; however, its effect on brain function after a traumatic or ischemic insult has not been assessed. This study compares the electrophysiologic response to hemorrhage and resuscitation with 7.5% NaCl + 6% dextran (HSD), 6% hetastarch (HE), or 0.9% NaCl (NS) using somatosensory evoked potentials (SSEP). Resuscitation with HE resulted in a better return of electrocortical function than with either HSD or NS (SSEP grade 2.0 +/- 0.2 for HE vs. 3.2 +/- 0.3 for HSD and 2.9 +/- 0.3 for NS; p less than .01). SSEP response correlated closet with mean arterial pressure (MAP) (r = -.53). There was no correlation between the SSEP response and cardiac index (r = .06) or ICP (r = -.04). HSD blunted the usual early increase in ICP after fluid infusion, and resulted in a lower ICP throughout resuscitation. However, the restoration of MAP and cerebral perfusion pressure (CPP) after HSD infusion was poor. The vasodilatory properties of hypertonic saline have been well described, both in the systemic and in the pulmonary vascular bed. While these characteristic usually are cited as advantages of this solution, in the case of ischemic cerebral dysfunction, this diminished vascular tone prevents early restoration of the MAP and CPP. The result is suboptimal electrocortical recovery after hemorrhage.

A comparison of the cerebral and cardiovascular effects of complete resuscitation with isotonic and hypertonic saline, hetastarch, and whole blood following hemorrhage.

Hemorrhagic shock and closed head injury often accompany severe trauma. Hypertonic saline may be beneficial in these patients, but few have examined its properties when sufficient volume is infused to achieve sustained resuscitation. Solutions of 6% NaCl (HS), 0.9% NaCl (NS), 6% hetastarch (HE), and whole blood (WB) were used to resuscitate swine in hemorrhagic shock (MAP less than 30 mm Hg). The endpoint of resuscitation was normal oxygen delivery (DO2). Measurements of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and intracranial elastance (ICE) were made in the absence and presence of an epidural mass, created by inflating an epidural balloon. HS resuscitation resulted in a lower ICP [5 +/- 1 versus 9 +/- 2 (HE), 17 +/- 3 (NS), and 10 +/- 3 (WB) mm Hg; p = 0.016], and normalization of CPP throughout resuscitation. Animals resuscitated with NS had a lower CPP by the end of resuscitation [CPP = 45 +/- 4 for NS group, versus 63 +/- 4 (HE), 66 +/- 4 (HS), and 63 +/- 5 (WB) mm Hg; p = 0.009]. ICE fell markedly in the HS group, [a decrease of 12 +/- 2 vs. a rise of 5 +/- 3 (HE), 2 +/- 3 (NS), and 6 +/- 3 (WB) mm Hg/ml; p = 0.0005]. This improvement was even more dramatic in the presence of an epidural mass [a fall of 21 +/- 3 vs. no change (HE, WB) and a rise of 4 +/- 3 (NS) mm Hg/ml; p = 0.0005]. For hemorrhage accompanied by severe head injury, resuscitation with HS may benefit victims by decreasing ICP and diminishing the effects of an intracranial mass.

Physiologic monitoring of combat casualties.

We discuss general concepts and organization of combat casualty care. We identify important issues regarding physiologic monitoring of combat casualties and examine inherent limitations of this monitoring. Effective and practical techniques for monitoring the cardiovascular, pulmonary, central nervous, renal, and coagulation systems are presented in detail.

von Hippel-Lindau disease affecting 43 members of a single kindred.

We present a 6-generation kindred of over 221 members, 43 of whom were affected with von Hippel-Lindau (vHL) disease. Through a simple screening protocol, we diagnosed vHL retrospectively in 15 cases, and for the first time in 28, 11 of whom were presymptomatic. We found many complications of vHL in previously diagnosed relatives and in new cases. This study has demonstrated the utility and benefit of preventive surveillance in those known to have vHL, and of presymptomatic screening for affected relatives in families with vHL. The features of vHL were reviewed in our 43 cases and 511 cases from the medical literature. The patterns, frequencies, and ages of onset for each lesion were compared. Renal malignancies caused almost as much mortality in vHL as CNS malignancies. This family was exceptional for absence of pheochromocytoma and erythrocythemia, for more renal and pancreatic cysts and malignancies, and for slightly fewer eye or CNS lesions. Bilateral renal adenocarcinomata were found presymptomatically in five young subjects, who had bilateral nephrectomy and hemodialysis. Three survived long-term after renal transplants. Five relatives had pancreatic malignancies, which are definite although uncommon manifestations of vHL. Recommendations are made for family screening, which was economical and effective. Bayesian calculations help to predict risks for genetic counseling. The molecular basis of vHL may soon be found, since it has been linked to DNA markers on the short arm of chromosome 3.

Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients.

Adrenal function was studied in 2 groups of intensive care unit (ICU) patients with varying degrees of illness, as determined by Acute Physiological and Chronic Health Evaluation (APACHE). The 15 seriously ill patients with high APACHE scores (greater than or equal to 25) had elevated Therapeutic Intervention Scores and increased mortality compared to the 15 ill patients (APACHE, less than or equal to 10; 67% vs. 27%). Plasma cortisol, aldosterone, and androstenedione concentrations were increased in the ICU patients compared to those in normal subjects (n = 23), being greater in the seriously ill patients. Plasma dehydroepiandrosterone sulfate (DHEAS) concentrations were low in both groups of ICU patients. The ratios of aldosterone or androstenedione to cortisol were not altered, whereas the DHEAS to cortisol ratios were reduced in the ICU patients. ACTH injection elicited increases in plasma cortisol, aldosterone, and androstenedione concentrations in both groups of ICU patients, and the ratios of aldosterone and androstenedione to cortisol did not change. In the seriously ill patients, plasma DHEAS increased, so that the DHEAS to cortisol ratio did not change, whereas in less ill patients plasma DHEAS did not increase, so that the DHEAS to cortisol ratio was reduced. In this study of patients admitted to an ICU, impairment of adrenal steroid secretion appears to be specific for DHEAS. Although plasma cortisol was elevated in ill patients proportional to the degree of illness, the contribution of the concomitant decrease in DHEAS to this increase is not clear.

Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma.

Von Hippel-Lindau disease (VHL) is an autosomal dominant disorder with inherited susceptibility to various forms of cancer, including hemangioblastomas of the central nervous system, phaeochromocytomas, pancreatic malignancies, and renal cell carcinomas. Renal cell carcinomas constitute a particularly frequent cause of death in this disorder, occurring as bilateral and multifocal tumours, and presenting at an earlier age than in sporadic, non-familial cases of this tumour type. We report here that the VHL gene is linked to the locus encoding the human homologoue of the RAF1 oncogene, which maps to chromosome 3p25 (ref. 4). Crossovers with the VHL locus suggest that the defect responsible for the VHL phenotype is not a mutation in the RAF1 gene itself. An alternative or prior event to oncogene activation in tumour formation may be the inactivation of a putative 'tumour suppressor' which can be associated with both the inherited and sporadic forms of the cancer. Sporadic renal cell carcinomas have previously been associated with the loss of regions on chromosome 3p (refs 5, 6). Consequently, sporadic and VHL-associated forms of renal cell carcinoma might both result from alterations causing loss of function of the same 'tumour suppressor' gene on this chromosome.

Spectrum of serum cortisol response to ACTH in ICU patients. Correlation with degree of illness and mortality.

Recent reports suggest adrenal insufficiency in critically ill patients is common. We found only one case of de novo adrenal insufficiency using admission ACTH injection in 70 selected intensive care unit (ICU) patients. Random serum cortisol levels correlated positively with illness severity in ICU patients using proven methods for assessing illness severity. Those with the highest random serum cortisol levels (greater than 60 micrograms/dl) had the greatest mortality, while those with lower random cortisol levels which stimulated to more than 18 micrograms/dl after ACTH injection had improved outcomes. Based on our results, routine screening for adrenal insufficiency in ICU patients is not warranted. If it is suspected, the cosyntropin test should be performed since low random cortisol levels (even to 5 micrograms/dl) are not diagnostic of adrenal insufficiency.

Segregation and linkage analyses of von Hippel Lindau disease among 220 descendants from one kindred.

Von Hippel Lindau disease (vHL), an autosomal dominant precancerous condition, had segregated in a large kindred. Fourteen relatives were known to have been affected; record reviews disclosed features of vHL in 15 previously undiagnosed relatives; presymptomatic evaluations detected vHL in 13 additional members of this kindred. Altogether, among 220 descendants of an ancestral couple, 41 had vHL. We screened for HLA haplotypes and for polymorphic gene markers at 31 loci in 102 direct descendants and 16 spouses from this kindred, including 23 with vHL. Linkage analyses failed to reveal a significant lod score with any locus tested, or any HLA linkage disequilibrium. Expression of vHL among the affected relatives was compared with 384 other reported cases of vHL. The age of onset, tissue involvement, and life expectancy in this family were similar to the other reported cases. The sigmoid age-of-onset distribution for vHL most closely matched a square-foot transformation (mean = 26.2(-2) years; variance = 1.224).

Early identification of retinal angiomas in a large kindred von Hippel-Lindau disease.

We studied prospectively a large kindred afflicted with von Hippel-Lindau disease. Of 111 members examined ophthalmoscopically, 14 definite retinal angiomas were found and three lesions were thought to be angiomas. The lesions found could be divided into the following three groups: (1) classic angiomas, (2) atypical angiomas, and (3) lesions indicative of early angiomas. A correlation between increasing age, systemic evidence of disease, and size and appearance of angiomas was found.

Von Hippel-Lindau disease simulating polycystic kidney disease.

Polycystic kidney disease and the renal manifestations of von Hippel-Lindau disease have much in common. Making the distinction between these two diseases is important. There is a strong association of renal cell carcinoma with von Hippel-Lindau disease, whereas renal cell carcinoma is rare in polycystic kidney disease. Furthermore, the many extrarenal manifestations of von Hippel-Lindau disease are serious and can be fatal while those of polycystic kidney disease are generally benign. Early diagnosis of the lesions of von Hippel-Lindau disease could lead to effective surgical treatment and prevent death. A case of von Hippel-Lindau disease is presented which was incorrectly diagnosed as polycystic kidney disease for sixteen years. The case is instructive in that the possibility of making the correct diagnosis prior to the patient's terminal illness was only through careful assessment of the family. The case is also remarkable in that the patient suffered from progressive renal failure requiring hemodialysis, which has not been associated previously with von Hippel-Lindau disease.