Expression of scatter factor in human bladder carcinoma.

BACKGROUND: Scatter factor (SF) is a protein secreted by stromal (supporting) cells that induces disruption of intercellular junctions and stimulates motility and invasiveness of carcinoma cells. SF is also a potent inducer of angiogenesis (new blood vessel formation), a process required for tumor growth and dissemination. Invasion and angiogenesis are characteristics of biologically aggressive tumors, suggesting that the accumulation of SF within tumors might promote progression to a more malignant phenotype. PURPOSE: This study was designed to determine if SF is overexpressed in carcinoma of the bladder and to evaluate the potential mechanisms that might account for such overproduction. METHODS: We measured the SF content in urine from 20 patients with carcinoma of the bladder and various control groups. We also measured expression of SF in bladder tumor extracts, histologic sections of tumors, and cell culture models, using a variety of techniques, including enzyme-linked immunosorbent assays, immunohistochemistry, and Western and Northern blot analyses. Statistical comparisons were performed using two-tailed t tests. RESULTS: Urinary SF content was found to be significantly elevated in patients with bladder carcinoma as compared with normal control subjects (P < .001), patients with benign prostatic hypertrophy (P = .0055), and patients with prostate carcinoma, another genitourinary malignancy (P = .002). Extracts of bladder cancers, especially those from high-grade, invasive tumors, contained very high levels of SF. Both SF and its proto-oncogene (c-met)-encoded receptor were detected in bladder carcinoma tissue sections by immunostaining. Three different bladder carcinoma cell lines produced no detectable SF but produced very high titers of a high-molecular-weight (> 30 kd), heat-sensitive protein that stimulates SF production by stromal cell types. High titers of a similar SF-inducing activity were detected in vivo, in bladder carcinoma extracts, and in the urine of patients with bladder carcinoma. CONCLUSIONS: Our results suggest that SF is overproduced in bladder carcinomas and accumulates within the tumor and in the urine. Overproduction of SF may result from an abnormal urothelial-stromal interaction in which dysplastic or carcinomatous urothelium secretes factors that stimulate SF expression by bladder wall stromal cells. IMPLICATION: Quantitation of SF in the urine and tumor deserves further study as a possible marker of urothelial malignancy.

Molecular analysis of genetic changes in the origin and development of renal cell carcinoma.

Renal cell carcinoma has been characterized by an abnormality on the short arm of chromosome 3 which suggests the presence of a tumor suppressor gene at this location. In order to more precisely define the location of the renal cell carcinoma gene and to differentiate molecular changes occurring in early stages of renal neoplasia versus those occurring later in malignant progression, DNA from normal and tumor tissue from 60 patients with various stages of renal cell carcinoma was analyzed for loss of alleles at different chromosomal loci. In tumor tissue from 51 of 58 evaluable patients (88%) there was loss of heterozygosity at one or more of 10 loci tested on chromosome 3 independently of tumor stage. Analysis of the genotypes identified the distal portion of 3p bounded by D3S2 and D3S22 (3p21-26) as the region of the disease gene. In tumor tissue from patients with advanced renal cell carcinoma, we found loss of heterozygosity on chromosome 11p in 5 of 21 (24%), on chromosome 13 in 3 of 9 (33%), and on chromosome 17 in 2 of 19 (11%). We found no loss of heterozygosity at the loci on chromosomes 11, 13, or 17 in tumor tissue from patients with localized renal cell carcinoma (N = 5). These data suggest the existence of a tumor suppressor gene on chromosome 3p which may be essential to the genesis of sporadic renal cell carcinoma and that other tumor suppressor genes are associated with progression of this malignancy.

Suramin in adrenal cancer: modulation of steroid hormone production, cytotoxicity in vitro, and clinical antitumor effect.

Suramin, a drug known to have antiparasitic effects, has been previously shown to have adrenocorticolytic activity in primates. We now confirm preferential accumulation of this compound in the normal adrenal gland, evaluate its in vitro effect against two human adrenocortical carcinoma cell lines (SW-13 and NCI-H295), and report the clinical activity of suramin in 17 patients with metastatic adrenocortical carcinoma. Inhibition of colony formation occurred in both adrenal cell lines in vitro at concentrations that are clinically achievable in humans. In addition, suramin concentrations as low as 100 micrograms/mL were able to inhibit glucocorticoid, mineralocorticoid, and androgen production by the NCI-H295 cell line. Of 16 patients with adrenocortical carcinoma now evaluable for tumor response, 2 achieved a partial response, 2 had a minor response, and 5 remained with stable disease for periods ranging from 3-10 months; the remainder progressed. One of 7 patients with excessive steroid hormone production achieved a partial normalization of her steroid levels for the duration of suramin therapy in the setting of radiographic disease stabilization. An additional patient treated off-study for lack of radiographically measurable disease, achieved complete normalization of plasma aldosterone levels. We conclude that suramin preferentially accumulates in adrenal cells, induces cytotoxicity and significant down-regulation of steroid hormone production in vitro, and has some therapeutic efficacy as a single agent in patients with metastatic adrenocortical carcinoma.

Predicting posttraumatic epilepsy in penetrating head injury.

Using data derived from a 15-year follow-up study of 520 veterans surviving penetrating brain wounds received in the Vietnam war, we have developed a predictive formula and tables for posttraumatic epilepsy based on time elapsed postinjury and presence of specific clinical and computed tomographic scan risk factors. Such patients remain at some increased risk for epilepsy even ten to 15 years postinjury, although most can be 95% certain of avoiding epilepsy if they have been seizure free for three years posttrauma. Epilepsy onset latency was independent of any risk factors identified.

Life expectancy and causes of death in a group of head-injured veterans of World War I.

The life spans and causes of death were examined for a group of Bavarian veterans of World War I who had suffered head injuries and for comparable control subjects who had not. The occurrence of posttraumatic fits was a significant prognostic factor for a higher death rate after the age of 50 years. Other indicators of the severity of injury did not lead to differences in the death rates. There were significantly more deaths due to cerebrovascular causes in the head-injured group than in the control group, but no subgroup was found to have significantly more cerebrovascular deaths than any other.

Language and motor disorders after penetrating head injury in Viet Nam.

Aphasia occurred in 244 of 1030 patients with head wounds, correlating with gunshot cause (p < 0.03) and initial loss of consciousness (p < 10(-6)). Aphasia disappeared within 10 years in 84 cases (34%). Sensorimotor aphasia usually changed to motor aphasia; motor aphasia disappeared; and sensory aphasia persisted. These improvements continued years after the accompanying hemiparesis stabilized, and were not related to wound site, depth, or whether the wound was caused by gunshot or fragment. Parietal wounds caused hemiparesis more often (p < 10(-6))than did wounds elsewhere. Regardless of the features of the hemiparesis initially, the severity of the final syndrome was greatest in the hand and arm and least in the face.

Regional ventilatory clearance by xenon scintigraphy: a critical evaluation of two estimation procedures.

Estimates of ventilatory clearance are usually made by inspecting xenon washout images. Quantitative computer procedures have been described that produce regional clearance rates, yet their accuracy is not well established. We define a mathematical model for scintigraphic ventilation data based on 96 clinical studies, and with this model we test the accuracy of two procedures used to estimate ventilatory clearance. The least-squares curve-fitting technique for both washin and washout data has the same accuracy as a modified Stewart-Hamilton method (A/H) that uses washout data alone. Both procedures demonstrate relative errors of less than 5% and coefficients of variation of 10-20% when regions with equilibrium count rates of 3 cps and clearance times between 10 and 90 sec are examined. Because the A/H procedure is preferred for its simplicity and speed, we analyze two of its main sources of error: early washin/washout termination and background activity. To measure regional ventilation by the A/H procedure, we recommend: (a) washin and washout periods at least three times the largest clearance time of clinical interest; b) a regional equilibrium count rate of at least 3cps; and c) a 25- to 50-sec average of the equilibrium count rate.

Changes in urinary magnesium, citrate, and oxalate levels due to cola consumption.

The serum concentration and urinary excretion of four potential stone constituents: calcium, oxalate, phosphate, and uric acid; and of two potential inhibitors of urinary stone formation, citrate and magnesium, were studied before and during ingestion of a carbonated cola beverage. Four participants, after baseline serum determinations, abstained for forty-eight hours from cola consumption and then attempted to drink 3 quarts per day of cola in the following forty-eight hours. One participant failed to drink more than two quarts per day of cola. In all 4 participants twenty-four-hour urinary excretion of magnesium decreased by an average of 2.6 mg. In the 3 participants who succeeded in drinking 3 quarts of cola per day, twenty-four-hour urinary excretion of oxalate increased an average of 8.3 mg and excretion of citrate decreased an average of 122 mg. These results demonstrate changes in urine constituents which could contribute to enhanced kidney stone formation in patients who drink large quantities of cola-flavored carbonated beverages.

Lymphoceles after laparoscopic pelvic node dissection.

OBJECTIVE: Lymphocele formation has been infrequently reported as a complication of laparoscopic pelvic lymph node dissection (LPLND). We determined the incidence of clinical and subclinical lymphocele formation in patients undergoing transperitoneal LPLND. METHODS: Charts and radiological records of 111 patients undergoing transperitoneal LPLND at this institution between January 1991 and December 1995 were reviewed to determine the incidence of lymphocele formation. RESULTS: Of 111 patients undergoing LPLND, 12.6% had positive lymph nodes and received hormonal therapy. Radical retropubic (12) or perineal (28) prostatectomy was performed either simultaneously or within 2 weeks in 41% of the node-negative patients. Radiation therapy was the treatment modality in the remaining node negative patients (N = 57). Twenty-three patients undergoing radiation therapy had preplanning pelvic computed tomography (CT) scans 2 to 16 weeks (mean 8.2 weeks) after LPLND. These were reviewed by a single radiologist to determine the presence of subclinical lymphoceles. Seven patients (30.4%) had lymphoceles of varying sizes (3 large and 4 small). Although most were identified on CT scans 4 weeks after the procedure, two were identified on scans 12 and 16 weeks after the procedure (mean 6.5 weeks). None of these patients developed symptoms referable to or had treatment for the lymphocele during a 2 to 37 month follow-up (mean 20 months). Only two patients (3.5%) undergoing LPLND as an isolated procedure had clinical evidence of lymphocele formation, both of which were subsequently confirmed with CT scans (1 large, 1 small). One was treated with CT-guided drainage and sclerosis and the other resolved spontaneously. CONCLUSION: The clinical incidence of lymphocele formation following LPLND remains relatively low. Only a portion of these patients requires intervention. Subclinical lymphoceles, as detected on follow-up CT scans, occur with a much greater frequency. These seldom become symptomatic requiring treatment. Rather, they appear to resolve spontaneously. Nevertheless, clinical suspicion should remain high in order to detect and properly treat symptomatic lymphoceles when they occur.

Cytoreductive surgery prior to interleukin-2-based therapy in patients with metastatic renal cell carcinoma.

From May 1985 to December 1990, 93 patients with the clinical diagnosis of metastatic renal cell carcinoma and their primary tumor in place were evaluated for cytoreductive surgery as preparation for systemic therapy with regimens based on interleukin-2. These patients had typical sites of metastatic disease and manifestations of paraneoplastic syndromes. Patients underwent removal of the primary tumor, as well as debulking when this could be performed safely. Thirty-two percent of patients (30/93) had a second surgical resection in addition to their nephrectomy, frequently because of the large size of the primary tumor and its invasion of adjacent structures. Thirteen percent of patients (12/93) experienced postoperative complications. There were no perioperative mortalities. Forty percent of patients (37/93) who underwent nephrectomy could not be treated with immunotherapy, usually because of progression of disease. A preoperative ECOG status greater than or equal to 2 was the only significant risk factor associated with failure to undergo immunotherapy (P = 0.043). The response rate to immunotherapy in the 56 patients receiving interleukin-2 was 27 percent (4 CR, 11 PR).

Prostate cancer screening and management.

Several other newer therapeutic modalities are being investigated to determine their potential role in the treatment of prostate cancer. Cryotherapy, microwave hyperthermia, laser therapy, and high-intensity focused ultrasound have all been introduced in recent years. Each of these techniques is based on a different principle, yet they all attempt to kill prostate cancer cells in a minimally invasive manner. Insufficient follow-up data are available to allow strong recommendations regarding these treatments.

Numerical study of the Johnston-Ogston effect in two-component systems.

Numerical solutions of the Lamm equation are presented for systems exhibiting the Johnston--Ogston effect. From these solutions it is apparent that the movement of the maxima of the concentration gradient curves reflects the sedimentation velocity of the slow or fast components in their appropriate plateaus. A simple generalization of the Johnston--Ogston analysis is presented, valid for all centrifugation times in a radial field and sector shaped cell provided only that there exist both a plateau of the slow component by itself and the mixed plateau with both slow and fast components present.

Cranioplasty: a review of 1030 cases of penetrating head injury.

A total of 491 cranioplasties performed in a population of 1030 cases of penetrating head injury are reviewed. The morbidity rate was 5.5%, and the mortality rate was 0.2%. The clinical criteria of improving cosmetic defects and restoring craniocerebral protection are established, based on the location and size of the skull defect. Cranioplasty after penetrating head injury should be deferred for a minimum of 1 year to control morbidity. Complication of the original injury and surgical debridement increase the morbidity rate of cranioplasty. Post-traumatic epilepsy is not related to skull defects per se; neither is it affected by cranioplasty. Acrylic is an acceptable cranioplasty material if there is strict adherence to good surgical technique.

Analysis of brain abscess after penetrating craniocerebral injuries in Vietnam.

A population of 1221 patients from the Vietnam War with penetrating craniocerebral trauma was analyzed. Thirty-seven cases of brain abscess were documented (incidence 3%). This sequela occurred more frequently in association with extensive, deep penetrating injuries; deep, prolonged coma; cerebrospinal fluid fistulas; wound infections; facio-orbital cranial/air sinus injuries; and retained bone fragments. The mortality rate was 54%, and, of the patients who survived, 82% had significant morbidity. This is the last large population study of brain abscess after penetrating craniocerebral trauma before the availability of computed tomographic scanning and more comprehensive coma care. It should serve as base line data against which we can measure improvement.

Mortality following penetrating craniocerebral injuries. An analysis of the deaths in the Vietnam Head Injury Registry population.

A population of 1127 men with penetrating craniocerebral injuries who were alive 1 week after their injuries has been followed for 15 years. During this time, 90 deaths (8%) occurred. Most of the deaths occurred early in the 1st year after trauma and were secondary to the direct effects of brain injury or the sequelae of coma. Complications, particularly infections, were significant mortality factors. Coma was the best prognostic guideline. Posttraumatic epilepsy was not related to mortality except for the risks accompanying each ictus. The population now appears to be approaching the actuarial norm of their peers.

Evolution of craniotomy as a debridement technique for penetrating craniocerebral injuries.

A craniotomy debridement technique was recommended for penetrating craniocerebral injuries as early as 1940, in World War II. However, with due consideration for the bacterial contamination of penetrating injuries, the safety of this technique was questionable. The technique has been recommended in each succeeding war, but no data substantiating the safety or eventual sequelae have been available. Analysis of the data from the large Head Injury Registry of Vietnam casualties indicates that, in properly selected cases, debridement by craniotomy technique can be safe and efficacious.

Cerebrospinal fluid fistulas complicating missile wounds of the brain.

The records of 101 casualties of the war in Vietnam have been analyzed, with particular attention to missile wounds of the brain complicated by a cerebrospinal fluid (CSF) fistula. Fifty-four developed CSF drainage at the wound site, 30 presented with rhinorrhea, and 23 with otorrhea. Fifty of the 101 men developed infection, an incidence of 49.5%. The occurrence of a fistula in vertex wounds can usually be traced to failure to close the dura, or to achieve watertight closure of the dura primarily, or by graft. Approximately two-thirds of compound basilar fractures, complicated by rhinorrhea or otorrhea, are due to direct fractures of the anterior, middle, or posterior fossa. The remaining one-third are due to elusive "discrete" fractures of the base of the skull, occurring at a distance from the entry wound, and not in continuity with the fracture of the vault. While direct basilar fractures can readily be recognized, facilitating repair of the dura overlying the basilar fractures, "discontinuous" fractures pose a challenging diagnostic problem. More commonly occurring in vertex wounds crossing the midline, discontinuous fractures producing rhinorrhea or otorrhea may be identified with the aid of tomograms of the base of the skull. Their early diagnosis may well prove to be a significant factor in the reduction of morbidity and mortality of missile wounds of the brain complicated by a CSF fistula.

Asymmetry of protein peaks in capillary zone electrophoresis: effect of starting zone length and presence of polymer.

The asymmetry of R-phycoerythrin (M(r) = 240,000) peaks in capillary zone electrophoresis measured as In[(tm-t1)/(t2-tm)], where tm, t1 and t2 are migration times of the peak mode and at the intersection of the peak width at half-height with the ascending and descending limbs, respectively, was found to undergo a transition from negative to positive values with increasing starting zone length. The transition is compatible with a mathematical model of peak dispersion which assumes that an interaction of protein with the capillary walls governs the evolution of the peak during capillary zone electrophoresis. Models assuming a final peak shape defined solely by longitudinal diffusion, or by a heterogeneity with regard to mobility or by a conductivity difference between analyte zone and background electrolyte, have failed to give rise to a change in the sign of peak asymmetry when the starting zone length is varied. The presence of polyethylene glycol in the buffer within a concentration range up to 4% does not appreciably affect the peak asymmetry regardless of whether the concentration regime is dilute or semi-dilute. Above 4% of polyethylene glycol, the asymmetry becomes nearly independent of starting zone length, and progressively negative with increasing polymer concentration. The concentration range at which the transition from negative to positive asymmetry disappears coincides with that at which the average mesh size of the polymer network falls below the size of the protein.

Protein band spreading in capillary zone electrophoresis effects of sample zone length and presence of polymer.

It is commonly accepted that intra-column zone dispersion in CZE rests on multiple mechanisms, viz. diffusion, interaction of analyte with the capillary walls, Joule heat and conductivity differences between sample zone and the surrounding buffer. The most important extra-column contributor to bandwidth is thought to be the starting zone width. The present study shows that the length of the starting zone above 10 mm is linearly related to the bandwidth of R-phycoerythrin (M(r) 290.10(3)). Below that length, bandwidth demonstrates a plateau preceded by a slight rise. Within the 'plateau range', the ratio of bandwidth to effective capillary length is close to constant while it is independent of electric field strength in the range of 37 to 370 V cm-1 and of protein concentration in the range of 0.1 to 1000 micrograms ml-1. The experimental observations support the notion that the analyte-wall interaction is the determining source of intra-column zone dispersion. A slight rise observed at initial zone lengths of less than 2 mm was accounted for by a diffusion model taking into account a non-local initial concentration of analyte. The presence of polyethyleneglycol in the buffer within a concentration range up to 6% does not affect bandwidth. Above that concentration, the level of constant bandwidth is raised.

Effects of time delay in cardiac blood flow measurements by bolus H2(15)O.

Myocardial blood flow (rMBF) can be measured using dynamic positron emission tomography (PET) and bolus injection of H2(15)O. Recent studies indicate that large errors in the estimates of flow (f) can be produced by time shifts between the true arterial input function and the measured input function [A(t)]. We have investigated this phenomenon further using A(t) derived from patient data, and using simulated myocardial time activity curves [M(t)]. We found that with judicious choice of scan parameters and region of interest (ROI) placement, these errors can be greatly reduced. In particular, when A(t) is measured from the left ventricular (LV) cavity, the bias in f is negligible over a wide range of circumstances. However, when A(t) is not measured from the LV cavity, the bias in flow can be large for short scans (< 2 min) or low flow values (f < 0.4 ml/g/min). We show that the bias is primarily due to the spill-over term in the model that is most commonly used to compute rMBF and suggest some correction methods. We conclude that it is possible to avoid errors in estimates of flow due to time delay.