Nonadditive Developmental Toxicity in Mixtures of Trichloroethylene, Di(2-ethylhexyl) Phthalate, and Heptachlor in a 5x5x5 Design

In order to identify nonadditive effects on development, threecompounds were combined using five dosages of each agent (a5x5x5 full-factorial design). Trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administeredby gavage to Fischer-344 rats on Gestation Days 6–15.Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE;0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8,2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliverand their pups were weighed and examined postnatally. Maternaldeath showed no main effects but DEHP and HEPT were synergistic.For maternal weight gain on Gestational Days 6–8, maineffects for all three agents were observed, as well as TCE-DEHPsynergism, and DEHP-HEPT antagonism. Maternal weight gain onGestational Days 6–20 adjusted for litter weight showedmain effects for TCE and HEPT, but no interactions. Main effectsfor all three agents were evident for full-litter resorptionsand prenatal loss. The HEPT main effects were unexpected andwere interpreted as reflecting potentiation by HEPT of the otheragents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactionswere antagonistic, perhaps due to a "ceiling" effect. For prenatalloss, the TCE-DEHP interaction was synergistic. Postnatal lossshowed DEHP and HEPT main effects but no interactions. Analysisof pup weights on Day 1 revealed TCE and DEHP main effects andDEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects,DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmiaand anophthalmia incidences revealed TCE and DEHP main effectsbut no interactions. This extensive examination of a full-factorialdesign elucidates the complexities of studying and interpretingmixture toxicity. The data are available for further analysis.     

A 90-Day Chloroform Inhalation Study in F-344 Rats: Profile of Toxicity and Relevance to Cancer Studies

Composition of diet may influence growth, diseases, tumor rates,and responses to chemical treatment. Since 1980 the NIH–07open formula nonpurified diet has been the selected diet forthe National Toxicology Program (NTP) toxicity and carcinogenicitystudies in rodents. Studies with nonpurified experimental dietswith lower protein and higher fat and fiber than the NIH-07diet indicated that the diet for Fischer-344 (F344) rats inlong-term studies could be modified to decrease the severityof chronic diseases and to decrease/delay the development ofspontaneous tumors. Based on the results of these studies anew open formula nonpurified diet designated as NTP-2000 wasformulated to contain 14.5% protein, 8.5% fat, and 9.5% fiber.Corn, wheat, and wheat middlings contribute to about 60% ofthe ingredients; soybean meal, fish meal, and alfalfa meal arethe additional sources of protein; purified cellulose, oat hulls,and alfalfa meal are the major sources of fiber; and soy oiland corn oil are the major sources of fat in the NTP-2000 diet.The Ca:P ratio and mineral and vitamin concentrations were reformulatedbased on AIN-93 and NRC-95 recommendations. The NIH-07 and theNTP-2000 diets were fed to groups of 6-week-old F344 rats for13 weeks and evaluated for growth patterns, food and water consumptions,hematology and clinical chemistry parameters, and organ weightsand pathological changes. Growth patterns and body weights weresimilar for both diets. Food consumptions were slightly higherand water consumptions were slightly lower for the groups fedNTP-2000 diet. There were no differences in hematological parametersbetween the groups fed the above diets. Serum levels of cholesterol,alkaline phosphatase, and 5' nucleotidase were slightly higherin groups fed the NTP–2000 diet possibly due to higherfat content of this diet. However, the serum triglyceride levelswere slightly lower in groups fed the NTP–2000 diet andit may be related to higher fiber content of the NTP–2000diet. The liver and kidney weights of the groups fed NTP–2000diet were significantly lower possibly due to lower proteincontent of this diet and lower protein consumption associatedchanges in Phase I and Phase II drug metabolizing enzyme systems.The adrenal weights were also lower in groups fed the new diet.The NTP–2000 diet prevented nephrocalcinosis and decreasedthe severity of nephropathy and cardiomyopathy, the common lesionsof F344 rats in 13–week studies. These results indicatethat the NTP–2000 diet is adequate for growth and maintenance of rats and appears to prevent or decrease the severityof diet-associated lesions.     

The Effect of Saline Iontophoresis on Skin Integrity in Human Volunteers: I. Methodology and Reproducibility

This study, conducted in 36 human volunteers, was an evaluationof the effects of saline iontophoresis on skin temperature,irritation, and barrier function. The major objectives wereto assess the effects of low-level ionic currents, to validatethe proposed methodology of assessment, and to establish reproducibilityin repeated saline iontophoresis applications. This was thefirst of a multistage study designed to assess the safety of24-hr saline iontophoresis episodes at selected currents andcurrent densities. Since an iontophoresis patch challenges theskin harrier both by occluding the skin surface and by passingionic current through the skin, the experimental protocol wasdesigned to permit measurement of the contribution of each ofthese processes to the overall response. In this first stagewe investigated the effect of 10 min of current delivery, at0.1 mA/cm² on a 1-cm² area patch and 0.2 mA/cm² on a 6.5-cm²area patch compared to unpowered control patches. Twelve subjectswere tested under each condition on two separate occasions toexamine reproducibility of the response variable measurements.A further 12 subjects were tested once under the 0.2 mA/cm 6.5-cm2condition. Skin irritation was evaluated via repeated measurementsof transepidermal water loss, capacitance, skin temperature,skin color, and a visual scoring system, before the iontophoresisepisode and after patch removal. No damage to skin harrier functionin terms of skin-water loss or skin-water content was detected.Slight, subclinical, short-lasting erythema was observed forboth conditions. Assessment of correlation coefficients showedhighly statistically significant indications of reproducibilityfor all five response variables measured. The experimental design,in combination with a repeated measures analysis, provided clearseparation of the occlusion and ionic current components ofthe iontophoretic patch challenge. Further, the repeated measuresanalysis gave a highly sensitive assessment of skin irritationand resolution after patch removal. We conclude that the experimentalmethodology is appropriate for assessing possible changes inskin integrity resulting from saline iontophoresis under similaroperating conditions for longer durations and for other skinchallenges from which a subclinical response is expected.     

A POSTOPERATIVE PROGNOSTIC NOMOGRAM FOR RENAL CELL CARCINOMA

PURPOSE: Few published studies have combined prognostic factors to predict the likelihood of recurrence after surgery for renal cell carcinoma. We developed a nomogram for this purpose. MATERIALS AND METHODS: With Cox proportional hazards regression analysis, we modeled pathological data and disease followup for 601 patients with renal cell carcinoma who were treated with nephrectomy. Predictor variables were patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathological stage. Treatment failure was recorded when there was either clinical evidence of disease recurrence or death from disease. Validation was performed with a statistical (bootstrapping) technique. RESULTS: Disease recurrence was noted in 66 of the 601 patients, and those in whom treatment was successful had a median and maximum followup of 40 and 123 months, respectively. The 5-year probability of freedom from failure for the patient cohort was 86% (95% confidence interval 82 to 89). With statistical validation, predictions by the nomogram appeared accurate and discriminating with an area under the receiver operating characteristic curve, that is a comparison of the predicted probability with the actual outcome of 0.74. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among patients with newly diagnosed renal cell carcinoma. The nomogram may be useful for patient counseling, clinical trial design and patient followup planning.     

PROSTATE CANCER DIAGNOSIS USING A SATURATION NEEDLE BIOPSY TECHNIQUE AFTER PREVIOUS NEGATIVE SEXTANT BIOPSIES

PURPOSE: We hypothesized that markedly increasing the number of cores obtained during prostate needle biopsy may improve the cancer detection rate in men with persistent indications for repeat biopsy. MATERIALS AND METHODS: We performed saturation ultrasound guided transrectal prostate needle biopsy in 224 men under anesthesia in an outpatient surgical setting in whom previous negative biopsies had been performed in the office. The mean number of previous sextant biopsy sessions plus or minus standard deviation before saturation biopsy was 1.8 (range 1 to 7). A mean of 23 saturation biopsy cores (range 14 to 45) were distributed throughout the whole prostate, including the peripheral, medial and anterior regions. Indications for repeat biopsy were persistent elevated serum prostate specific antigen (PSA) in 108 cases, persistent elevated PSA and abnormal rectal examination in 27, persistent abnormal rectal examination in 4, high grade prostatic intraepithelial neoplasia in the previous biopsy in 64 and atypia in the previous biopsy in 21. RESULTS: Cancer was detected in 77 of 224 patients (34%). The number of previous negative sextant biopsies was not predictive of subsequent cancer detection by saturation biopsy. Median PSA was 8.7 ng./ml. and median PSA velocity was 0.63 ng./ml. yearly. Of the 77 patients in whom cancer was detected radical prostatectomy was performed in 52. Pathological stage was pT2 in 48 patients and pT3 in 4, while Gleason score was 4 to 5, 6 to 7 and 8 in 5, 46 and 1, respectively. At prostatectomy median cancer volume was 1.04 cc and 85.7% of removed tumors were clinically significant, assuming a 3-year doubling time. The overall complication rate for saturation needle biopsy was 12% and hematuria requiring hospital admission was the most common event. CONCLUSIONS: Saturation needle biopsy of the prostate is a useful diagnostic technique in men at risk for prostate cancer with previous negative office biopsies. This technique allows adequate sampling of the whole prostate gland and has a detection rate of 34% in this cohort of patients.     

LOWER POLE I: A PROSPECTIVE RANDOMIZED TRIAL OF EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY AND PERCUTANEOUS NEPHROSTOLITHOTOMY FOR LOWER POLE NEPHROLITHIASIS—INITIAL RESULTS

PURPOSE: The efficacy of shock wave lithotripsy and percutaneous stone removal for the treatment of symptomatic lower pole renal calculi was determined. MATERIALS AND METHODS: A prospective randomized, multicenter clinical trial was performed comparing shock wave lithotripsy and percutaneous stone removal for symptomatic lower pole only renal calculi 30 mm. or less. RESULTS: Of 128 patients enrolled in the study 60 with a mean stone size of 14.43 mm. were randomized to percutaneous stone removal (58 treated, 2 awaiting treatment) and 68 with a mean stone size of 14.03 mm. were randomized to shock wave lithotripsy (64 treated, 4 awaiting treatment). Followup at 3 months was available for 88% of treated patients. The 3-month postoperative stone-free rates overall were 95% for percutaneous removal versus 37% lithotripsy (p <0.001). Shock wave lithotripsy results varied inversely with stone burden while percutaneous stone-free rates were independent of stone burden. Stone clearance from the lower pole following shock wave lithotripsy was particularly problematic for calculi greater than 10 mm. in diameter with only 7 of 33 (21%) patients becoming stone-free. Re-treatment was necessary in 10 (16%) lithotripsy and 5 (9%) percutaneous cases. There were 9 treatment failures in the lithotripsy group and none in the percutaneous group. Ancillary treatment was necessary in 13% of lithotripsy and 2% percutaneous cases. Morbidity was low overall and did not differ significantly between the groups (percutaneous stone removal 22%, shock wave lithotripsy 11%, p =0.087). In the shock wave lithotripsy group there was no difference in lower pole anatomical measurements between kidneys in which complete stone clearance did or did not occur. CONCLUSIONS: Stone clearance from the lower pole following shock wave lithotripsy is poor, especially for stones greater than 10 mm. in diameter. Calculi greater than 10 mm. in diameter are better managed initially with percutaneous removal due to its high degree of efficacy and acceptably low morbidity.     

Ruptured mitral chordae tendineae may be a frequent and insignificant complication in the mitral valve prolapse syndrome

In this study, we performed 512 echocardiographic studies on264 consecutive, unselected patients with the idiopathic mitralvalve prolapse syndrome. Twenty-eight patients (10.6%) had evidenceof ruptured chordae tendineae of the mitral valve on M-modeexamination and in 24 the diagnosis was confirmed by two-dimensionalechocardiography. Mild to severe mitral insufficiency was provenin all of them by left ventriculography during cardiac catheterization.Eight patients underwent surgery to relieve symptomatic severemitral regurgitation. At operation all had myxomatous degenerationof the mitral valve, two patients were found to have ruptureof anterior mitral chordae, and six had rupture of posteriormitral chordae. Twenty (71%) patients with chordal rupture hadeither mild symptoms or were completely asymptomatic. It isconcluded that chordal rupture in patients with the mitral valveprolapse syndrome may be present in asymptomatic patients andgo undetected clinically in a substantial number of patientsunless a high index of suspicion is maintained. Serial M-modeand two-dimensional echocardiographic studies are of importancein identifying the progression of prolapse findings and mayreveal the natural history of this pathologic condition in asymptomaticpatients.