Biomedical subjects
Publications and source records attributed to J P Long.
Metastasis of renal cell carcinoma (RCC) to the penis or spermatic cord is rare. We present an unusual case of initial metastasis to the cord with delayed involvement of the penis. This is the first report of metachronous involvement of the genitalia from RCC metastases.
PURPOSE: Several reports have documented that the MB isoenzyme of creatine kinase is present in prostatic tissue. However, since it has been shown that lower urinary tract manipulations, including transurethral prostatectomy, do not significantly increase serum creatine kinase isoenzyme MB levels, such elevations, which are found in patients after prostatic surgery, are believed to be specific for myocardial infarction. We examined whether cryosurgical ablation of the prostate altered serum creatine kinase or isoenzyme MB levels. MATERIALS AND METHODS: In 81 consecutive patients undergoing routine cryosurgical ablation of the prostate serum levels of creatine kinase and creatine kinase isoenzyme MB were measured from peripheral blood specimens drawn preoperatively, in the recovery room and at 8 and 24 hours postoperatively. Postoperative electrocardiograms were compared to the preoperative study. RESULTS: In 72 of 81 patients (89%) significant elevations in creatine kinase and creatine kinase isoenzyme MB levels were noted at all time points after cryosurgical ablation of the prostate and appeared to reach a peak at 16 hours postoperatively. The mean increases within the first 8 hours after cryosurgical ablation of the prostate were 1,355 units per 1. for creatine kinase and 46.6 ng./ml. for creatine kinase isoenzyme MB. No patient had any significant changes on the postoperative electrocardiogram. All 9 patients (11%) who did not have significant creatine kinase or creatine kinase isoenzyme MB levels after cryosurgery had undergone prior cryosurgery or combined radiation and hormonal therapy. CONCLUSIONS: Cryosurgical ablation of the prostate appears to produce elevations in serum creatine kinase and creatine kinase isoenzyme MB, which are specific to the procedure. Assays for creatine kinase isoenzyme MB are unreliable to render a diagnosis of myocardial infarction after cryosurgical ablation of the prostate.
It is impossible to adequately answer the question of whether there is a role for CSAP in the management of localized prostate carcinoma without considering the relative advantages and limitations of using other therapies to manage this disease (radical prostatectomy, radiation therapy, hormonal therapy, brachytherapy, expectant observation, and so on). Obviously, this is beyond the scope of this article. It is probably fair to point out, however, that the management of localized prostate carcinoma in the United States is generally quite controversial at the present time, and that despite a considerable amount of data pertaining to these therapeutic alternatives, it is difficult to discern a standard approach that can be broadly applied for all men with this disease. Therefore, if an absence of consensus on the management of localized prostate carcinoma does exist, it seems evident that investigations into alternative therapies are justified, and the preliminary results and efforts investigating CSAP fall well into this paradigm. In this context, several points can be made based on the available information. Significant numbers of patients who undergo CSAP can sustain undetectable levels of PSA for durable periods of time (more than 24 months). Thus, on a clinical level it seems possible to ablate the entire prostate with percutaneous CSAP, although rates of achieving this may be lower than originally anticipated. The reasons for persistence of carcinoma post CSAP are likely technical and related to the difficulties in determining the effective probe placements, number of probes to be used, number of freeze-thaw-freeze cycles to be used, and so on. Previous radiation exposure appears to confer an increased risk of CSAP-related morbidity, with incontinence, tissue sloughing, and rectal injury most prominent. Among nonradiated patients, incontinence is rare, and the most prominent postoperative concern involves BOO/tissue sloughing in a minority of patients. The longest follow-up data available on CSAP suggests that for patients with nonmetastatic prostate carcinoma, CSAP is associated with persistence of carcinoma in only 25% of patients. This compares favorably with the available biopsy data following external beam radiotherapy, in which most reports document positive biopsy results ranging between 30% and 100%, with the majority in the 40% to 50% range. Notably, the positive biopsy rate among patients with stage T3 disease following CSAP at 2 years can be less than 30%, which compares very favorably with previously reported positive biopsy result for these patients following external beam radiation therapy, which ranged between 40% and 100%. The management of patients with persistent carcinoma following CSAP poses fewer concerns to physicians than for those with persistent carcinoma following radiation therapy. Given the number of patients with prostate carcinoma who currently undergo radiotherapy as primary management, these data indicate that CSAP can now be considered a very viable therapeutic alternative for selected patients. With standardizations of technique as well as improved modifications in equipment, these preliminary CSAP results may well improve steadily in the near future. In the absence of randomized, comparative trials, it is difficult to draw meaningful comparisons between CSAP and radical prostatectomy. Based on available information, CSAP appears to be associated with a much lower incidence of stress and total incontinence than is radical prostatectomy. The rates of impotence following CSAP are somewhat comparable to those seen after radical prostatectomy, with wide variation among individual series. For patients who would be ideal candidates for radical prostatectomy (for example, less than stage T2c disease, PSA less than 10 ng/mL, and Gleason score of 7 or less), several authors have noted that the positive biopsy rate between 6 and 12 months is less than 10%.
The authors describe what appears to be the first case of transperitoneal marsupialization of a lymphocele following laparoscopic pelvic lymph node dissection. The 9.7 x 5.6 x 6-cm collection was opened, its edges were cauterized, and the internal membranes were resected with an operative time of 90 minutes and a blood loss of less than 30 mL. A multicenter trial may be useful to determine whether excision of a portion of the peritoneum or an inverted-V rather than a linear incision would decrease the incidence of lymphoceles after laparoscopic pelvic lymphadenectomy.
The 4-methyl piperidine analog (A-4) of hemicholinium-3 is a tertiary amine. A-4, like hemicholinium-3, inhibits sodium-dependent, high-affinity choline transport. The present study examined whether central cholinergic systems are involved in the expression of genetic hypertension. We examined the effects of i.v. and i.c.v. administration of A-4 in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; control). Basal mean arterial pressure and heart rate values were 108 +/- 4 mm Hg and 370 +/- 5 bpm in WKY and 167 +/- 5 mm Hg and 337 +/- 13 bpm in SHR. The i.v. injection of A-4 (5, 10 and 20 mumol/kg) evoked a dose-dependent decrease in MAP in SHR, but not in WKY. The maximal decrease in MAP was 18 +/- 6 mm Hg (P < .01) in SHR. Depressor responses appeared within 1 min and reached maximum within 10 min. The reductions in MAP were not associated with reductions in peripheral vascular resistances, suggesting that the hypotension was due to a reduction in cardiac output. The i.c.v. injection of A-4 (100 nmol/rat) significantly decreased MAP in SHR (-23.8 +/- 2.4 mm Hg, P < .01), but not in WKY. The maximal decrease in MAP appeared within 1 min and reached maximum 10 min later. These falls in MAP were associated with falls in vascular resistances, suggesting that the hypotension was due to peripheral vasodilation. This dose was ineffective when given i.v. in either strain. A-4-induced decreases in MAP were accompanied by significant tachycardia, which was maximal within 3 min of injection. These studies demonstrate that A-4 lowers MAP in SHR, but not in WKY. The rapid onset of hypotension in SHR after A-4 administration suggests that there is rapid turnover of brain acetylcholine which may be directly involved in maintaining elevated arterial pressure in SHR.
(R)- And (S)-11-hydroxy-10-methylaporphine 1 and 2 are, respectively, a potent, highly specific serotonergic (5-HT1A) agonist and antagonist. In an ongoing structure-activity study, racemates of the positional isomers 8-hydroxy-9-methyl- and 8-methyl-9-hydroxyaporphine were prepared by modifications of literature methods and were resolved. The methyl ethers of the target compounds were also evaluated pharmacologically. All of the free phenolic derivatives [(+)- and (-)-8 and 10] were inert in an assay for 5-HT1A receptor activity. All of the methyl ethers [(+)- and (-)-9 and 11] demonstrated quantitatively similar low potency stimulant effect at 5-HT1A receptors. The agonist or antagonist activity exhibited by 1 and 2 reflects the high degree of structural specificity required of aporphine derivatives for action at 5-HT1A receptors.
The most common genetic aberration seen in nonpapillary renal cell carcinoma is believed to be the loss or inactivation of allelic material on the short arm of chromosome 3 (3p). Two patients underwent nephrectomy at our institution, each initially receiving a histologic diagnosis of renal cell carcinoma. Molecular analysis of these tissues revealed no genetic deletion on 3p, prompting further histologic and immunohistochemical evaluation of the original specimens. These additional studies confirmed alternate histologies other than renal cell carcinoma in each case. These data suggest that the loss of genetic material on the short arm of chromosome 3 may be specific for nonpapillary renal cell carcinoma. Molecular analysis may prove to be a useful adjunct in establishing the diagnosis in renal neoplasms with equivocal histologies.
In this article we review noradrenergic activities of nitroglycerin in the central and peripheral nervous systems. Nitroglycerin may cause paradoxical bradycardia and occasional life threatening hypotension in patients. Intracisternal injections and microinjections of nitroglycerin into nucleus tractus solitarii produce hypotension and bradycardia, effects which mimic the baroreflex and may involve central noradrenergic mechanisms. The drug also triggers an alpha 2-adrenoceptor-mediated sympatho-inhibition reflex through vagal afferents. Nitroglycerin mimics biological responses associated with sympathetic neuronal activity, e.g., increase in outflow of norepinephrine and its metabolites from perfused guinea pig atria, medulla-pons tissue and cerebrospinal fluid. The sympathomimetic effects of nitroglycerin are antagonized by pre-treatment with yohimbine or rauwolscine. Clinical studies and animal experiments show that hemodynamics of nitroglycerin and sodium nitroprusside are different. Nitroglycerin is lipophilic and the compounds readily enters cells to form nitric oxide, but sodium nitroprusside is very hydrophilic and the compound has difficulty crossing membranes. Thus, intravenous nitroglycerin-induced increases in central noradrenergic activation and inhibitory reflexes may account for at least some of the therapeutic actions and side effects of the drug. In contrast, minimal central responses are produced by intravenous administration of sodium nitroprusside.
p-Dimethoxyaryl analogs of certain potent catechol-derived dopaminergic agonists show dopaminergic properties for which no structure-activity relationship has yet been defined. (S)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine (1, S-"3-PPP") is a dopaminergic autoreceptor agonist, and at high doses it also exhibits postsynaptic antagonism. (R)-1 is a postsynaptic agonist. In a continuation of studies of effects of the p-dimethoxy moiety at dopamine receptors, synthesis and resolution of the 2,5-dimethoxy analog 3 of 3-PPP was undertaken. The two enantiomers and the racemic modification showed cardiovascular effects consistent with actions at DA-2 receptors. The potency of all three compounds was much lower than that of 3-PPP, although they displayed approximately the same duration of action. Absolute configuration does not seem to be a major determinant of these compounds' ability to interact with DA-2 receptors.
The subject compounds were prepared as a part of a continuing structure-activity study of the contrasting actions (agonism-antagonism) of (+)- and (-)-11-hydroxy-10-methylaporphine at serotonin (5-HT1A) receptors. None of the targeted nonoxygenated aporphine derivatives demonstrated significant activity in assays for any effects at serotonin 5-HT1A receptors. It is concluded that, in the aporphine series, serotonergic agonist or antagonism requires an alkyl group ortho to a phenolic OH group in the A ring.
The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively.
The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expanding. Among patients who achieve significant responses to these regimens the subsequent development of isolated recurrences raises difficult management questions. We report 2 unusual cases of isolated recurrence in the remaining kidney following a sustained, complete response to interleukin-2 based adoptive immunotherapy. Both patients were treated with interleukin-2 based therapy following surgical resection of the primary renal tumor. The disease course of each patient is described and the literature is reviewed. Both patients were free of disease after relatively short-term followup. Surgery for patients with limited recurrence of renal cell carcinoma following an objective response to immunotherapy may, in select cases, be a reasonable treatment alternative.
Nitroglycerin (NTG) may cause paradoxical bradycardia and occasional life-threatening hypotension. The mechanism is unclear. In this study, we compared the cardiovascular responses of sodium nitroprusside (SNP) with that of NTG in rats with sinoaortic deafferentation (SAD). Intravenous (i.v.) injection of SNP and NTG produced dose-dependent decreases in mean arterial pressure (MAP). SNP was more effective than NTG in increasing heart rate (HR). After SAD, tachycardiac responses to i.v. SNP were abolished, but i.v. NTG caused bradycardia. SAD enhanced the hypotensive responses of both NTG or SNP after i.v. administration. The bradycardic and hypotensive effects of NTG were attenuated by either bilateral vagotomy or intracisternal (i.c.) pretreatment with 20 nmol rauwolscine, but the responses were not altered by i.v. atropine methylbromide (M-atropine), 0.6 mumol. In contrast, cardiovascular responses to i.v. SNP after SAD were not altered by these pretreatments. Tachycardiac responses to intracerebroventricular (i.c.v.) injection of NTG were reduced by SAD, but SAD did not alter bradycardic responses to i.c. injection of NTG. These results suggest that NTG induces inhibitory reflexes that may contribute to its complex cardiovascular responses in rats. The drug may stimulate peripheral sensory receptors with vagal afferents to the medulla, which then triggers an alpha 2-adrenoceptor-mediated sympathoinhibition.
A model whereby a known number of coagulase-negative staphylococci were packed into capillary tubes and implanted into the peritoneal cavity of mice proved to be a satisfactory method for generating abscesses that could be easily removed free of extraneous host tissue, and that permitted measurement of the survival of the organisms and accumulation of lipid in the lesion. Strains of S. epidermidis, S. schleiferi and S. lugdunensis, differing in their ability to produce fatty acid modifying enzyme (FAME) and lipase, were packed into either glass or plastic capillary tubes and used to generate abscesses. Abscesses produced by S. aureus served as comparators. Lipids accumulated within the abscesses caused by S. aureus in the same manner as previously described for the organism inoculated without tubes. Lipids also accumulated within abscesses produced by all the coagulase-negative staphylococci, but the rate of accumulation was slower and the lipid droplets were smaller than seen with S. aureus. The mobilisation of lipid did not differ in response to cocci in plastic or glass tubes. Strains of S. epidermidis and S. schleiferi producing FAME and lipase were better able to survive within abscesses than strains unable to produce these enzymes. However, FAME and lipase production did not appear to be the sole determinants of survival within abscesses. Regardless of whether they produced FAME and lipase, the two S. epidermidis strains were significantly better able to survive within plastic tubes than in glass tubes. No such difference was seen with S. aureus between plastic and glass tubes.
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The usefulness of serum acid phosphatase (SAP) in monitoring patients with advanced prostate carcinoma has been questioned. We reviewed a series of 59 patients with stage D2 prostate carcinoma. All patients had extended follow-up through at least one clinical relapse, or death. Responses to a variety of therapies were characterized as absent, subjective, or objective. All patients with an elevated pre-treatment SAP that fell to normal following therapy had prolonged survivals and improved prognoses. Conversely, all patients with an elevated SAP which did not normalize following therapy had poorer survivals. Among 36 objective responses to therapy, the SAP was elevated prior to or simultaneous with disease progression in 33 (93% sensitivity). In each ease where the pretreatment SAP normalized following therapy, any subsequent elevation in SAP above normal was always associated with clinical evidence of disease progression (100% specificity). Changes in SAP following therapy correlate well with both disease regression and disease progression in patients with advanced prostatic carcinoma.
5-Methoxy-1-methyl-4-(2-N,N-di-n-propylaminoethyl)indole (12) was synthesized from 5-hydroxyindole by a multistep synthesis. This target compound was designed as a bioisostere of "p-dimethoxy" catechol congeners of dopaminergic agonists derived from a variety of ring systems, in some of which p-dimethoxy-substituted systems are potent, active dopaminergic agonists. To complete the indole series, all possible combinations of N- and O-demethylated derivatives of 12 were prepared and were also evaluated pharmacologically. All members of this indole-derived series showed a low order of cardiovascular activity, which appeared to be independent of dopamine receptors. The lack of dopaminergic activity of 12 is cited as yet another example of the unpredictable effect of replacement of the catechol moiety of a dopaminergic agonist with a p-dimethoxy moiety.