Transanal Endoscopic Microsurgery (TEM) for rectal GI stromal tumor.

BACKGROUND: Transanal endoscopic microsurgery (TEM) is effective in treating adenomas and select early rectal cancers. Our objective is to evaluate TEM in treating early rectal GISTs. METHODS: Patients were identified in a prospective database with pathology confirmed rectal GIST prior to TEM over 10 years. Demographic, pathologic, operative and follow-up data was analysed and presented with descriptive statistics. RESULTS: 7 cases of rectal GIST were treated with TEM with a follow-up time of 31 months (0-71). Median tumor distance from the anal verge was 4 cm (2.5-6) and median tumor size was 3 cm (2-5.7). Negative margins were achieved in 4/7 patients. Those with positive margins were treated with repeat TEM or imatinib. 1 patient had local recurrence successfully treated by TEM. CONCLUSIONS: Overall, TEM is safe for locally excising GISTs. As rectal GISTs are rare, a multicenter registry may better elucidate outcomes with this treatment.

Can nomograms improve our ability to select candidates for active surveillance for prostate cancer?

BACKGROUND: Our goal was to compare the ability of active surveillance (AS) criteria and preoperative nomograms to identify patients with pathologically low-risk prostate cancer. METHODS: The study cohort consisted of 402 radical prostatectomy patients with Gleason 6 prostate cancer on at least 10-core biopsy. In this group, we analyzed the ability of Kattan and Truong nomograms to select patients with Gleason 3+3 or 3+4 organ-confined prostate cancer, and compared it with that of AS criteria of John Hopkins (JH) and University of California at San Francisco (UCSF) medical centers, and Prostate Cancer Research International: Active Surveillance (PRIAS) study. The performance of each tool was evaluated with respect to discrimination and predictive accuracy. RESULTS: About 30% of patients were upgraded and 8% were upstaged in the final pathology. The nomograms demonstrated slightly higher discrimination in detecting organ-confined Gleason 3+3 and 3+4 disease. The predictive accuracy of the nomograms in selecting patients with low-grade organ-confined prostate cancer was superior to that of JH and UCSF criteria but not to PRIAS criteria. Furthermore, the nomograms were unable to select larger subgroups of patients with the same prevalence of Gleason 3+3 organ-confined prostate cancer as in men who met the PRIAS criteria. No difference was seen between the studied nomograms and AS criteria in their ability to identify patients with Gleason 3+4 organ-confined prostate cancer. CONCLUSIONS: PRIAS criteria demonstrate optimal balance between sensitivity and specificity and are not inferior to the available pathological nomograms in selecting patients with low-grade organ-confined prostate cancer.

Nationally representative trends and geographic variation in treatment of localized prostate cancer: the Urologic Diseases in America project.

BACKGROUND: Several treatment options for clinically localized prostate cancer currently exist under the established guidelines. We aim to assess nationally representative trends in treatment over time and determine potential geographic variation using two large national claims registries. METHODS: Men with prostate cancer insured by Medicare (1998-2006) or a private insurer (Ingenix database, 2002-2006) were identified using International Classification of Diseases-9 and Current Procedural Terminology-4 codes. Geographic variation and trends in the type of treatment utilized over time were assessed. Geographic data were mapped using the GeoCommons online mapping platform. Predictors of any treatment were determined using a hierarchical generalized linear mixed model using the logit link function. RESULTS: The use of radical prostatectomy increased, 33-48%, in the privately insured i3 database while remaining stable at 12% in the Medicare population. There was a rapid uptake in the use of newer technologies over time in both the Medicare and i3 cohorts. The use of laparoscopic-assisted prostatectomy increased from 1% in 2002 to 41% in 2006 in i3 patients, whereas the incidence increased from 3% in 2002 to 35% in 2006 for Medicare patients. The use of neoadjuvant/adjuvant androgen deprivation therapy was lower in the i3 cohort and has decreased over time in both i3 and Medicare. Physician density had an impact on the type of primary treatment received in the New England region; however, this trend was not seen in the western or southern regions of the United States. CONCLUSIONS: Using two large national claims registries, we have demonstrated trends over time and substantial geographic variation in the type of primary treatment used for localized prostate cancer. Specifically, there has been a large increase in the use of newer technologies (that is, laparoscopic-assisted prostatectomy and intensity-modulated radiation therapy). These results elucidate the need for improved data collection on prostate cancer treatment outcomes to reduce unwarranted variation in care.

Active surveillance: does serial prostate biopsy increase histological inflammation?

BACKGROUND: Active surveillance (AS) is an appropriate management strategy for men with low-risk prostate cancer. Most protocols recommend repeated prostate biopsy every 12-24 months. The purpose of this paper is to describe histological inflammation patterns in men on AS who underwent serial prostate biopsy for disease monitoring. METHODS: We reviewed records of men on AS from January 1999 through February 2011 who had a diagnostic plus ≥1 repeat transrectal ultrasound-guided biopsies performed at our institution. The type and degree of inflammatory infiltrate were grossly reviewed and scored for each patient's biopsy by a single pathologist. Relationship of inflammation severity and number of serial biopsies was assessed using a repeated measures mixed model. Unpaired t-test and χ(2)-square analysis assessed variance in degree of inflammation and location of inflammation relative to cancer grade progression defined as Gleason sum increase. RESULTS: Fifty-six men met study inclusion criteria. Mean age was 62.1 (6.5) years, 71% were stage cT1c, 79% had a PSA level <10 ng ml(-1), and 98% had diagnostic Gleason sum ≤6. A small, statistically significant increase in maximum chronic inflammation (CI) scores with greater number of repeat biopsies was observed. CI scores were not associated with number of biopsies based on upgrade status. The main limitation to our study is our small sample size. Potential unmeasured confounders, such as unreported antibiotic use or symptomatic prostatitis, may have also affected our findings. CONCLUSIONS: In this pilot study of 56 men on AS for localized prostate cancer, degree of chronic histological inflammation increased with greater number of prostate biopsies, but was not associated with subsequent risk of grade progression.

Ventrolateral medullary pressor area: site of hypotensive action of clonidine.

Intravenous injections of clonidine produce an initial transient increase in blood pressure followed by a long-lasting hypotension and bradycardia. The initial pressor response is due to activation of vascular alpha 1-adrenergic receptors while the hypotension and bradycardia are caused by the central actions of clonidine. Although, hypothalamus, nucleus tractus solitarius (NTS), ventrolateral medulla and the intermediolateral cell column of the thoracolumbar spinal cord (IML) have been implicated, the exact site of these actions of clonidine in the central nervous system is not established. The results of this investigation suggest that the pressor area in the ventrolateral medulla (VLPA) is the site of hypotensive and bradycardic actions of intravenously administered clonidine. This conclusion is based on the observation that microinjections of idazoxan, a specific alpha 2-adrenergic receptor blocker, into the VLPA prevented and reversed the hypotension and bradycardia despite the fact that other proposed sites of these actions (NTS, hypothalamus and IML) were intact and accessible to intravenously administered clonidine.

Cardiovascular responses to medullary microinjections of opiate agonists in urethane-anesthetized rats.

Pressor (VLPA) and depressor (VLDA) areas of the ventrolateral medulla were identified by microinjections of L-glutamate in urethane-anesthetized rats. Cardiovascular effects of opiate agonists microinjected into the same sites were then studied. Agents used to stimulate mu, delta, sigma, kappa, and beta-endorphin (epsilon) receptors were morphiceptin, D-Ala2-D-Leu5-enkephalin, N-allyl-normetazocine, dynorphin, and beta-endorphin, respectively. Opiate receptor stimulation in VLPA decreased blood pressure (BP) and heart rate (HR), while in VLDA it increased BP and HR. Thus, it is the site of injection rather than the type of opiate receptor that determines cardiovascular responses. Naloxone, an opiate antagonist, reversed and prevented these responses. Abolition of cardiovascular responses by spinal transection at the C1 level indicated that the sympathetic nervous system mediated these responses. The following mechanism is proposed for these actions of opiates: Cell bodies in VLPA, but not in VLDA, project to the intermediolateral cell column of the spinal cord. Opiates inhibit VLPA and lower BP and HR by decreasing sympathetic outflow. Opiate-induced inhibition of VLDA, which has an inhibitory effect on VLPA, results in an increase in BP and HR.

Medullary pressor area: site of action of intravenous physostigmine.

Physostigmine, a choline-esterase inhibitor, is known to elevate endogenous levels of acetylcholine. Intravenously administered physostigmine causes a rise in blood pressure via its action in the central nervous system. Exact site of this action of physostigmine is not known. In this paper, it was demonstrated that microinjections of tetrodotoxin (a fast sodium channel blocker), lidocaine (a local anesthetic) and scopolamine (a cholinergic muscarinic receptor blocker) into the rostral ventrolateral medullary pressor area abolished the pressor action of intravenously administered physostigmine. These results demonstrate that the rostral ventrolateral medulla is the site of action of intravenously administered physostigmine and this action is mediated via cholinergic muscarinic receptors.

Blockade of cholinergic receptors in the C1 area abolishes hypertensive response to opiates in the A1 area of the ventrolateral medulla.

Opiate receptor stimulation by microinjections of a delta-receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE) into the caudal depressor (A1) area of the ventrolateral medulla produced a hypertensive response which was prevented as well as reversed by the blockade of cholinergic receptors in the rostral pressor (C1) area. These results suggest that the hypertensive responses to opiates in the A1 area are mediated via cholinergic mechanisms in the rostral C1 area of the ventrolateral medulla and acetylcholine may be the neurotransmitter released in the ventrolateral pressor area.

Cardiovascular control by cholinergic mechanisms in the rostral ventrolateral medulla.

The cardiovascular effects associated with the microinjection (100 nl) of carbachol, physostigmine and atropine into the pressor area in the ventrolateral medulla (VLPA) were studied. In urethane anesthetized rats, VLPAs were functionally identified bilaterally by microinjection of the neuroexcitatory amino acid L-glutamate (300 ng/site). L-Glutamate microinjections into the VLPA cause a transient rise in blood pressure (BP) and heart rate (HR). The bilateral microinjection of carbachol into the VLPA caused a prolonged dose-related increase in BP and HR in the dose range of 0.8 to 400.0 ng/site. At higher doses (1-10 micrograms), carbachol caused a decrease in BP and HR; indicative of depolarization blockade. Acetylcholine esterase inhibition by physostigmine microinjections in the VLPA caused cardiovascular effects similar to those observed with carbachol. The hypertensive responses evoked by muscarinic receptor stimulation in the VLPA were mediated by increasing sympathetic outflow. The pathway by which cholinergic receptor stimulation in the VLPA activates vasomotor outflow appears to be entirely descending as coronal knife cuts at the level of the trapezoid body failed to alter the hypertensive responses. Pressor responses elicited by both physostigmine and carbachol were reversed completely by the i.v. administration of atropine sulfate (0.5-3 mg/kg i.v.). Muscarinic receptor blockade in the VLPA after atropine sulfate microinjection caused a dose-related (0.4-15.0 micrograms/site) fall in the BP and HR suggesting that cholinergic mechanisms in the VLPA are tonically active.

Interdependence of rostral and caudal ventrolateral medullary areas in the control of blood pressure.

Pharmacologic experiments were carried out to test the degree of interdependence of rostral vasopressor and caudal vasodepressor neuron pools in the ventrolateral medulla (VLPA and VLDA, respectively). In two groups of urethane-anesthetized rats, the gamma-aminobutyric acid (GABA) agonist muscimol (10 ng/site) was bilaterally microinjected into both the VLPA and VLDA to inhibit neuronal activity at these sites. In one group of experiments, muscimol was microinjected first into the VLPA and then into the VLDA. Following muscimol microinjection in the VLPA the mean arterial pressure (MAP) and heart rate (HR) decreased to 40 +/- 6 mm Hg and 310 +/- 21 beats/min (bpm) from a control level of 90 +/- 3 mm Hg and 403 +/- 23 bpm. Subsequent microinjection of muscimol in the VLDA had no significant effect on BP or HR. This lack of response was not due to severe fall in BP caused by microinjection of muscimol into the VLPA. In the second group of experiments muscimol was first injected into the VLDA followed by muscimol microinjection into the VLPA. In the VLDA muscimol significantly increased MAP and HR to 139 +/- 4 mm Hg and 427 +/- 4 bpm from a control level of 87 +/- 2 mm Hg and 356 +/- 23 bmp. The aortic depressor nerve response (-37 +/- 1 mm Hg and -47 +/- 4 bpm) was converted to an aortic 'pressor' response (+20 +/- 1 mm Hg and -13 +/- 6 bpm). Subsequent microinjection of muscimol into the VLPA caused MAP and HR to fall to 43 +/- 5 mm Hg and 338 +/- 17 bpm. The aortic 'pressor' response was also abolished (2 +/- 2 mm Hg). These results indicate that neuronal activity in the rostral VLPA is an important determinant for changes in BP and its reflex regulation mediated by the VLDA. However, BP changes mediated by the rostral VLPA are independent of the level of neuronal activity in the VLDA. Sites of VLPA and VLDA interaction are discussed.

Cardiovascular response to injections of enkephalin in the pressor area of the ventrolateral medulla.

The cardiovascular effects of the injection of an enkephalin analogue, [D-ala2-met5]enkephalinamide (DAME) into the pressor area of the rostral ventrolateral medulla were studied in urethane-anesthetized and decerebrate rats. The excitatory amino acid L-glutamate was used to identify the ventrolateral medulla. The pressor responses to L-glutamate were elicited from an area that included the nucleus reticularis gigantocellularis, the medial aspect of the nucleus reticularis parvocellularis and the dorsal portion of the nucleus reticularis lateralis. Injection (0.1 microliter volume) of DAME (2.5-500.0 ng/site) into the ventrolateral medulla elicited a dose-related decrease in arterial blood pressure and heart rate and attenuated the carotid occlusion response (COR). Control injections (0.1-0.2 microliter vol) of saline into the same area failed to produce any response. The specificity of this opiate response was tested with naloxone HCl, an opiate antagonist, which prevented, as well as reversed, the action of DAME both by intravenous (i.v.) administration and by injection into the ventrolateral medulla. It was concluded that the ventrolateral medulla plays a role in the generation of vasomotor tone and that stimulation of opiate receptors in this area by an enkephalin analogue produced hypotension, bradycardia and modification of cardiovascular reflexes.

Hypertensive response following stimulation of opiate receptors in the caudal ventrolateral medulla.

In urethane-anesthetized rats, vasodepressor neuron pools were located bilaterally in and adjacent to the A1 area of the ventrolateral medulla by injecting the neuroexcitatory amino acid, L-glutamate. Ventrolateral vasodepressor areas included the caudalateral part of the nucleus reticularis gigantocellularis, the rostrolateral part of the nucleus reticularis ventralis, and the dorsal nucleus reticularis lateralis. In the ventrolateral vasodepressor areas L-glutamate elicited a transient fall in blood pressure (BP) and heart rate (HR). The opiate agonist (D-ala2-met5)-enkephalinamide (DAME) was used to stimulate opiate receptors in vasodepressor sites, identified with L-glutamate. In these sites, bilateral injections (0.1 microliter/site) of DAME caused a dose-related (2.5-500.0 ng) increase in blood pressure and heart rate, as well as exaggeration of the response to occlusion of the carotid. The effects of DAME on blood pressure were completely abolished by alpha-adrenergic blockade (phentolamine, 2 mg/kg, i.v.) and all effects of DAME were reversed by the administration of naloxone HCl (1 mg/kg, i.v.). Naloxone reversal was accompanied by an unexpected "rebound" hypertension. Saline had no significant effects when injected, or administered intravenously, in the absence or presence of DAME. It was concluded that stimulation of opiate receptors in the ventrolateral vasodepressor areas activated sympathetic outflow. An enkephalinergic system in this area of the brain stem may serve to modulate blood pressure, heart rate and cardiovascular reflexes.

Cardiac vagolytic action of some neuromuscular blockers.

Cardiac vagolytic effect of four commonly used neuromuscular blockers, (viz. D-tubocurarine, decamethonium, pancuronium and gallamine) was compared in midcollicular decerebrate rats. The intravenous doses of neuromuscular blockers used (d-tubocurarine: 0.1 mg/kg; decamethonium: 2 mg/kg; pancuronium: 0.1 mg/kg; gallamine: 20 mg/kg) were sufficient to produce the paralysis of respiratory muscles. Bradycardia was induced by electrical stimulation of the vagus or by injecting dimethyl-phenyl-piperazinium (DMPP; a ganglionic stimulant). It was observed that d-tubocurarine and decamethonium were devoid of cardiac vagolytic action. On the other hand, pancuronium and gallamine inhibited significantly the bradycardia induced by electrical stimulation of the vagus or injection of DMPP; gallamine was found to have greater vagolytic action. The pressor responses to DMPP were not attenuated by pancuronium and gallamine indicating that in the dose administered, these agents did not block the ganglia. Bradycardia induced by the administration of acetylcholine in the left atrium was also attenuated by pancuronium and gallamine suggesting that the drugs produce cardiac vagolytic action by acting on the post-synaptic cholinergic receptors of the heart.