Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Choice of endpoints in antiplatelet trials: which outcomes are most relevant to stroke patients?

The relative efficacies of different antiplatelet agents for stroke prevention are unclear because of differences in clinical trial design, a lack of direct comparisons between individual agents, and differences in the choice of primary endpoints. Individual endpoints in a clinical trial are often combined into a single primary endpoint cluster. Theoretically, a combined endpoint may reduce the sample size required to demonstrate significant benefits of an effective therapy. However, unless all components of a composite endpoint are affected in the same direction and to a similar degree, their inclusion may not provide the anticipated increase in statistical power. In fact, the use of a combined endpoint may lead to an underestimate of therapeutic benefits when patients at high risk for one particular endpoint are studied. For patients with stroke or TIA, the single outcome of stroke is particularly important because these patients have a higher risk of recurrent stroke than any other vascular outcome during the initial years after a stroke. Because of the low incidence of myocardial infarction (MI) in stroke trials, the inclusion of MI in the primary endpoint will usually have minimal influence on trial outcome, and antiplatelet therapy has not been shown to be beneficial in preventing nonvascular death. Chance variations in the incidence of MI or death may detract from the benefit of the agent for stroke prevention when it is included in a combined endpoint. The benefit of antiplatelet therapies for patients with recent cerebrovascular events is determined most accurately if stroke alone is chosen as the primary endpoint.     

Selfotel in acute ischemic stroke : possible neurotoxic effects of an NMDA antagonist

BACKGROUND AND PURPOSE: Based on neuroprotective efficacy in animal models, we evaluated the N-methyl D-aspartate antagonist Selfotel in patients with ischemic stroke, after doses up to 1.5 mg/kg were shown to be safe in phase 1 and phase 2a studies. METHODS: Two pivotal phase 3 ischemic stroke trials tested the hypothesis, by double-blind, randomized, placebo-controlled parallel design, that a single intravenous 1.5 mg/kg dose of Selfotel, administered within 6 hours of stroke onset, would improve functional outcome at 90 days, defined as the proportion of patients achieving a Barthel Index score of >/=60. The trials were performed in patients aged 40 to 85 years with acute ischemic hemispheric stroke and a motor deficit. RESULTS: The 2 trials were suspended on advice of the independent Data Safety Monitoring Board because of an imbalance in mortality after a total enrollment of 567 patients. The groups were well matched for initial stroke severity and time from stroke onset to therapy. There was no difference in the 90-day mortality rate, with 62 deaths (22%) in the Selfotel group and 49 (17%) in the placebo-treated group (RR=1.3; 95% CI 0.92 to 1.83; P=0.15). However, early mortality was higher in the Selfotel-treated patients (day 30: 54 of 280 versus 37 of 286; P=0.05). In patients with severe stroke, mortality imbalance was significant throughout the trial (P=0.05). CONCLUSIONS: Selfotel was not an effective treatment for acute ischemic stroke. Furthermore, a trend toward increased mortality, particularly within the first 30 days and in patients with severe stroke, suggests that the drug might have a neurotoxic effect in brain ischemia.     

Predictors of occult metastasis in clinical stage I nonseminoma: a systematic review.

PURPOSE: Patients with clinical stage I nonseminomatous testicular germ cell tumor should ideally receive adjuvant therapy only when they are at high risk for occult metastasis. We aimed to quantify the importance of predictors for occult metastasis by performing a systematic review of the relevant literature. In addition, we reviewed published multivariable models and risk-adapted treatment policies. PATIENTS AND METHODS: We identified 23 publications between 1979 and 2001, reporting a total of 2,587 patients. Twenty-nine percent of the patients (759 of 2,587 patients) had occult metastases, which was diagnosed either at retroperitoneal lymph node dissection (n = 193) or during follow-up (n = 566). Odds ratios (OR) were pooled using meta-analysis techniques. RESULTS: The presence of vascular invasion of the primary tumor cells had the strongest effect (OR, 5.2; 95% CI, 4.0 to 6.8). Immunohistochemical staining of the primary tumor cells with the MIB-1 monoclonal antibody showing proliferative activity was a promising predictor (OR, 4.7; 95% CI, 2.0 to 11). Intermediate effects were found for embryonal carcinoma in the primary tumor (OR, 2.9; 95% CI, 2.0 to 4.4) and a high pathologic stage of the tumor (OR, 2.6; 95% CI, 1.8 to 3.8). Size of the primary tumor and age of the patient had weaker though also statistically significant associations with occult metastasis. Until now, multivariable models often included vascular invasion and embryonal carcinoma with one or two weaker predictors. None of the published risk-adapted treatment policies included MIB-1 staining. CONCLUSION: Several strong predictors for occult metastasis were identified. A risk-adapted treatment policy should be developed that incorporates all relevant predictors so that adjuvant therapy is targeted better to those with occult metastases.     

Treatment of localized prostate cancer using a combination of high dose rate Iridium‐192 brachytherapy and external beam irradiation: Initial Australian experience

Combination high dose rate brachytherapy (HDRB) and external beam radiation therapy is technically and clinically feasible as definitive treatment for localized prostate cancer. We report the first large Australian experience using this technique of radiation dose escalation in 82 patients with intermediate‐ and high‐risk disease. With a median follow up of 3 years (156 weeks), complications were low and overall prostate‐specific antigen progression‐free survival was 91% using the American Society for Therapeutic Radiology and Oncology consensus definition. The delivery of hypofractionated radiation through the HDRB component shortens overall treatment time and is both biologically and logistically advantageous. As a radiation boost strategy, HDRB is easy to learn and could be introduced into most facilities with brachytherapy capability.     

Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

PURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS: Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION: Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.     

Intestinal permeability in kwashiorkor

Intestinal permeability can be assessed non-invasively using the lactulose-rhamnose (L-R) test, which is a reliable measure of small intestinal integrity. AIMS: To determine risk factors for abnormal intestinal permeability in kwashiorkor, and to measure changes in L-R ratios with inpatient rehabilitation. DESIGN: A case-control study of 149 kwashiorkor cases and 45 hospital controls. The L-R test was adapted to study kwashiorkor in Malawi, with testing at weekly intervals during nutritional rehabilitation. Urine sugars were measured by thin layer chromatography in London. RESULTS: The initial geometric mean L-R ratios (x100) (with 95% confidence interval) in kwashiorkor were 17.3 (15.0 to 19.8) compared with 7.0 (5.6 to 8.7) for controls. Normal ratios are < 5, so the high ratios in controls indicate tropical enteropathy syndrome. Abnormal permeability in kwashiorkor was associated with death, oliguria, sepsis, diarrhoea, wasting and young age. Diarrhoea and death were associated with both decreased L-rhamnose absorption (diminished absorptive surface area) and increased lactulose permeation (impaired barrier function) whereas nutritional wasting affected only L-rhamnose absorption. Despite, clinical recovery, mean L-R ratios improved little on treatment, with mean weekly ratios of 16.3 (14.0 to 19.0), 13.3 (11.1 to 15.9) and 14.4 (11.0 to 18.8). CONCLUSION: Abnormal intestinal permeability in kwashiorkor correlates with disease severity, and improves only slowly with nutritional rehabilitation.