A Phase II trial of 8 weeks of degarelix for prostate volume reduction: Efficacy and hormonal recovery.

PURPOSE: The purpose of this study was to determine the efficacy of 8 weeks of degarelix for prostate downsizing before interstitial brachytherapy. We also report associated toxicity and the time course of endocrine recovery over the following 12 months. METHODS AND MATERIALS: Fifty patients were accrued to an open-label Phase II clinical trial (www.clinicaltrials.gov ID NCT01446991). Baseline prostate transrectal ultrasound (TRUS) was performed on all patients followed by degarelix administration and a repeat TRUS at Week 8. Brachytherapy was performed within 4 weeks of the 8-week TRUS for all patients who achieved suitable downsizing. RESULTS: The median prostate volume was reduced from 65.0 cc (interquartile range [IQR]: 55.2-80.0 cc) to 48.2 cc at 8 weeks (IQR: 41.2-59.3 cc), representing a median decrease of 26.2% (IQR: 21-31%). Functional recovery of testosterone within an age-adjusted normal range occurred at a median of 34.1 weeks (IQR: 28.2-44.5 weeks) from the date of the final injection. Despite this recovery, follicle-stimulating hormone and luteinizing hormone levels remained abnormally elevated throughout 12 months. Quality-of-life implications are discussed. CONCLUSIONS: Degarelix is effective for prostate downsizing before prostate brachytherapy with a median volume decrease of 26.2% by 8 weeks. Despite the short course of treatment and eventual testosterone recovery, follicle-stimulating hormone and luteinizing hormone remain elevated beyond 12 months. Further investigation with randomized comparisons to other hormonal agents is warranted.

Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects.

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, and a key neurotransmitter in prefrontal cortical function. Converging lines of evidence implicate prefrontal cortical dysfunction in the neurobiology of schizophrenia. Thus, aberrant glutamate neurotransmission may underlie schizophrenia and other complex disorders of behavior. Group II metabotropic receptors (mGluRs) are important modulators of glutamatergic and non-glutamatergic neurotransmission. Moreover, in an animal model, an agonist for group II mGluRs has been shown to reverse the behavioral, locomotor, and cognitive effects of the psychotomimetic drug phencyclidine. Accordingly, group II mGluRs constitute attractive targets for the pharmacotherapeutics and study of schizophrenia. Using immunocytochemistry and Western immunoblotting, we compared the localization and levels of group II mGluRs in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Consistent with previous reports, we found that immunolabeling of group II mGluRs is prominent in Brodmann's area 46. The majority of labeling was present on axon terminals distributed in a lamina-specific fashion. No apparent difference in the cellular localization or laminar distribution of immunoreactive group II mGluRs was noted between the two diagnostic groups. Similarly, the levels of receptor immunoreactivity determined by quantitative Western immunoblotting were comparable between schizophrenic patients and normal subjects. We conclude that while the function of group II mGluRs in Brodmann's area 46 of dorsolateral prefrontal cortex may be altered in patients with schizophrenia, this is not evident at the level of protein expression using an antibody against mGluR2 and mGluR3.

Reliability of the lumbar flexion, lumbar extension, and passive straight leg raise test in normal populations embedded within a complete physical examination.

STUDY DESIGN: The study measured the reliability of the passive straight leg raise (SLR) test and lumbar range of motion (LROM) tests measured as continuous variables embedded within a comprehensive physical examination. OBJECTIVES: To determine the reliability of the SLR and LROM test scores when they are measured with a Cybex electronic inclinometer (Lumex, Inc., New York, NY) within a physical examination. SUMMARY OF BACKGROUND DATA: Good published empirical reliability exists for the Cybex and for SLR and LROM tests when the measurements are taken in isolation from other physical examination procedures. Reliability of the Cybex for continuous SLR and LROM measurement within a physical examination has not been assessed, however. METHODS: Forty-five participants were seen by one of two physician/physiotherapist teams. Participants were examined by both team members. The first examiner conducted the first tests and retested 1 week later (intrarater reliability). The second examined the participants the day after their first appointment (inter-rater reliability). RESULTS: Only two scores showed substantial reliability (defined as r > or = 0.60). These scores were left (r = 0.81) and right (r = 0.79) SLR intrarater reliability. All other scores fell below the specified cutoff. CONCLUSIONS: SLR and LROM scores used clinically are collected during comprehensive physical examinations. Most scores gathered under these conditions were not reliable. These findings have implications for the use of clinically derived SLR and LROM scores.

Commentary on the American Medical Association guides' lumbar impairment validity checks.

STUDY DESIGN: The American Medical Association's (AMA) Guides to the Evaluation of Permanent Impairment range of motion-based (ROM) lumbar impairment model validity checks were reviewed. Published literature of lumbar ROM (LROM) testing also was reviewed for application of the AMA validity checking protocols. OBJECTIVE: The utility and feasibility of use of the AMA Guides' ROM lumbar impairment ratings were examined. SUMMARY OF BACKGROUND DATA: Although they appear to be essential components of the ROM model, few published studies report use of these validity checks. Of at least 22 reviewed studies of LROM testing, only six studies included at least three measurements (the bare minimum) of LROM. Furthermore, only two (9.1%) reported performance of the LROM validity check. Only one, however, reported the results. METHODS: English language journals were searched on Medline using "region, lumbar," "range of motion," "validity of results," "observer variation," and "low back pain" as title and subject search terms. The study methodologies approximating the AMA Guides' specifications were included in the analysis. RESULTS: Under normal conditions of ROM measurement, 33% of three consecutive lumbar flexion and 27% of three consecutive lumbar extension measurements failed the LROM validity check. In addition, across three different experimental sessions (each with more than three consecutive LROM measurements taken) only 15 participants (33%) had valid flexion scores and only 24 participants (53%) had valid extension scores across all three sessions. CONCLUSION: Technical complications inherent in the ROM-based impairment-rating model render the validity checks difficult to perform satisfactorily and thus rarely used.

Analysis of the convergent and discriminant validity of published lumbar flexion, extension, and lateral flexion scores.

STUDY DESIGN: Articles reflecting the convergent or discriminant validity of the lumbar range of motion tests were reviewed and compared. Mean scores and standard deviations for lumber range of motion from healthy control subjects were plotted against those from patients with low back injuries. OBJECTIVE: To use published research to analyze the convergent and discriminant validity of lumbar range of motion tests for the characterization of low back pain and injury. SUMMARY OF BACKGROUND DATA: Several publications have addressed lumbar range of motion validity. Individual studies suggest that the tests possess convergent validity, but that their discriminant validity is indeterminate. METHODS: English-language journals were searched on Medline using "region," "lumbar," "range of motion," "validity of results," "observer variation," and "low back pain" as title and subject search terms. The study methods approximating the specifications of the American Medical Association Guides to the Evaluation of Permanent Impairment were included in the analysis. RESULTS: Convergent validity research showed inconsistent relations between inclinometric and radiographic lumbar range of motion measurements. Some studies showed strong relation, whereas others showed essentially no relation between the two techniques. Correlations between lumbar range of motion scores and spinal disability and function were similarly inconclusive. Studies reporting mean scores and standard deviations for lumbar range of motion measurements showed a high degree of overlap between the scores of participants with low back injuries and those without such injuries. CONCLUSIONS: Convergent and discriminant validities of the lumbar range of motion tests currently require further substantiation. Absolute lumbar range of motion scores may not be suitable as the sole determinants of low back pathology diagnosis. Implications for using the lumbar range of motion tests to characterize low back injuries in medicolegal situations are discussed.

Cholinergic systems and schizophrenia: primary pathology or epiphenomena?

Post mortem schizophrenia research has been driven first by the dopamine and then the glutamate hypotheses. These hypotheses posit primary pathology in pathways dependent upon dopamine or glutamate neurotransmission. Although the dopamine and glutamate hypotheses retain considerable theoretical strength, neurobiological findings of altered dopamine or glutamate activity in schizophrenia do not explain all features of this disorder. A more synthetic approach would suggest that focal pathological change in either the prefrontal cortex or mesial temporal lobe leads to neurochemical changes in multiple neurotransmitter systems. Despite the limited experimental evidence for abnormal cholinergic neurotransmission in psychiatric disorders, increased understanding of the role of acetylcholine in the human brain and its relationship to other neurotransmitter systems has led to a rapidly growing interest in the cholinergic system in schizophrenia. This review focuses on the basic anatomy of the mammalian cholinergic system, and its possible involvement in the neurobiology of schizophrenia. Summaries of cholinergic cell groups, projection pathways, and receptor systems, in the primate and human brain, are followed by a brief discussion of the functional correlations between aberrant cholinergic neurotransmission and the signs and symptoms of schizophrenia.

Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment.

OBJECTIVE: Aberrant cholinergic inputs and synaptic neurotransmission in the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M(1) and M(4) receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia. METHOD: Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [(3)H]pirenzepine binding in rat frontal cortex following administration of antipsychotic drugs or benztropine mesylate were performed. RESULTS: Relative to those of comparison subjects, the mean levels of [(3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [(3)H]pirenzepine-labeled receptors in rat frontal cortex. CONCLUSIONS: Because M(1) and M(4) receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.

Combined physiological-anatomical approaches to study lateral inhibition.

In the visual cortex, large basket cells form the cellular basis of long-range lateral inhibition. The present paper focuses on combinations of methods with which large basket cells can be studied in the context of extensive neuronal representations. In the first approach, the topographic relationship between large basket axons and known functional representations such as orientation, direction, and ocular dominance is analysed. Functional mapping is carried out using extracellular electrode recordings or optical imaging of intrinsic signals followed by 3-dimensional anatomical reconstruction of biocytin stained large basket cells in the same regions. In the second approach, the contribution of lateral inhibition to orientation and direction selectivity is assessed using the GABA inactivation paradigm and direct inhibitory projections from the inactivation to recording sites are demonstrated with biocytin staining and injections of [3H]nipecotic acid, a radioactive marker for GABAergic cells. The limitation of these approaches is that they can only be used in cortical regions which lie on the surface of the brain.

Intermittent androgen suppression for prostate cancer: Canadian Prospective Trial and related observations.

The Canadian Prospective Trial of intermittent androgen suppression was a prototype therapeutic initiative started in 1995 for the management of patients in biochemical relapse after radiation for localized prostate cancer. An interim analysis has yielded several observations on the relations between baseline serum prostate specific antigen (PSA), nadir serum PSA, Gleason score, and time off-treatment. In a typical androgen-dependent tumor, the response of serum PSA to androgen withdrawal is biphasic, but with early tumor progression, plateauing of serum PSA is observed. Ligand-independent activation of the androgen receptor, a mechanism subserving the initiation of androgen independence, can be counteracted experimentally with decoy molecules and clinically with nonsteroidal antiandrogens. In some patients, it is possible to lengthen the off-treatment interval by inhibiting the enzyme 5 alpha-reductase, an effect that can be reinforced by lowering serum testosterone with an antigonadotropin. Serial measurements of serum PSA indicate that intermittent androgen suppression engenders a more diverse range of hormone-related responses than previously appreciated. These include: (1) repeated differentiation of tumor with recovery of apoptotic potential; (2) inhibition of tumor growth by rapid restoration of serum testosterone; and (3) restraint of tumor growth by subnormal levels of serum testosterone. These responses are aspects of regulation that should be taken into account when planning long-term treatment of prostate cancer with intermittent androgen suppression.

Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation.

BACKGROUND: Acetylcholine is important to hippocampal function, including the processes of learning and memory. Patients with schizophrenia show impaired learning and memory and hippocampal dysfunction. Thus, acetylcholinergic systems may be primarily or secondarily disrupted in the hippocampal formation of schizophrenic patients. The present study tested the hypothesis that [(3)H]pirenzepine-labeled muscarinic cholinergic receptor levels are altered in the hippocampal formation of patients with schizophrenia. METHODS: We have used quantitative autoradiography to measure [(3)H]pirenzepine binding to M(1) and M(4) receptors in the hippocampal formation from 15 schizophrenic and 18 nonschizophrenic subjects. RESULTS: The mean density of [(3)H]pirenzepine binding was reduced in all regions studied, including the dentate gyrus, subdivisions of Ammon's Horn (CA1-CA4), subiculum, and the parahippocampal gyrus, of the schizophrenic cohort. Moreover, unlike controls, there was no significant variation between the mean levels of [(3)H]pirenzepine binding across the subregions of the hippocampal formation from schizophrenic subjects. CONCLUSIONS: These findings provide support for a possible involvement of the muscarinic cholinergic system in the pathology and/or treatment of schizophrenia.

Respiratory-induced prostate motion: quantification and characterization.

PURPOSE: The precise localization of the prostate is critical for dose-escalated conformal radiotherapy. This study identifies and characterizes a potential cause of inaccurate prostatic localization-respiratory-induced movement. METHODS AND MATERIALS: Prostate movement during respiration was measured fluoroscopically using implanted gold fiducial markers. Twenty sequential patients with CT(1)-T(3) N(0) M(0) prostate carcinoma were evaluated prone, immobilized in customized thermoplastic shells. A second 20 patients were evaluated both prone (with and without their thermoplastic shells) and supine (without their shells). RESULTS: When the patients were immobilized prone in thermoplastic shells, the prostate moved synchronously with respiration. In the study the prostate was displaced a mean distance of 3.3 +/- 1.8 (SD) mm (range, 1-10.2 mm), with 23% (9/40) of the displacements being 4 mm or greater. The respiratory-associated prostate movement decreased significantly when the thermoplastic shells were removed. CONCLUSION: Significant prostate movement can be induced by respiration when patients are immobilized in thermoplastic shells. This movement presumably is related to transmitted intraabdominal pressure within the confined space of the shells. Careful attention to the details of immobilization and to the possibility of respiratory-induced prostate movements is important when employing small field margins in prostatic radiotherapy.

Muscarinic1 and 2 receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia.

Studies using tissue obtained at autopsy suggest that changes in cholinergic neurons could be important in the pathology of schizophrenia.1-4 We have previously reported a decrease in [3H]pirenzepine binding5 and [3H]AF-DX 384 binding6 to caudate-putamen (CP) from subjects who had schizophrenia. Under the conditions chosen, [3H]pirenzepine would predominately bind to muscarinic1 (M1) and muscarinic4 (M4) receptors,7whereas [3H]AF-DX 384 would mainly bind to muscarinic2 (M2) and M4 receptors.8 Given the relative concentrations of M1, M2 and M4 receptors in the human CP and the magnitude of the decreases in radioligand binding in schizophrenia, our results most likely reflected a change in the density of M1 and M2 receptors in the CP from the schizophrenic subjects. In situ hybridisation has now been used to determine levels of m1 and m2 mRNA in CP from 14 schizophrenic and 16 control subjects previously used for radioligand binding. m2 mRNA in the CP from the schizophrenic and control subjects was below the sensitivity of in situhybridisation. There was no difference in the levels of m1 mRNA in CP from schizophrenic and control subjects (mean +/- SEM: 103 +/- 16 vs106 +/- 17 fmol [35S]oligonucleotide probe g-1estimated tissue equivalents, P = 0.91). In conclusion, data from our radioligand binding studies show decreases in [3H]pirenzepine binding that are likely to reflect a decrease in the density of M1 receptors in CP from schizophrenic subjects. Our data in this study show the absence of a concomitant change in mRNA coding for that receptor.

The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia.

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [3H]AF-DX 384 labelled receptors (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 +/- 10.3 vs 145 +/- 901 fmol mg(-1) TE; mean +/- s.e.; p = 0.007). Preliminary analysis of patient drug data as well as rat studies suggest that the reduced [3H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not wholly due to antipsychotic drug treatment, or anticholinergic medication for the treatment of extrapyramidal effects. These data suggest that the muscarinic cholinergic system may be involved in the pathology of schizophrenia.

Intermittent androgen suppression in the management of prostate cancer.

OBJECTIVES: Intermittent androgen suppression (IAS) has been suggested as a means of attenuating the androgen deprivation syndrome in men with incurable prostate cancer. Laboratory data suggest that intermittent therapy may prolong the duration of androgen dependence. METHODS: Since October 1993, 54 patients have entered a Phase II protocol consisting of 8 months of total androgen blockade (TAB) using leuprolide (Lupron) depot and nilutamide (Anandron) followed by an off-treatment interval of variable length. Eleven patients had biopsy-proven local failure after radiotherapy, 4 had biochemical failure, 24 had distant metastases (fewer than six axial sites on bone scan), 11 had combined local and distant failure, and 4 were treated as primary management for nodal disease. Mean prostate-specific antigen (PSA) at entry was 37 ng/mL (range 3.8 to 196). After 8 months of TAB, hormonal therapy was discontinued for those patients whose PSA was less than 4.0 ng/mL and stable or decreasing and was resumed (cycle 2) when PSA increased to greater than 10 ng/mL. RESULTS: As of April 1 998, mean follow-up was 33 months (range 14 to 53). Patients have completed at least one, and up to five treatment cycles. The mean time to nadir PSA in cycle 1 was 20 weeks, and the mean time off was 35 weeks (31 weeks for those with metastatic disease versus 39 for local or biochemical failure). In cycle 2, the mean time to PSA nadir was 17 weeks, and the mean time off was 30 weeks (28 weeks for metastatic disease and 38 weeks for local or biochemical failure). In cycle 3, the time to PSA nadir was 19 weeks. Full testosterone data are available for 40 patients in cycle 1. Normal levels were achieved during the off-treatment interval in 73% by a mean of 18 weeks (median 9). Testosterone normalization in cycle 2 was achieved in 71% at a mean time of 17 weeks (median 14). CONCLUSIONS: TAB can be used intermittently, and appears to be more appropriate for patients with local or biochemical failure. Testosterone recovery is not universal in the off-treatment intervals. IAS needs to be investigated in a randomized trial to determine the effect on overall survival and quality of life.

Use of strontium-89 in endocrine-refractory prostate cancer metastatic to bone. Provincial Genitourinary Cancer Disease Site Group.

GUIDELINE QUESTION: What is the role of strontium-89 in effective palliative care of patients with stage D endocrine-refractory prostate cancer and multiple sites of painful bone metastases? OBJECTIVE: To make recommendations about the routine use of 89Sr in this clinical setting. OUTCOMES: Effective palliation is the primary outcome of interest. Patient survival and toxic effects of treatment are also considered. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 3 members of the Genitourinary Cancer Disease Site Group (Genitourinary Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. Earlier drafts of the guideline were circulated and reviewed by members of the DSG. The Genitourinary Cancer DSG comprises medical oncologists, radiation oncologists, urologists, a pathologist and a community representative. Guideline approval requires input from community representatives. QUALITY OF EVIDENCE: Three randomized controlled trials (RCTs) were available for evaluation. Two compared 89Sr with placebo, and one RCT compared 89Sr with conventional radiation (either hemibody or involved-field radiotherapy, as determined before randomization). BENEFITS: One of the 2 studies comparing 89Sr with placebo demonstrated the palliative efficacy of the intervention (p < 0.01); the other showed no benefit. The third study, comparing 89Sr with conventional radiation, concluded that all treatments provided equally effective pain relief and that improvement was sustained for at least 3 months in similar proportions of patients. The difference in the median duration of patient survival between groups in this study was neither clinically nor statistically significant. HARMS: The use of 89Sr may cause bone marrow suppression, but clinically significant sequelae are uncommon. The use of 89Sr may preclude further systemic chemotherapy or eligibility for clinical trials of systemic therapy. Symptoms other than those due to bone marrow suppression are rare. PRACTICE GUIDELINE: 89Sr is recommended for use in patients with endocrine-refractory prostate cancer who have multiple uncontrolled painful sites of bone metastases on both sides of the diaphragm not adequately controlled with conventional analgesic therapy, and in whom the use of multiple single fields of external beam radiation is not possible. 89Sr has proven to be efficacious in the palliation of hormone-refractory painful bone metastases from prostate cancer. It has not been shown to lengthen the average duration of patient survival. There is limited evidence on the relative efficacy of 89Sr compared with wide-field radiotherapy. 89Sr is the treatment of choice given all the following specific indications: Established diagnosis of prostate cancer metastatic to bone. Metastatic disease refractory to hormone therapy. Progressive sites of pain poorly controlled with conventional narcotics. Painful sites of disease on both sides of the diaphragm (otherwise, hemibody radiotherapy is equally efficacious). Patient or tumour factors (number of involved sites, location of involved sites or level of pain control) that are relative contraindications to the use of multiple single fields of radiation as an alternative. No evidence of impending spinal cord compression. Adequate bone marrow reserve. Evidence from a diagnostic bone scan of radionuclide concentration in painful bone lesions. PRACTICE GUIDELINE DATE: Nov. 23, 1997. Part 2. GUIDELINE QUESTION: What is the role of 89Sr in effective palliative care of patients with stage D hormone-refractory prostate cancer receiving involved-field radiotherapy for isolated painful bone metastases? OBJECTIVE: To make recommendations about the routine use of 89Sr in this clinical setting. OUTCOMES: Effective palliation is the primary outcome of interest. Patient survival and toxic effects of treatment are also considered. PERSPECTIVE (VALUES): As described in preceding abstract (Part 1). QUALITY OF EVIDENCE: One RCT was available for evaluati

Evidence for a contribution of lateral inhibition to orientation tuning and direction selectivity in cat visual cortex: reversible inactivation of functionally characterized sites combined with neuroanatomical tracing techniques.

We have previously reported that cells in cat areas 17 and 18 can show increases in response to non-optimal orientations or directions, commensurate with a loss of inhibition, during inactivation of laterally remote, visuotopically corresponding sites by iontophoresis of gamma-aminobutyric acid (GABA). We now present anatomical evidence for inhibitory projections from inactivation sites to recording sites where 'disinhibitory' effects were elicited. We made microinjections of [3H]-nipecotic acid, which selectively exploits the GABA re-uptake mechanism, < 100 microm from recording sites where cells had shown either an increase in response to non-optimal orientations during inactivation of a cross-orientation site (n = 2) or an increase in response to the non-preferred direction during inactivation of an iso-orientation site with opposite direction preference (n = 5). Retrogradely labelled GABAergic neurons were detected autoradiographically and their distribution was reconstructed from series of horizontal sections. In every case, radiolabelled cells were found in the vicinity of the inactivation site (three to six within 150 microm). The injection and inactivation sites were located in layers II/III-IV and their horizontal separation ranged from 400 to 560 microm. In another experiment, iontophoresis of biocytin at an inactivation site in layer III labelled two large basket cells with terminals in close proximity to cross-orientation recording sites in layers II/III where disinhibitory effects on orientation tuning had been elicited. We argue that the inactivation of inhibitory projections from inactivation to recording sites made a major contribution to the observed effects by reducing the strength of inhibition during non-optimal stimulation in recurrently connected excitatory neurons presynaptic to a recorded cell. The results provide further evidence that cortical orientation tuning and direction selectivity are sharpened, respectively, by cross-orientation inhibition and iso-orientation inhibition between cells with opposite direction preferences.

Percent free prostate-specific antigen after radiotherapy for prostate cancer.

OBJECTIVES: The range of "normal" prostate-specific antigen (PSA) values compatible with cure following radiotherapy (RT) for prostate cancer (PCa) has yet to be established. Various thresholds, ranging from 0.5 to 4.0 ng/mL are used to define biochemical disease-free status. Because the proportion of free PSA is lower in men with PCa, the ratio of free PSA to total PSA could theoretically be useful in determining cancer-free status after RT. METHODS: One hundred two men treated with standard external beam RT from October 1988 to October 1994 (median dose, 66 Gy) were chosen for measurement of percent free PSA because they had a routine follow-up visit in November or December of 1996. All patients had undergone systematic transrectal ultrasound-guided biopsies after RT. Biopsies were negative in 66 patients, positive in 21, and indeterminate in 15 (rare, degenerated cancer cells with no evidence of proliferation by immunohistochemical stains). Stage distribution was T1b, 8; T1c, 9; T2a, 25; T2b/c, 40; and T3, 20. Median follow-up is 40 months. RESULTS: Total serum PSA ranged from 0. 1 to 10.0 ng/mL. Because the mean (+/-SD) percent free PSA for patients with negative (n = 66) and indeterminate (n = 15) biopsies were 29% +/- 18% and 25% +/- 7%, respectively (P = 0.13), these were combined. The mean (+/-SD) percent free PSA for those with positive biopsies (n = 21) was 15% +/- 8% and was significantly different from those with negative or indeterminate biopsies (P < 0.001). Patients with negative or indeterminate biopsies were grouped according to their total PSA as 0.1 to 0.5 ng/mL (n = 33), 0.6 to 1.0 ng/mL (n = 23), 1.1 to 2.0 ng/mL (n = 17), and greater than 2.0 ng/mL (n = 7). The mean percent free PSAs were 34%, 28%, 21%, and 12%, respectively. CONCLUSIONS: Percent free PSA may be a useful adjunct in diagnosing recurrent PCa after RT. The ratio is significantly different in patients of known biopsy status, distinguishing a group with positive biopsies from those with negative. However, there is overlap in individual values, and because patients with negative biopsies after RT may have subclinical distant disease, more follow-up is necessary before percent free PSA can be incorporated into a definition of biochemical disease-free status. Percent free PSA may be most useful for PSA from 0.6 to 2.0 ng/mL, where failure is common, but not universal.

Serum prostate-specific antigen profile following radiotherapy for prostate cancer: implications for patterns of failure and definition of cure.

OBJECTIVES: A reference range of prostate-specific antigen (PSA) values compatible with cure following radiotherapy (RT) for prostate cancer (PCa) has yet to be established. Various thresholds, as low as 0.5 ng/mL, have been used to define biochemical disease-free status. We report PSA profiles in 118 patients who were systematically biopsied following standard RT, with a minimum 4-year follow-up. METHODS: One hundred eighteen patients were treated with standard external beam RT from May 1987 to October 1991, and were followed prospectively with transrectal ultrasound (TRUS)-guided biopsies and measurement of serum PSA levels. Stage distribution was as follows: T1b: 25 patients, T2a: 27 patients, T2b/c: 42 patients, T3: 23 patients, T4: 1 patient. Median follow-up for patients without clinical failure is 68 months (range 48 to 108). Treatment failures were categorized as biochemical (biochemical failure [chemF]: PSA level of 2.0 ng/mL or more and greater than 1 ng/mL over nadir), local (local failure [LF]: positive biopsy and PSA level greater than 2.0), and distant failure (DF). RESULTS: PCa recurred in 55% of patients: 38% LF (n = 45; 30 isolated and 15 with DF), 25% DF (n = 30; 15 isolated and 15 with LF), and 4% chemF (n = 5). Mean PSA nadir was 0.4 for patients with no evidence of disease (NED) and occurred at 33 months, 3.2 for LF at 17 months, 7.7 for DF at 12 months, and 1.4 for chemF at 24 months. After reaching the nadir, PSA in patients with recurrence followed first-order kinetics, rising exponentially over time. The mean PSA doubling time was 12.6 months for LF, 5.2 months for DF, and 21.8 months for chemF (P = 0.004). At last follow-up, the median PSA for patients without evidence of disease is 0.5 ng/mL. Four such patients had PSA values that rose to between 1 and 2 ng/mL for 5 to 38 months, but these eventually fell again to less than 1 ng/mL. Three patients had PSA values between 2 and 3 ng/mL, but 2 now have decreasing levels and the third has a rising level. All patients whose PSA levels rose to greater than 3 ng/mL exhibited a persistently rising pattern and ultimate tumor recurrence. CONCLUSIONS: There is a range of PSA values following RT for PCa that is compatible with cure. A definition of biochemical disease-free status at any absolute threshold of PSA level less than 3 ng/mL will overdiagnose failure in a significant proportion of patients. Patients with a PSA level between 1.5 and 3 ng/mL should be observed until there is unequivocal evidence of disease recurrence. In the absence of known biopsy status, PSA doubling time can be a useful indicator of whether failure is local or distant.