Search

Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex that is associated with a poor prognosis. Developing effective treatment options for ACC is challenging owing to the current lack of representative preclinical models. This study addressed this limitation by developing and characterizing 3-dimensional (3D) cell cultures incorporating the ACC cell lines, MUC-1, HAC15, and H295R in a type I collagen matrix. ACC tissue samples were analyzed by immunohistochemistry to determine the presence of type I collagen in the tumor microenvironment. Cell viability and proliferation were assessed using flow cytometry and confocal microscopy. mRNA expression of steroidogenic enzymes and steroid secretion was analyzed by comparing the 3D and monolayer cell culture models. All cells were successfully cultured in a type I collagen matrix, which is highly expressed in the ACC tumor microenvironment and showed optimal viability until day 7. All 3 models showed increased metabolic and proliferative activity over time. Three-dimensional cell cultures were steroidogenic and demonstrated increased resistance to the gold standard chemotherapy, mitotane, compared with monolayer. The use of these models may lead to an improved understanding of disease pathology and provide a better representative platform for testing and screening of potential therapies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Primary aldosteronism (PA) is the most common cause of secondary hypertension and is associated with increased morbidity and mortality when compared with blood pressure-matched cases of primary hypertension. Current limitations in patient care stem from delayed recognition of the condition, limited access to key diagnostic procedures, and lack of a definitive therapy option for nonsurgical candidates. However, several recent advances have the potential to address these barriers to optimal care. From a diagnostic perspective, machine-learning algorithms have shown promise in the prediction of PA subtypes, while the development of noninvasive alternatives to adrenal vein sampling (including molecular positron emission tomography imaging) has made accurate localization of functioning adrenal nodules possible. In parallel, more selective approaches to targeting the causative aldosterone-producing adrenal adenoma/nodule (APA/APN) have emerged with the advent of partial adrenalectomy or precision ablation. Additionally, the development of novel pharmacological agents may help to mitigate off-target effects of aldosterone and improve clinical efficacy and outcomes. Here, we consider how each of these innovations might change our approach to the patient with PA, to allow more tailored investigation and treatment plans, with corresponding improvement in clinical outcomes and resource utilization, for this highly prevalent disorder., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Primary aldosteronism is the most common cause of secondary hypertension. The first-line treatment adrenalectomy resects adrenal nodules and adjacent normal tissue, limiting suitability to those who present with unilateral disease. Use of thermal ablation represents an emerging approach as a possible minimally invasive therapy for unilateral and bilateral disease, to target and disrupt hypersecreting aldosterone-producing adenomas, while preserving adjacent normal adrenal cortex. To determine the extent of damage to adrenal cells upon exposure to hyperthermia, the steroidogenic adrenocortical cell lines H295R and HAC15 were treated with hyperthermia at temperatures between 37 and 50°C with the effects of hyperthermia on steroidogenesis evaluated following stimulation with forskolin and ANGII. Cell death, protein/mRNA expression of steroidogenic enzymes and damage markers (HSP70/90), and steroid secretion were analyzed immediately and 7 days after treatment. Following treatment with hyperthermia, 42°C and 45°C did not induce cell death and were deemed sublethal doses while ≥50°C caused excess cell death in adrenal cells. Sublethal hyperthermia (45°C) caused a significant reduction in cortisol secretion immediately following treatment while differentially affecting the expression of various steroidogenic enzymes, although recovery of steroidogenesis was evident 7 days after treatment. As such, sublethal hyperthermia, which occurs in the transitional zone during thermal ablation induces a short-lived, unsustained inhibition of cortisol steroidogenesis in adrenocortical cells in vitro., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To investigate the feasibility and efficacy of localized, subtotal, cortical-sparing microwave thermal ablation (MTA) as a potential curative management for primary aldosteronism. The study investigated with equal importance the selected ablation of small volumes of adrenal cortex while sparing adjacent cortex. Method: An in-vivo study was carried out in swine ( n  = 8) where MTA was applied under direct visualization, to the adrenal glands at 45 W or 70 W for 60 s, using a lateral, side-firing probe and a non-penetrative approach. Animals were survived for 48 h post-procedurally. Animals were investigated for markers of histological, immunohistochemical and biochemical evidence of adrenal function and adrenal damage by assessing samples drawn intra-operatively and at the time of euthanasia. Results: Selected MTA (70 W for 60 s) successfully ablated small adrenocortical volumes (∼0.8 cm 3 ) characterized by coagulative necrosis and abnormal expression of functional markers (CYP11B1 and CYP17). Non-ablated, adjacent cortex was not affected and preserved normal expression of functional markers, without increased expression of markers of heat damage (HSP-70 and HMGB-1). Limited adrenal medullary damage was demonstrated histologically, clinically and biochemically. Conclusion: MTA offers potential as an efficient methodology for delivering targeted subtotal cortical-sparing adrenal ablation. Image-guided targeted MTA may also represent a safe future modality for curative management of PA, in the setting of both unilateral and bilateral disease.

All currently marketed neuroleptics induce extrapyramidal symptoms (EPS). These EPS are a function of biological sensitivity, neuroleptic molecular structure, dose, age, sex, and duration of neuroleptic treatment. Because of their association with EPS, at times irreversible, and their modest efficacy in the non-schizophrenic patients, neuroleptic administration should be limited predominantly to schizophrenic patients. Furthermore EPS should not be used as a guideline for the efficacy of neuroleptics as formerly assumed. For EPS may occur at subtherapeutic doses of neuroleptics and may be absent in patients experiencing clinical response. Neuroleptic dose should be the lowest efficacious dose required to provide symptom remission. In addition, antiparkinsonian (AP) agents should be administered predominently contraactively and not routinely in combination with neuroleptics. With the judicious administration of neuroleptic agents and AP medication, distressing EPS can be prevented or minimized, while providing control of schizophrenic symptoms.

The authors studied 44 acutely decompensated, hospitalized schizophrenic patients who were placed on a double-blind basis for 10 days in three treatment groups: patients given high, moderate, and standard doses of haloperidol. To assess changes in the patients' concentration, abstract thinking, and ability to respond appropriately they administered two clinical rating scales and three psychological tests. Patients in all three treatment groups showed similar and significant improvements according to both clinical and psychological ratings after haloperidol administration. Normal control subjects showed no change in psychological test scores over time. The authors conclude that brief treatment with neuroleptics produces measurable improvement in schizophrenic thinking.

The relative efficacy of three oral regimens of haloperidol was compared in a ten-day, double-blind study of 63 acutely ill schizophrenic patients newly admitted to the hospital. One group of patients received 20 mg of haloperidol on day 1, then increasing increments of 20 mg a day, reaching a maximum dosage of 100 mg daily on day 5. Another group received 10 mg of haloperidol on day 1, then increasing increments of 10 mg daily, reaching 100 mg daily on day 10. A third group of patients received a fixed dosage of 10 mg daily for ten days. Haloperidol was well tolerated by the patients; there were no serious adverse reactions. The data indicated that the regimens had similar therapeutic efficacy, suggesting that acutely ill schizophrenic patients respond to a wide range of doses of haloperidol but that onset of response and efficacy are not increased in most patients by providing a high initial loading dosage. Adequate, safe dosage must be determined in each case.

Five cases of successful suicides from thioridazine and mesoridazine occurred. The clinical course and management are outlined. A sixth case of reversible total heart block associated with thioridazine is presented giving further evidence that the deaths from overdose probably resulted from drug cardiotoxicity.

Two large aftercare clinics were established to provide treatment and rehabilitative care for a chronic mentally ill population requiring neuroleptic drugs. The clinics have evolved rapidly and expanded their service over the past 3 years but have required constant monitoring and modification in order to provide quality as well as quantity care in the community setting. These modifications are described and the importance of further community-based investigation in the rehabilitation and treatment of the chronic mentally ill is stressed.

The early signs and symptoms of schizophrenic decompensation are subtle and variegated. Today's community patient often presents with vague complaints of brief duration making it imperative that today's diagnostician be able to recognize and appropriately treat early psychopathology. This paper collates a number of observations of developing psychotic phenomena -- self reports, clinical studies and controlled experiments -- and provides a useful format for organizing these complex and changing behaviors. Data are presented and discussed using our clinical schema for detailing the natural progression of developing psychotic phenomena into four distinct stages. Efficacy of early recognition and treatment in aborting or diminishing a major psychotic episode is discussed. The advantages of recognizing the early signs of psychotic decompensation are apparent. First, with adequate intervention and treatment, the overt psychotic state may be attenuated. Although the feasibility of reducing the incidence of schizophrenia through intervention in "high risk" groups, or those experiencing insidious symptoms remain speculative (further investigation in this area is urgently needed), nonetheless, early diagnosis and comprehensive rehabilitative care significantly improves social and occupational adjustment. A second advantage accrues from early diagnosis. It enables patient and family to better cope with the illness. We have previously outlined a schema detailing the natural progression of developing psychotic phenomena into four distinct stages. The phenomena, when identified, can be seen as a continuum. However, many clinicians fail to recognize the earlier phases and typically the diagnosis of psychosis is made relatively late at what we call stage three of the four stages we described.

Clobazam, a 1,5-benzodiazepine, was compared with placebo in 190 psychoneurotic outpatients with prominent symptoms of anxiety and tension of at least two weeks of duration. The design was one of double-blind parallel groups treated for one week. Clobazam subjects began on 40 mg daily in divided dosage, which was increased to 80 mg daily be day 3 if the drug was well tolerated. Two patients receiving clobazam had laboratory chemistry abnormalities which were possibly drug related. Adverse effects occurred more frequently in the clobazam group and were typical of those of marketed benzodiazepines. This study indicates that clobazam is an effective anxiolytic agent demonstrating its clinical effects during the first week of treatment.

This paper reviews the diagnosis and medical treatment of the major affective disorders. Patients with severe mood disturbances are frequently seen by the family physician. The diagnosis may be delayed since the patient may focus predominantly on somatic concerns which may mimic physical illness. The characteristics, course, and differential diagnosis of depression and mania are discussed. Antidepressants and lithium therapy greatly improve the prognosis of these disorders; monoamine oxidase inhibitors and neuroleptics are indicated for special subtypes of depression. Dosage schedules, interactional effects, adverse and toxic effects are reviewed for tricyclic antidepressants and lithium.

In this study, chronic schizophrenic outpatients who had been maintained on various neuroleptics for an average of about 4 years had their previous medications (approximately equivalent to 695 mg of chlorpromazine per day) changed abruptly to either pimozide or fluphenazine given in single daily oral doses on a double-blind basis for a period of 52 weeks. Average daily doses were pimozide 9.6 mg and fluphenazine 12.5 mg. Measurements of the therapeutic effects of the two drugs were made immediately prior to starting the study, at the end of the 2nd and 4th weeks, and thereafter every 4th week to the end of the study. Three psychometric scales were used for evaluation: Brief Psychiatric Rating Scale (BPRS); Evaluation of Social Functioning (ESFR); and Clinical Global Impressions (CGI). In addition, patients participated in a Social Adjustment Inventory (SAI) evaluation. Statistical analysis with the use of several statistical techniques for between- and within-drug group comparisons revealed that pimozide and fluphenazine were equally effective in maintaining control of symptomatology of chronic schizophrenics at a level commensurate with or better than that provided by their previous medication. Side effects were characteristic of marketed neuroleptics, similar in severity and occurrence between study-drug groups, mainly extrapyramidal symptoms, and readily controlled with antiparkinsonian medication. Pimozide, slightly more potent than fluphenazine, proved to be equally effective for the long-term management of chronic schizophrenic patients.

This investigation is a 52-week double-blind study comparing the efficacy and safety of penfluridol and trifluoperazine in 25 chronic schizophrenic outpatients. Penfluridol was administered once weekly and trifluoperazine daily. Measurements were made at baseline, various fixed intervals during the study period and termination. The data reveals that both agents were similarly effective in maintaining control of the symptoms of chronic schizophrenic patients at a level commensurate with or better than that provided by their previous medication. Besides being effective, medications were also well tolerated. The side effects were characteristic of marketed neuroleptics. Akathisia was more common with penfluridol but readily controlled with anti-parkinsonian medication. Other side effects were similar in severity and occurrence between study-drug groups. Both agents had low autonomic liability, and neither agent was depressogenic.

Neuroleptic agents by providing symptoms remission allow community physicians to treat the schizophrenic patient in all phases of the illness. The questions of the safety and efficacy of high dose neuroleptic therapy in subjects resistant to standard dose or requiring rapid symptom remission are frequently debated. Definitive research is, however, lacking. The author concludes, after reviewing available literature, that high dose treatment is indicated for some patients. In general, the incidence of adverse effects are dose related. The decision to administer high dose medication should weigh the added risk against the potential merit of treatment.

Indications for high dosage neuroleptics have become increasingly more debatable with recent emphasis on outpatient community management of the severely ill schizophrenic patient. Early studies suggest that high dose neuroleptics have greater effectiveness with some schizophrenic patients while remaining low in toxicity. As part of a rater blind study, 16 patients with the diagnosis of either chronic undifferentiated or chronic paranoid schizophrenia were placed on standard dose piperacetazine following a washout period. The dosage was then gradually increased until the patient achieved maximal effect with a minimum of side effects. Eight patients required standard dose (25-160 mg/day) while the remaining eight required high dose (160-400 mg/day). The two clinical groups are compared for therapeutic efficacy and toxicity. High dose piperacetazine was found to be effective in seven patients refractory to low dosage. Although the incidence of side effects was higher with the high dose patients, toxicity (liver, blood, renal) was not increased in patients requiring high dose medication. Indications for high dose neuroleptics are briefly discussed.

About one percent of the population will develop schizophrenic symptoms sometime during their life. Etiologies are poorly understood and the course is highly variable. The differential diagnosis and medical treatment of the schizophrenias are discussed. Neuroleptic drugs are the most effective single treatment, for they allow most patients to be treated on an ambulatory basis, under the care of community physicians. Adverse effects of neuroleptic agents are common and often subjectively annoying. They may be prevented or minimized by agent selection, dosage schedules, or contra-active treatment.

Cardiac effects of tricyclics and tetracyclics, while common, are most frequently benign and well-tolerated. For older patients with underlying disease, however, closer clinical monitoring is needed. The most common effect of MAOIs in healthy adults taking normal dosages is orthostatic hypotension. The most serious reaction to MAOIs is hypertensive crisis, which may be fatal.

The authors review the literature on the rapid neuroleptization (titration) method with I.M. haloperidol. Most of the approximately 650 predominantly schizophrenic and manic patients represented in the studies calmed down rapidly on medication, and some demonstrated an early reduction in core psychotic symptoms. The initial doses varied widely, ranging from 1 to 30 mg, with a maximum total daily dosage of 100 mg. The medication seemed to have been well tolerated in all cases, with no reported major complications. The authors conclude that the method shows definite merit with agitated and belligerent patients. However, they make a number of specific recommendations for further research to clearly establish the effectiveness and safety of this method of neuroleptic administration.

Numerous factors are involved in determining the efficacy of tricyclic antidepressant agents in the treatment of depression. The list includes diagnosis and patient selection; pharmacodynamics, bioavailability and tissue sensitivity; natural history; placebo response, nonspecific factors; compliance and adverse effects; the effects of concurrent life events, illness and treatment, and the bias in evaluating the outcome of treatment. Physicians should be aware of the factors that influence clinical response so they can maximize therapeutic effects and utilize the agents properly.

This double-blind investigation compared onset of action, efficacy, and safety of amoxapine and amitriptyline in 46 endogenously depressed outpatients. Statistical analysis demonstrated relatively few significant differences in improvement between the two groups. Most of the differences favored amoxapine, however, and on all measures there were clear trends favoring amoxapine for more rapid onset of action or greater overall efficacy or both.

This rater blind project compared the efficacy and safety of using an oral rapid or neuroleptization method (maximum 80 mg./day) versus fixed standard dosage (20 mg./day) fluphenazine, a commonly used neuroleptic. There were 32 hospitalized, acutely decompensated schizophrenic patients in the experiment; the study period for each patient was a maximum of 7 days. The data were collected using the Benjamin Proverb Test and rating scales for psychopathology and adverse effects. Data analysis by means of the analysis of covariance demonstrated few significant differences between the 2 treatment methods: both methods produced a similar reduction in psychopathological symptoms and incidence of adverse effects. The authors conclude that the rapid neuroleptization method is not superior to the fixed standard dosage method in treating acute schizophrenia.

The authors found moderate to severe depression in 60% of a group of schizophrenic patients experiencing acute decompensations (N=30). The course of the depression was followed over an 8-week period8,during which patients were treated with depot fluphenazines. There was a statistically significant reduction in depression that closely paralleled the correction of the cognitive disorder. The authors discuss problems in identifying and quantifying depression during acute schizophrenic decompensation and suggest that the Hamilton scale anxiety/depression factor and the BRPS depression factor may be useful diagnositc tools.