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Journal of Veterinary Internal Medicine Mar 2023Severe muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon.
BACKGROUND
Severe muscle stiffness (SMS) in dogs with hypercortisolism (HC) is uncommon.
OBJECTIVES
To evaluate signalment, presentation, treatments, and long-term outcomes of dogs with concurrent HC and SMS.
ANIMALS
Thirty-seven dogs.
METHODS
Medical records of dogs with HC and concurrent SMS were recruited from 10 institutions. Clinical information, test results, therapeutic responses, and survival times were reviewed.
RESULTS
All 37 dogs with HC and SMS had pituitary-dependent hypercortisolism (PDH); 36/37 weighed <20 kg. Signs and test results were typical of PDH aside from SMS, initially diagnosed in all 4 limbs in 9, pelvic limbs of 22, and thoracic limbs of 6 dogs. Hypercortisolism and SMS were diagnosed together in 3 dogs; HC 1-36 months before SMS in 23; SMS 1-12 months before HC in 11. Mitotane or trilostane, given to control HC in 36/37 dogs, improved or resolved HC signs in 28; SMS did not resolve, remaining static or worsening in 31/36 dogs, mildly improving in 5/19 dogs given additional therapies. Progression of SMS included additional limbs in 10 dogs and the masticatory muscles of 2. The median survival time from diagnosis of SMS was 965 days (range, 8-1188).
CONCLUSIONS AND CLINICAL IMPORTANCE
Concurrent SMS and HC is uncommon, possibly affecting only dogs with PDH. Development of SMS might occur before or after diagnosis of HC. Apart from SMS, the clinical picture and survival time of these dogs seem indistinguishable from those of dogs with HC in general. However, while muscle weakness usually resolves with HC treatment SMS does not.
Topics: Dogs; Animals; Cushing Syndrome; Dog Diseases; Pituitary ACTH Hypersecretion; Mitotane; Muscles
PubMed: 36798032
DOI: 10.1111/jvim.16620 -
Endocrine Pathology Mar 2023The introduction of Ki67 immunohistochemistry in the work-up of neuroendocrine neoplasms (NENs) has opened a new approach for their diagnosis and prognostic evaluation.... (Review)
Review
The introduction of Ki67 immunohistochemistry in the work-up of neuroendocrine neoplasms (NENs) has opened a new approach for their diagnosis and prognostic evaluation. Since the first demonstration of the prognostic role of Ki67 proliferative index in pancreatic NENs in 1996, several studies have been performed to explore its prognostic, diagnostic, and predictive role in other neuroendocrine and endocrine neoplasms. A large amount of information is now available and published results globally indicate that Ki67 proliferative index is useful to this scope, although some differences exist in relation to tumor site and type. In gut and pancreatic NENs, the Ki67 proliferative index has a well-documented and accepted diagnostic and prognostic role and its evaluation is mandatory in their diagnostic work-up. In the lung, the Ki67 index is recommended for the diagnosis of NENs on biopsy specimens, but its diagnostic role in surgical specimens still remains to be officially accepted, although its prognostic role is now well documented. In other organs, such as the pituitary, parathyroid, thyroid (follicular cell-derived neoplasms), and adrenal medulla, the Ki67 index does not play a diagnostic role and its prognostic value still remains a controversial issue. In medullary thyroid carcinoma, the Ki67 labelling index is used to define the tumor grade together with other morphological parameters, while in the adrenal cortical carcinoma, it is useful to select patients to treated with mitotane therapy. In the present review, the most important information on the diagnostic, prognostic, and predictive role of Ki67 proliferative index is presented discussing the current knowledge. In addition, technical issues related to the evaluation of Ki67 proliferative index and the future perspectives of the application of Ki67 immunostaining in endocrine and neuroendocrine neoplasms is discussed.
Topics: Humans; Prognosis; Ki-67 Antigen; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Pancreatic Neoplasms
PubMed: 36797453
DOI: 10.1007/s12022-023-09755-3 -
Endocrine-related Cancer Apr 2023Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin, and cisplatin (EDP). Although both therapies...
Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin, and cisplatin (EDP). Although both therapies are widely used, markers of response are still lacking. Since inflammation-based scores have been proposed as prognostic factors in ACC, we aimed to investigate their role in predicting the response to first-line chemotherapy. We performed a retrospective analysis of patients with advanced ACC treated with mitotane monotherapy or EDP ± mitotane. Clinical parameters (tumour stage at diagnosis, resection status, Ki67, time from diagnosis to treatment start, performance status, plasma mitotane levels, time in mitotane target ≥ 80%, clinically overt cortisol hypersecretion), and pretreatment inflammation-based scores (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio) were investigated. The primary endpoints were overall survival (OS) and time-to-progression (TTP) from treatment initiation, the secondary endpoint was the best objective response to treatment. We included 90 patients (59% = women, median age = 51 years) treated with mitotane monotherapy (n = 40) or EDP ± mitotane (n = 50). In the mitotane monotherapy cohort, NLR ≥ 5 and PLR ≥ 190 predicted shorter OS (hazard ratio (HR): 145.83, 95% CI: 1.87-11,323.83; HR: 165.50, 95% CI: 1.76-15,538.04, respectively), remaining significant at multivariable analysis including clinical variables. NLR was also associated with shorter TTP (HR: 2.58, 95% CI: 1.28-5.20), but only at univariable analysis. Patients with NLR ≥ 5 showed a worse treatment response than those with NLR < 5 (P = 0.040). In the EDP ± mitotane cohort, NLR ≥ 5 predicted shorter OS (HR: 2.52, 95% CI: 1.30-4.88) and TTP (HR: 1.95, 95% CI: 1.04-3.66) at univariable analysis. In conclusion, inflammation-based scores, calculated from routinely measured parameters, may help predict response to chemotherapy in advanced ACC.
Topics: Humans; Female; Middle Aged; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Retrospective Studies; Inflammation; Prognosis; Lymphocytes
PubMed: 36715606
DOI: 10.1530/ERC-22-0372 -
Problemy Endokrinologii Jan 2023Adrenocortical cancer (ACC) is an orphan malignant tumor of the adrenal cortex with a predominantly poor prognosis and an aggressive clinical course. Nowadays, mitotane...
BACKGROUND
Adrenocortical cancer (ACC) is an orphan malignant tumor of the adrenal cortex with a predominantly poor prognosis and an aggressive clinical course. Nowadays, mitotane is a non-alternative drug in the treatment of ACC. The search for prognostic parameters that determine the sensitivity of ACC to ongoing treatment is currently an urgent task. Expression levels of the large subunit of ribonucleotide reductase M1 (RRM1), cytochrome P450 2W1 (CYP2W1), and sterol- O-acyltransferase-1 (SOAT1) are considered as potential predictors of response to mitotane therapy.
AIM
To assess the immunohistochemical expression of RRM1, CYP2W1 and SOAT1 in ACC as markers of clinical outcomes and response to the therapy with mitotane.
MATERIALS AND METHODS
The study included 62 patients older than 17 years of age with a diagnosis of ACC confirmed histologically and immunohistochemically. Mitotane therapy was initiated in 29 patients in the postoperative period, 33 patients were under dynamic observation without concomitant drug treatment. Antibodies to RRM1, CYP2W1, SOAT1 were used diluted in accordance with recommendations of firms-manufacturers for immunohistochemical detection.
RESULTS
In the group of patients with low and moderate RRM1, CYP2W1 and SOAT1 immunoreactivity in the tumor and no antitumor therapy, a better DFS was noted (p=0.037, p=0.020 and p=0.001, respectively) compared to the group of patients receiving mitotane therapy at this level of marker expression. With high immunoreactivity of the markers, no statistically significant differences in DFS were found.
CONCLUSION
Consistent with the findings in our study, low expression of RRM1, CYP2W1 and SOAT1 was associated with worse DFS with antitumor therapy. The results of the work indicate the need to assess the levels of immunoreactivity of these markers in patients with ACC before starting treatment with mitotane in order to predict the efficiency of therapy.
Topics: Humans; Mitotane; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Adrenal Cortex Neoplasms; Adrenal Cortex; Cytochrome P-450 Enzyme System
PubMed: 36689714
DOI: 10.14341/probl13172 -
JPMA. the Journal of the Pakistan... Oct 2022The case of a 45-year-old male patient diagnosed with European Network for the Study of Adrenal Tumours (ENSAT) criteria, stage IV adrenocortical carcinoma (ACC) with...
The case of a 45-year-old male patient diagnosed with European Network for the Study of Adrenal Tumours (ENSAT) criteria, stage IV adrenocortical carcinoma (ACC) with unexpectedly prolonged survival is being reported. The patient underwent resection of stage IV ACC and despite suboptimal adherence to postoperative mitotane and chemotherapy, had a prolonged survival spanning almost seven years. The possible reasons for such an outcome are discussed. ACC is a rare tumour with stage 4 disease known to be associated with a particularly grim prognosis. A low grade on histology (mitotic index 11-12 per 50 HPF) was likely responsible for the prolonged survival of our patient. Low grade disease may predict extended survival in stage IV ACC.
Topics: Male; Humans; Middle Aged; Adrenocortical Carcinoma; Adrenal Cortex Neoplasms; Prognosis; Mitotane
PubMed: 36661007
DOI: 10.47391/JPMA.3494 -
Open Veterinary Journal 2022In humans, ectopic Cushing's syndrome (ECS) is characterized by hypercortisolemia, which is caused by small lung carcinoma, bronchial carcinoids, and pheochromocytoma....
BACKGROUND
In humans, ectopic Cushing's syndrome (ECS) is characterized by hypercortisolemia, which is caused by small lung carcinoma, bronchial carcinoids, and pheochromocytoma. In dogs, only a few cases of ECS associated with pheochromocytoma have been reported to date.
CASE DESCRIPTION
Herein, we describe a canine case of malignant pheochromocytoma that is presumed to be the cause of ECS. An 11-year-old, castrated, male Toy Poodle with hypercortisolemia was diagnosed with an adrenal tumor (AT) and treated with mitotane. Although repeated adrenocorticotropic hormone stimulation tests revealed improvement in the dog's condition by mitotane treatment, its condition started declining 197 days post-diagnosis, and he died on day 280. The necropsy revealed the AT was a pheochromocytoma, not an adrenocortical tumor. However, because of no pathological change in the pituitary gland and the other adrenal gland, pheochromocytoma was presumed to be the cause of ECS.
CONCLUSION
This is the first report that describes the effectiveness of mitotane against presumed ECS-related pheochromocytoma.
Topics: Humans; Dogs; Male; Animals; Cushing Syndrome; Pheochromocytoma; Mitotane; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Dog Diseases
PubMed: 36589399
DOI: 10.5455/OVJ.2022.v12.i5.22 -
Pharmaceuticals (Basel, Switzerland) Nov 2022In South Brazil, the incidence of pediatric adrenocortical carcinoma (ACC) is higher than in other regions and countries worldwide. The ACC treatment includes therapy...
In South Brazil, the incidence of pediatric adrenocortical carcinoma (ACC) is higher than in other regions and countries worldwide. The ACC treatment includes therapy with mitotane, the only adrenolytic drug approved by the FDA. The mitotane metabolism occurs via two main reactions: the β-hydroxylation, which yields the final product o,p'-DDA, and the α-hydroxylation, which will give the final product o,p'-DDE. It is speculated that o,p'-DDE may be an active metabolite since it has a cytotoxic effect on adrenocortical carcinoma cells (H295R). No further studies have been conducted to confirm this hypothesis; however, it was found that mitotane and its metabolites are present at significantly different concentrations in the plasma of the patients. Our study aimed to assess the in vitro effects of o,p'-DDE and o,p'-DDD in cell death pathways, oxidative parameters, and interaction with adrenal CYP's involved in the steroidogenic process in the H295R cell line. It was found that o,p'-DDE had a different effect than the o,p'-DDD on apoptosis, inhibiting this cell death pathway, but it promotes cell necrosis at higher concentrations. In contrast to o,p'-DDD, the o,p'-DDE did not have effects on the different oxidative parameters evaluated, but exhibited stimulatory interactions with steroidogenic CYP's, at intermediate concentrations. Therefore, we demonstrated important cell effects of o,p'-DDE; its plasma levels during mitotane therapy should be monitored as an important therapeutic parameter.
PubMed: 36558937
DOI: 10.3390/ph15121486 -
European Journal of Medical Research Dec 2022Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and...
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and metastatic biomarkers are lacking for ACC patients. This study aims at screening potential prognostic biomarkers and therapeutic targets of ACC through bioinformatic methods and immunohistochemical (IHC) analysis.
METHODS
In the present study, by using the Gene Expression Omnibus (GEO) database we identified differentially expressed genes (DEGs) in ACC and validated these DEGs in The Cancer Genome Atlas (TCGA) ACC cohort. A DEGs-based signature was additionally constructed and we assessed its prognosis and prescient worth for ACC by survival analysis and nomogram. Immunohistochemistry (IHC) was used to verify the relationship between hub gene-GMNN expressions and clinicopathologic outcomes in ACC patients.
RESULTS
A total of 24 DEGs correlated with the prognosis of ACC were screened from the TCGA and GEO databases. Five DEGs were subsequently selected in a signature which was closely related to the survival rates of ACC patients and GMNN was identified as the core gene in this signature. Univariate and multivariate Cox regression showed that the GMNN was an independent prognostic factor for ACC patients (P < 0.05). Meanwhile, GMNN was closely related to the OS and PFI of ACC patients treated with mitotane (P < 0.001). IHC confirmed that GMNN protein was overexpressed in ACC tissues compared with normal adrenal tissues and significantly correlated with stage (P = 0.011), metastasis (P = 0.028) and Ki-67 index (P = 0.014).
CONCLUSIONS
GMNN is a novel tumor marker for predicting the malignant progression, metastasis and prognosis of ACC, and may be a potential therapeutic target for ACC.
Topics: Humans; Adrenocortical Carcinoma; Prognosis; Survival Analysis; Biomarkers, Tumor; Adrenal Cortex Neoplasms; Geminin
PubMed: 36539849
DOI: 10.1186/s40001-022-00950-2 -
AACE Clinical Case Reports 2022Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and...
BACKGROUND
Adrenal Cushing syndrome (CS) is usually benign in etiology; however, although rarely, it can be due to adrenocortical carcinoma (ACC); in which case, diagnosis and management are quite complicated.
CASE REPORT
A 34-year-old woman presented with worsening confusion, weight gain, new-onset diabetes, and hypertension. Her history was significant for a 7.4-cm left adrenal mass and CS, which were treated with left adrenalectomy 2 years ago. She received hydrocortisone replacement therapy after the surgery, which was discontinued on admission when evaluation showed hypokalemia, hypercortisolemia, and undetectable adrenocorticotropic hormone. Subsequent testing included 1-mg and 8-mg dexamethasone suppression tests, which did not suppress cortisol; late-night salivary cortisol measurement, which yielded a very high salivary cortisol level; and 24-hour urinary cortisol measurement. The level of 11-deoxycortisol was elevated. A computed tomography scan revealed multiple hepatic lesions, which were fluorodeoxyglucose avid, and a biopsy confirmed metastatic ACC. She received treatment with mitotane, metyrapone (later changed to mifepristone), doxorubicin, cisplatin, and etoposide. Over 8 weeks, mitotane levels became therapeutic at 20 mcg/mL, the hepatic masses decreased in size, and she transitioned to adrenal insufficiency and improved glycemic control. Next-generation sequencing of liver biopsy and germline testing revealed a frameshift loss-of-function allelic variant in the gene that encodes the protein fumarate hydratase.
DISCUSSION
We report a case of recurrent CS due to metastatic ACC in a patient with a previously resected adrenal adenoma and allelic variant.
CONCLUSION
Metastatic ACC presenting with severe CS presents a diagnostic and management challenge where combination therapy guided by a multidisciplinary team is essential. allelic variant may contribute to ACC progression.
PubMed: 36447829
DOI: 10.1016/j.aace.2022.09.003 -
Frontiers in Endocrinology 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.
Topics: Adult; Humans; Child; Young Adult; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Li-Fraumeni Syndrome
PubMed: 36387865
DOI: 10.3389/fendo.2022.961650