Imaging Agent Effectively Detects, Localizes Tumors in Cushing’s Syndrome

Wannachalee T, et al. Clin Endocrinol. 2019;doi:10.1111/cen.14008.
May 20, 2019

A radioactive diagnostic agent for PET imaging effectively localized primary tumors or metastases in most adults with ectopic Cushing’s syndrome, leading to changes in clinical management for 64% of patients, according to findings from a retrospective study published in Clinical Endocrinology.

As Endocrine Today previously reported, the FDA approved the first kit for the preparation of gallium Ga-68 dotatate injection (Netspot, Advanced Accelerator Applications USA Inc.), a radioactive diagnostic agent for PET scan imaging, in June 2016. The radioactive probe is designed to help locate tumors in adult and pediatric patients with somatostatin receptor-positive neuroendocrine tumors. Ga-68 dotatate, a positron-emitting analogue of somatostatin, works by binding to the hormone.

In a retrospective review, Richard Auchus, MD, PhD, professor of pharmacology and internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan, and colleagues analyzed data from 28 patients with ectopic Cushing’s syndrome who underwent imaging with gallium Ga-68 dotatate for identification of the primary tumor or follow-up between November 2016 and October 2018 (mean age, 50 years; 22 women). All imaging was completed at tertiary referral centers at Mayo Clinic, University of Michigan and The University of Texas MD Anderson Cancer Center. Researchers assessed patient demographics, imaging modalities, histopathological results and treatment data. Diagnosis of Cushing’s syndrome was confirmed by clinical and hormonal evaluation. The clinical impact of gallium Ga-68 dotatate was defined as the detection of primary ectopic Cushing’s syndrome or new metastatic foci, along with changes in clinical management.

Within the cohort, 17 patients underwent imaging with gallium Ga-68 dotatate for identification of the primary tumor and 11 underwent the imaging for follow-up. Researchers found that gallium Ga-68 dotatate identified suspected primary ectopic Cushing’s syndrome in 11 of 17 patients (65%), of which seven tumors were solitary and four were metastatic. Diagnosis was confirmed by pathology in eight of the 11 patients: Five patients had a bronchial neuroendocrine tumor, one patient had a thymic tumor, one had a pancreatic neuroendocrine tumor, and one metastatic neuroendocrine tumor was of unknown primary origin. One patient had a false positive scan, according to researchers.

Among the 11 patients with ectopic Cushing’s syndrome who underwent gallium Ga-68 dotatate imaging to assess disease burden or recurrence, the imaging led to changes in clinical management in seven cases (64%), according to researchers.

“Our study demonstrates the high sensitivity of [gallium Ga-68 dotatate] in the localization of [ectopic Cushing’s syndrome], for both occult primary tumors and metastatic lesions,” the researchers wrote. “Importantly, the use of [gallium Ga-68 dotatate] impacted clinical management in 64% of patients with [ectopic Cushing’s syndrome] overall.”

The researchers noted that the high cost and limited availability of PET/CT imaging might preclude the widespread use of gallium Ga-68 dotatate for imaging in patients with suspected ectopic Cushing’s syndrome, and that experience with the scans remains limited vs. other imaging studies.

“Nevertheless, combing the experience of three large referral centers, our study gathers the largest number of [patients with ectopic Cushing’s syndrome] imaged with [gallium Ga-68 dotatate] to date and provides a benchmark for the utility of this diagnostic modality for this rare but highly morbid condition,” the researchers wrote. – by Regina Schaffer

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7B69e458a8-e9a0-4567-a786-00868118b435%7D/imaging-agent-effectively-detects-localizes-tumors-in-cushings-syndrome

Rare Prostate Cancer Associated with Cushing’s Syndrome

A patient with depression developed Cushing’s syndrome (CS) because of a rare ACTH-secreting small cell cancer of the prostate, a case study reports.

The case report, “An unusual cause of depression in an older man: Cushing’s syndrome resulting from metastatic small cell cancer of the prostate,” was published in the “Lesson of the Month” section of Clinical Medicine.

Ectopic CS is a condition caused by an adrenocorticotropic hormone (ACTH)-secreting tumor outside the pituitary or adrenal glands. The excess ACTH then acts on the adrenal glands, causing them to produce too much cortisol.

Small cell cancer is more common in older men, those in their 60s or 70s. Sources of ectopic ACTH synthesis arising in the pelvis are rare; nonetheless, ACTH overproduction has been linked to tumors in the gonads and genitourinary organs, including the prostate.

Still, evidence suggests there are less than 30 published cases reporting ectopic CS caused by prostate cancer.

Researchers from the Southern Adelaide Local Health Network and the Royal Adelaide Hospital in Australia described the case of an 84-year-old man who complained of fatigue, back pain, and lack of appetite.

Blood tests revealed mildly elevated prostate-specific antigen (PSA) and creatinine levels, which could indicate the presence of prostate cancer and impaired kidney function, respectively.

The patient had a history of locally invasive prostate cancer even though he didn’t experience any symptoms of this disease.

Ultrasound examination showed an enlarged prostate plus obstructed ureters — the tubes that carry urine from the kidney to the bladder. To remove the obstruction, doctors inserted a thin tube into both ureters and restored urine flow.

After the procedure, the man had low levels of calcium, a depressed mood, and back pain, all of which compromised his recovery. Imaging of his back showed no obvious reason for his complaints, and he was discharged.

Eight days later, the patient went to the emergency room of a large public hospital because of back pain radiating to his left buttock. The man also had mild proximal weakness on both sides. He was thinner, and had low levels of calcium, high blood pressure and serum bicarbonate levels, plus elevated blood sugar. In addition, his depression was much worse.

A psychiatrist prescribed him an antidepressant called mirtazapine, and regular follow-up showed that his mood did improve with therapy.

A computed tomography (CT) scan revealed a 10.5 cm tumor on the prostate and metastasis on the lungs and liver. Further testing showed high serum cortisol and ACTH levels, consistent with a diagnosis of Cushing’s syndrome.

But researchers could not identify the ACTH source, and three weeks later, the patient died of a generalized bacterial infection, despite treatment with broad-spectrum antibiotics.

An autopsy revealed that the cancer had spread to the pelvic sidewalls and to one of the adrenal glands. Tissue analysis revealed that the patient had two types of cancer: acinar adenocarcinoma and small cell neuroendocrine carcinoma — which could explain the excess ACTH.

Cause of death was bronchopneumonia, a severe inflammation of the lungs, triggered by an invasive fungal infection.

Investigators believe there are things to be learned from this case, saying, “Neither the visceral metastases nor aggressive growth of the pelvic mass noted on imaging were typical of prostatic adenocarcinoma. [Plus], an incomplete diagnosis at death was the precipitant for a post-mortem examination. The autopsy findings were beneficial to the patient’s family and treating team. The case was discussed at a regular teaching meeting at a large tertiary hospital and, thus, was beneficial to a wide medical audience.”

Although a rare cause of ectopic ACTH synthesis, small cell prostate cancer should be considered in men presenting with Cushing’s syndrome, especially in those with a “mystery” source of ACTH overproduction.

“This case highlights the importance of multidisciplinary evaluation of clinical cases both [before and after death], and is a fine example of how autopsy findings can be used to benefit a wide audience,” the researchers concluded.

https://cushingsdiseasenews.com/2018/10/16/rare-prostate-cancer-prostate-associated-cushings-syndrome-case-report/

Etomidate Found Effective in Severe Cushing’s Syndrome

Etomidate — a steroid synthesis blocker — is an effective treatment for patients with severe Cushing’s syndrome who do not respond to ketoconazole, according to a new case report from Mexico.

The report, “Etomidate in the control of severe Cushing’s syndrome by neuroendocrine carcinoma,” appeared in the journal Clinical Case Reports.

The investigators reported the case of a 51-year-old woman with ectopic Cushing’s syndrome caused by a pancreatic tumor. Ectopic Cushing’s refers to cases of excess secretion of adrenocorticotropin hormone (ACTH) outside the pituitary or adrenal glands.

The patient underwent distal pancreatectomy — the surgical removal of the bottom half of the pancreas — in 2015 due to an ACTH-secreting tumor. Although she had a good initial response, liver metastasis was evident by 2016.

Compared to measurements in 2016, morning blood cortisol, 24-hour urinary-free cortisol, and ACTH levels significantly increased in 2017. The patient also showed low levels of the luteinizing and follicle-stimulating hormones, which the scientists attributed to her severe hypercortisolism (excess cortisol levels).

The woman was being treated with ketoconazole to lower her cortisol values and later received chemoembolization — a method to reduce blood supply and deliver chemotherapy directly to a tumor — for her liver metastasis.

Although ketoconazole is generally the treatment of choice for the control of hormone production in the adrenal glands, its effectiveness is often limited and is associated with side effects, clinicians noted.

In April 2017, the patient arrived at the emergency room with sepsis — a potentially life-threatening complication of an infection — that originated in the gut.

Because ketoconazole had failed to lower cortisol levels, the patient started receiving infused etomidate, an inhibitor of the enzyme 11‐beta‐hydroxylase that prevents cortisol synthesis.

This treatment was stopped one day before the bilateral removal of the adrenal glands as a definitive treatment for the elevated production of cortisol.

While the patient experienced decreased levels of potassium, calcium, and magnesium with an initial dose of 0.04 mg per kg body weight an hour of etomidate, a gradual decrease of etomidate — depending on her cortisol levels — corrected these alterations.

After surgery, the patient showed a significant improvement in her general health, including control of her sepsis. She is currently taking hydrocortisone and fludrocortisone, with treatment for liver metastasis pending.

“Etomidate is a very effective drug in severe Cushing’s syndrome that is refractory to ketoconazole,” the researchers wrote.

“Control of the serum cortisol levels in ectopic Cushing’s syndrome can be obtained with infusion rates much lower than those used in anesthesia, without respiratory side effects,” they added.

The authors recommend an initial dose of etomidate of 0.04 mg/kg per hour, daily monitoring of 24-hour urinary cortisol and cortisol levels, and a gradual decrease of the etomidate dose according to daily measurements of metabolites.

From https://cushingsdiseasenews.com/2018/05/17/severe-cushings-syndrome-case-study-finds-etomidate-effective-therapy/

Cushing’s Patients at Risk for Autoimmune Diseases After Condition Is Resolved

Children with Cushing’s syndrome are at risk of developing new autoimmune and related disorders after being cured of the disease, a new study shows.

The study, “Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children,” was published in Hormone and Metabolic Research.

Patients with Cushing’s syndrome have excess levels of the hormone cortisol, a corticosteroid that inhibits the effects of the immune system. As a result, these patients are protected from autoimmune and related diseases. But it is not known if the risk rises after their disease is resolved.

To address this, researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) examined 127 children with Cushing’s syndrome at the National Institutes of Health from 1997 until 2017.

Among the participants, 77.5 percent had a pituitary tumor causing the disease, 21.7 percent had ACTH-independent disease, and one patient had ectopic Cushing’s syndrome. All patients underwent surgery to treat their symptoms.

After a mean follow-up of 31.2 months, 7.8 percent of patients developed a new autoimmune or related disorder.

Researchers found no significant differences in age at diagnosis, gender, cortisol levels, and urinary-free cortisol at diagnosis, when comparing those who developed autoimmune disorders with those who didn’t. However, those who developed an immune disorder had a significantly shorter symptom duration of Cushing’s syndrome.

This suggests that increased cortisol levels, even for a short period of time, may contribute to more reactivity of the immune system after treatment.

The new disorder was diagnosed, on average, 9.8 months after Cushing’s treatment. The disorders reported were celiac disease, psoriasis, Hashimoto thyroiditis, Graves disease, optic nerve inflammation, skin hypopigmentation/vitiligo, allergic rhinitis/asthma, and nerve cell damage of unknown origin responsive to glucocorticoids.

“Although the size of our cohort did not allow for comparison of the frequency with the general population, it seems that there was a higher frequency of optic neuritis than expected,” the researchers stated.

It is still unclear why autoimmune disorders tend to develop after Cushing’s resolution, but the researchers hypothesized it could be a consequence of the impact of glucocorticoids on the immune system.

Overall, the study shows that children with Cushing’s syndrome are at risk for autoimmune and related disorders after their condition is managed. “The presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise,” the researchers stated.

Additional studies are warranted to further explore this link and improve care of this specific population.

From https://cushingsdiseasenews.com/2018/03/06/after-cushings-cured-autoimmune-disease-risk-looms-study/

Benefits of Medication Before Surgery for Cushing’s Syndrome Still Unclear

In Europe, nearly 20 percent of patients with Cushing’s syndrome receive some sort of medication for the disease before undergoing surgery, a new study shows.

Six months after surgery, these patients had remission and mortality rates similar to those who received surgery as a first-line treatment, despite having worse disease manifestations when the study began. However, preoperative medication may limit doctors’ ability to determine the immediate success of surgery, researchers said.

A randomized clinical trial is needed to conclusively address if preoperative medication is a good option for Cushing’s patients waiting for surgery, they stated.

The study, “Preoperative medical treatment in Cushing’s syndrome. Frequency of use and its impact on postoperative assessment. Data from ERCUSYN,” was published in the European Journal of Endocrinology. 

Surgery usually is the first-line treatment in patients with Cushing’s syndrome. But patients also may receive preoperative medication to improve cortisol excess and correct severe diseases occurring simultaneously with Cushing’s.

Multiple studies have hypothesized that preoperative medication can have a beneficial effect on patients who undergo surgery. However, data on the beneficial impact of medication on morbidity, and the immediate surgical and long-term outcomes in patients with Cushing’s syndrome, are limited and inconclusive.

So, researchers made use of the European Registry on Cushing’s Syndrome (ERCUSYN), the largest database that collects information on diagnosis, management, and long-term follow-up in Cushing’s patients.

The team set out to collect information of the prevalence of preoperative medication in Cushing’s patients throughout Europe, and whether it influences patients’ outcomes after surgery. It also aimed to determine the differences between patients who receive preoperative medication versus those who undergo surgery directly.

Researchers analyzed 1,143 patients in the ERCUSYN database from 57 centers in 26 countries. Depending on what was causing the disease, patients were included in four major groups: pituitary-dependent Cushing’s syndrome (68%), adrenal-dependent Cushing’s syndrome (25%), Cushing’s syndrome from an ectopic source (5%), and Cushing’s syndrome from other causes (1%).

Overall, 20 percent of patients received medication – ketoconazole, metyrapone, or a combination of both – before surgery. Patients with ectopic and pituitary disease were more likely to receive medication compared to patients whose disease stemmed from the adrenal glands. Preoperative treatment lasted for a median of 109 days.

Patients in the pituitary group who were prescribed preoperative medication had more severe clinical features at diagnosis and poorer quality of life compared to those who received surgery as first-line treatment. No differences were found in the other groups.

But patients with pituitary-dependent disease receiving medication were more likely to have normal cortisol within seven days of surgery, or the immediate postoperative period, compared to patients who had surgery without prior medication. These patients also had a lower remission rate.

Within six months of surgery, however, there were no differences in morbidity or remission rates observed between each group. Also, no differences were seen in perioperative mortality rates – within one month of surgery.

Interestingly, researchers noted that patients who took medication prior to surgery were less likely to be in remission immediately after surgery. The reason, they suggest, might be because the medication already had begun to improve the clinical and biochemical signs of the disease, “so changes that take place in the first week after surgery may be less dramatic.”

“A randomized trial assessing simple endpoints, such as length of hospital stay, surgical impression and adverse effects of surgery, is needed to conclusively demonstrate that [preoperative medication] is a valid option in patients waiting for surgical correction of hypercortisolism,” the team concluded.

From https://cushingsdiseasenews.com/2018/02/22/benefits-cushings-syndrome-pre-surgery-medication-unclear-study/

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