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MaryO

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  1. MeganOrrMD, JamesFindlingMD, NathanZwagermanMD, JenniferConnellyMD, KatherineAlbanoMS, JosephBoviMD Show more https://doi.org/10.1016/j.adro.2021.100813Get rights and content Under a Creative Commons license open access Abstract Pituitary carcinoma (PC) is an uncommon intracranial malignancy with a high rate of metastasis, mortality, and inconsistent response to therapy. Because PC is a rare condition (0.1%-0.2% of pituitary tumors), prospective studies and observable data are scarce. Some PC may have an endocrine secretory function and can arise from existing pituitary adenomas. Treatment often includes a combination of surgical resection, radiotherapy, and systemic therapies. Because of the poor treatment response rate and rapid progression, treatment is often palliative. Here we describe a unique, complete amelioration of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Summary Pituitary carcinoma is a rare malignancy with high rates of metastases at diagnosis, inconsistent therapeutic response, and high mortality. Treatment includes a combination of surgical resections, radiotherapy, and medications. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes the complete resolution of severe Cushing's disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation and concurrent temozolomide radio-sensitization. Introduction Pituitary adenomas (PA) are a common, benign tumor managed with combinations of surgery, radiotherapy, and medication. While uncommon, there are atypical PA with aggressive behaviors that are refractory to treatment. In rare instances, pituitary tumors can metastasize or spread. These malignant behaving tumors are called pituitary carcinomas (PC). PC is challenging to manage as they metastasize early and have a poor response to treatment. In reported PC cases, malignant transformation of atypical adrenocorticotrophic hormone (ACTH) secreting PA is a common pathogenesis.1 Features of PC include functional ACTH production and resistance to radiation. Because of the aggressive nature and systemic spread, the prognosis is poor with a high mortality rate of 66% at one year.2 Prospective studies and observable data are scarce. Prior reports of treatment include a combination of surgical resection, radiotherapy, and medication with inconsistent responses. Because of the poor treatment response rate and rapid progression, treatment is often palliative. This report describes a complete resolution of severe Cushing disease due to an ACTH secreting pituitary carcinoma followed by the development of pituitary hypoadrenalism after re-irradiation with concurrent temozolomide. Case Description A 53-year female presented with complaints of blurry vision, right-sided cranial nerve (CN) III palsy, diffuse edema of her face and extremities, and a 15 lb. weight gain over 2 weeks. Visual field testing revealed bitemporal hemianopsia which prompted imaging. MRI demonstrated a large intracranial sellar mass (4.0 × 4.3 cm) invading the suprasellar cistern and compressing the optic chiasm. ACTH and cortisol were elevated, which combined with radiographic evidence, established a diagnosis of an ACTH-secreting pituitary macroadenoma and Cushing's disease (CD). The patient underwent a transsphenoidal tumor debulking, followed by CyberKnife stereotactic radiosurgery two months after surgery (treated to 24 Gy, seeTable 2). Pathology revealed an atypical PA, positive for p53 and with a low Ki-67 index. Table 1. Clinical Course Date Condition 24 h urinary cortisol* Late salivary cortisol* Serum morning cortisol* ACTH* Nov 2009 Before 1st debulking surgery 3,192 N/A N/A 635 Feb 2010 Cyberknife 6.9 1.5 9.6 134 May 2014 Redo-Debulking 40.2 5.5 11.8 190.0 August 2017 3 months post RT 20.1 5.5 39.4 240.8 May 2018 1 year post RT 16.0 5.9 12.6 199.8 Feb 2019 1 year and 6 months post RT 2.1 3.6 6.8 111.8 Jan 2020 Post 3rd Debulking N/A N/A 8.4 88.5 ⁎ 24h urinary cortisol (NR:30-310 ug/24h). Late salivary cortisol(NR < 0.13 ug/dL). Serum morning cortisol (NR: 5-25 ug/dL). ACTH (NR <46 pg/dL) GC: glucocorticoids, CS: Cushing syndrome Table 2. CyberKnife Radiation Treatment Plan Cyber Knife Feb 2010 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) Standard deviation (SD)(cGy) CTV 7 2817 1214 2403 240 PTV 6 2817 1323 2457 204 Brain Stem 34 1023 28 250 160 Left Eye 7 65 16 29 7 LON 2 1069 39 233 223 Optic Chiasm 1 845 194 448 164 Right Eye 7 164 16 31 12 RON 2 1267 48 298 216 After three years in remission, she experienced worsening symptoms associated with cortisol excess. Medical management of cabergoline (D2 receptor agonist) followed by pasireotide (somatostatin analog) was tried without clinical improvement. Imaging demonstrated the mass had recurred with non-congruent intracranial spread. This noncontiguous intracranial growth met the criteria for PC. A second transsphenoidal subtotal resection was performed. Pathology revealed atypical ACTH secreting adenoma with a similarly low Ki-67, but with a new loss of p53 signaling. Despite debulking, she had biochemical persistence of hypercortisolism. Over the next two months, the patient declined rapidly with weakness, and worsening Cushing's symptoms. She was enrolled in a Phase III clinical trial with osilodrostat (11-Beta hydroxylase inhibitor) however, could not tolerate the investigational drug and was taken off. Subsequent MRI showed evidence of progression with gross residual disease and interval growth. She was referred to radiation oncology. She completed a course of image-guided, intensity modulated, radiotherapy (IG-IMRT) with concurrent temodar (TMZ) radiosensitization. TMZ was dosed at 75 mg/m2 per day for 42 days during radiation. Her IG-IMRT plan consisted of a gross tumor volume (GTV); drawn for MR defined gross disease and a clinical target volume (CTV) encompassing gross disease at risk areas of microscopic disease extension (Figure 1). These volumes were then expanded to 2 planning target volumes (PTV). The first, and larger, PTV was created by expanding the CTV to PTV1 and treated to 50.4 Gy in 28 fractions (180 cGy/fraction). The GTV alone was expanded to PTV2 (integrated boost) and was treated to a total dose of 56 Gy in 28 fractions (200 cGy/fraction) (See Table 3). Over the next two years, the patient had a steady decline in ACTH and cortisol levels and experienced a significant improvement in CD symptoms. Amazingly, she developed hypocortisolemia. Following concurrent chemo-RT, her leg strength and ambulation improved, and she endorsed improvements in vision. Surveillance images taken a year and a half after chemo-RT showed stable size and configuration of the residual sella and parasellar lesion with obvious shrinkage of the residual PC compared to prior scans. Download : Download high-res image (798KB) Download : Download full-size image Figure 1. IG-IMRT Planning Images Radiotherapy Planning session MRI T1 weighted images with contrast (March 2017) showing PTV's and prescribed isodose lines. Red lines: 5600 cGy, dose1. Yellow lines: 5040 cGy, dose 2. Orange lines: PTV1. Purple lines: PTV2. Table 3. IG-IMRT Radiation Treatment Plan IG-IMRT May 2017 Target/OAR Volume(cm3) Max Dose(cGy) Min Dose(cGy) Mean Dose(cGy) SD(cGy) EqD2 (cGy) GTV 83 6091 4922 5621 233 CTV 24 6083 5292 5793 102 PTV 1 241 6118 4753 5423 270 PTV 2 51 6118 5074 5779 106 Brain Stem 32 5784 2374 4701 586 4324 CHIASM PRV 5 5640 4881 5266 171 5109 Eye_L 8 3173 537 1355 574 841 Eye_R 7 3680 542 1551 644 990 EyeLens_L 0.1 997 614 765 81 435 EyeLens_R 0.1 830 626 719 41 406 InnerEar_L 0.5 5088 4235 4687 164 4305 InnerEar_R 0.4 5673 4853 5165 112 5175 LacrimalGland_L 0.7 2207 734 1313 382 810 LacrimalGland_R 0.8 2518 1064 1736 340 1137 OpticChiasm 0.8 5367 4881 5177 89 4981 OpticNerve_L 0.5 5325 2742 4723 592 4353 OpticNerve_R 0.6 5327 3149 4799 493 4456 EqD2: Equivalent dose in 2 Gy fractions Two years following concurrent chemo-RT, a new clival nodule was noted on imaging. Biopsy confirmed pituitary carcinoma. This was managed with single fraction Gamma Knife delivering a margin dose of 16 Gy (Figure 2) to the biopsied area of recurrence. She remains in clinical remission with stable tumor appearance on recent imaging (Figure 3). Download : Download high-res image (686KB) Download : Download full-size image Figure 2. Gamma Knife Radiation Therapy Planning Images Gamma Knife Planning session MRI T1 weighted images with contrast (May 2020) showing GTV and prescribed isodose line. Red lines: 1600 cGy prescribed dose. Blue lines: GTV. Download : Download high-res image (469KB) Download : Download full-size image Figure 3. Follow-up Imaging Follow up MRI imaging (Jan 2021) showing stable tumor appearance at 8 months post-GK, and 46 months post-IGMRT with TMZ. Discussion Over a ten-year history of persistent symptoms and aggressive tumor behavior, this patient's diagnosis evolved from an atypical ACTH secreting pituitary macroadenoma to an invasive ACTH secreting pituitary carcinoma (PC) that was managed by fractionated imaged-guided intensity modulated radiotherapy (IG-IMRT) with concurrent temozolomide (TMZ). Approximately two years post-IG-IMRT, ACTH/cortisol labs had declined, and the lesion was reduced radiographically. Remarkably, she developed hypocortisolemia mandating hydrocortisone replacement therapy despite an elevated plasma ACTH. It is postulated that the remission of Cushing's disease was likely related to chemo-radiotherapy-induced alterations in the post-translation processing of proopiomelanocortin (POMC) with the production of biologically inactive ACTH and significant decreases in cortisol biosynthesis.4 To date, the patient endorses substantial strength, visual, and cognitive improvement. The mainstay of PC treatment begins with surgical transsphenoidal resection, followed by radiotherapy for residual tumor growth, and adjuvant medical treatment. Studies show in the case of atypical PA that progress to PC, early and aggressive treatment provides the longest survival.3 Surgical resection is the initial intervention to avoid morbidity and mortality related to mass effect of these large aggressive tumors, however, it is rarely complete.3 As a result, the residual disease progresses, and multiple surgeries may be performed after a recurrence of disease. Primary pituitary tumors that present with metastases at diagnosis are termed PC. If no metastases are present, histological evaluation can aid in the management of the tumor.3 Tumors with a high mitotic index, high Ki-67 index >3%, and/or p53 immunoreactivity are termed atypical PA for their aggressive growth and tendency to recur after resection.3 In both PC and atypical PA guidelines, evidence of post-surgical growth is treated with radiation therapy. In general, radiotherapy provides a modest benefit of local tumor control, especially when administered before distant metastases arise in atypical PA with malignant potential.3 Focal stereotactic treatment has shown mostly palliative benefit with little prognostic improvement.3 Finally, medical therapy is used to combat tumor growth and hypersecretory function. Non-chemotherapy biotherapy includes somatostatin analogs, particularly in the case of GH and TSH-producing tumors, with variable tumor reduction and a limited period of control. Chemotherapy agents such as doxorubicin, cisplatin, and etoposide-based chemotherapy have been implicated in the treatment of PC.3 Responses are variable and not widely replicated, but observational studies indicated prolonged survival in cases of distant metastases, and in aggressive atypical PA before malignant transformation.1-3 One report demonstrated significant regression of an ACTH-secreting PC and distant metastases induced with cisplatin and etoposide, two cytotoxic platinum-based chemotherapy drugs.4 These agents have variable CNS penetrance, unlike TMZ, but have potential benefit in cases of PC with high mitotic indices. Without prospective, randomized studies, significant conclusions on the benefits of chemotherapeutic agents have yet to be made. Current guidelines for PC that demonstrate progression after primary tumor debulking and radiotherapy include further surgery (alpha), focused radiotherapy (beta), chemotherapy (gamma), and treatment with radionuclides (delta).3 In this case, a complex PC/recurrent atypical PA had a stable positive response to combined fractionated IG-IMRT and TMZ, demonstrating radiological decrease in tumor volume, clinical improvement, and endocrine remission status post 1 year and 8 months. The lasting results of a combined therapy approach in treating PC have been illustrated in other literature examples. In a similar case, an ACTH secreting PC was treated with a course of concurrent radiotherapy, TMZ, and bevacizumab, an anti-VEGF monoclonal antibody.5 The multimodality course was implemented six weeks post-resection. At eight weeks, the resolution of a distant metastasis helped established a positive outcome. The patient followed up this course with a year of adjuvant TMZ. Five years post treatment, there has been no evidence of recurrent disease on imaging or with ACTH monitoring.5 Another report found that an aggressive, functional ACTH-producing pituitary adenoma was managed with concurrent TMZ and radiotherapy after failing maximal conventional therapy. As in the presented PC case, this PA was recurrent after surgical, medical, and radiotherapy interventions. It rapidly progressed biochemically, radiologically, and clinically. After initiating the combined concurrent TMZ and radiation, a rapid biochemical response was observed with cortisol normalization and regression of intracranial tumor volume on MRI at 3 and 6 months. The TMZ therapy was stopped after the sixth cycle, and at twenty-two months out from treatment, the patient continues to have stable tumor volume and biochemical remission. Although the patient did not have metastasis necessary for classification of PC, the recurrent clinical course and aggressive functional nature of the tumor demonstrate the lasting positive outcome of a combined modality approach on tumor growth and endocrine remission.6 In presenting this case, fractionated IG-IMRT with TMZ was effective in achieving stable endocrine remission and partial tumor regression for several years’ duration. The recurrent clival PA is ACTH non-secreting after IG-IMRT and concurrent TMZ which has improved the patient's clinical condition. Although this mass recurred after treatment, it is quite remarkable that her tumor has remained hormonally nonfunctional, and the patient continues to have a resolution of CD symptoms. Limited clinical information exists on successful treatment options for PC. Recurrence, metastasis, and mortality are high after exhausting conventional treatment. The alternative combined therapeutic approach of current TMZ and radiation has shown rare, and lasting effects in this patient. These findings may further support the use of combined fractionated radiotherapy with concurrent TMZ treating in patients with ACTH-secreting PC who fail standard surgical and medical interventions. References 1 Joehlin-Price, A. S., Hardesty, D. A., Arnold, C. A., Kirschner, L. S., Prevedello, D. M., & Lehman, N. L. (2017). Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing's disease. Diagnostic Pathology, 12(1), 1–8. https://doi.org/10.1186/s13000-017-0624-5 2 Borba, C. G., Batista, R. L., Musolino, N. R. de C., Machado, V. C., Alcantara, A. E. E., Silva, G. O. da, … Cunha Neto, M. B. C. da. (2015). Progression of an Invasive ACTH Pituitary Macroadenoma with Cushing's Disease to Pituitary Carcinoma. Case Reports in Oncological Medicine, 2015(Cd), 1–4. https://doi.org/10.1155/2015/810367 3 Kaltsas, G. A., Nomikos, P., Kontogeorgos, G., Buchfelder, M., & Grossman, A. B. (2005). Clinical review: Diagnosis and management of pituitary carcinomas. Journal of Clinical Endocrinology and Metabolism, 90(5), 3089–3099. https://doi.org/10.1210/jc.2004-2231 4 Cornell, R.F., Kelly, D. F., Bordo, G., Corroll, T. B., Duong, H. T., Kim, J., Takasumi, Y., Thomas, J. P., Wong, Y. L., & Findling, J. W. (2013). Chemotherapy-Induced Regression of an Adrenocorticotropin-Secreting Pituitary Carcinoma Accompanied by Secondary Adrenal Insufficiency. Case Reports in Endocrinology, 2013;2013:675298 https://doi.org/10.1155/2013/675298 5 Touma, W., Hoostal, S., Peterson, R. A., Wiernik, A., SantaCruz, K. S., & Lou, E. (2017). Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. Journal of Clinical Neuroscience, 41, 75–77. https://doi.org/10.1016/j.jocn.2017.02.052 6 Misir Krpan, A., Dusek, T., Rakusic, Z., Solak, M., Kraljevic, I., Bisof, V., … Kastelan, D. (2017). A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma. Case Reports in Endocrinology, 2017, 1–5. https://doi.org/10.1155/2017/2419590 Funding: None Disclosures: Dr. Findling reports grants, personal fees and other from Novartis, personal fees and other from Corcept Therapeutics, personal fees from Recordati, outside the submitted work. Research data are stored in an institutional repository and will be shared upon request to the corresponding author. © 2021 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. From https://www.sciencedirect.com/science/article/pii/S2452109421001718
  2. A team of scientists in Montreal and Paris has succeeded in identifying the gene responsible for the development of a food-dependent form of Cushing’s Syndrome, a rare disease affecting both adrenal glands. In their study published in The Lancet Diabetes & Endocrinology, Dr. Isabelle Bourdeau and Dr. Peter Kamenicky identify in the gene KDM1A the mutations responsible for the development of this unusual form of the disease. The scientists also show, for the first time, that the disease is genetically transmitted. Bourdeau is a researcher and a Université de Montréal medical professor practising at the CHUM Research Centre (CRCHUM), while Kamenicky works at the Hôpital de Bicêtre, part of the Assistance publique-hôpitaux de Paris network in France. Cushing’s Syndrome is caused by the overproduction of cortisol, a steroid hormone, by the two adrenal glands located above the kidneys. “When the tissues of the human body are exposed to this excess of cortisol, the effects for those with the disease are serious: weight gain, high blood pressure, depression, osteoporosis, and heart complications, for example,” said Bourdeau, co-lead author of the study with Dr. Fanny Chasseloup, a colleague from the French team. This discovery comes nearly 30 years after food-induced Cushing’s Syndrome was first described in 1992 by a research group led by Dr. André Lacroix at the CRCHUM and his colleagues Drs. Johanne Tremblay and Pavel Hamet. The form of the disease being studied by Bourdeau and her colleagues is caused specifically by the abnormal expression of the receptors of a hormone named GIP (glucose-dependent insulinotropic peptide), in both adrenal glands of patients. This hormone is produced by the small intestine in response to food intake. For people with the disease, cortisol concentrations increase abnormally every time they ingest food. The discovery of the genetic mechanism by the French and Quebec teams was made possible through the use of recent cutting-edge genetic techniques on tissues of patients including those investigated by Dr Lacroix at CHUM. Bourdeau was aided by CRCHUM researcher Martine Tétreault during the computer analyses related to the research project. Earlier diagnosis thanks to genetic analysis “In general, rare diseases are generally underdiagnosed in clinics,” said Bourdeau, the medical director of the adrenal tumors multidisciplinary team at the CHUM. “By identifying this new gene, we now have a way of diagnosing our patients and their families earlier and thus offer more personalized medicine. At the CHUM, genetic analysis is already offered in our Genetic Medicine Division.” In a remarkable demonstration of scientific cooperation, the Quebec and French teams were able to collect and study tissue specimens available in local and international biobanks in Canada, France, Italy, Greece, Belgium and the Netherlands. Blood and adrenal gland tissue samples of 17 patients—mostly women—diagnosed with GIP-dependent Cushing’s Syndrome were compared genetically with those of 29 others with non-GIP-dependent bilateral adrenal Cushing’s Syndrome. This was quite an accomplishment, given the rarity of the disease in the general population. It allowed the researchers to identify the genetic mutations of the KDM1A gene and to determine that the disease is genetically transmitted. Since 2009, the CHUM has been designated as the adrenal tumors quaternary care centre of the Quebec Cancer Program. About this study  “Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: a multicenter retrospective cohort study,” by Drs. Fanny Chasseloup, Isabelle Bourdeau and their colleagues, was published Oct. 13, 2021, in The Lancet Diabetes & Endocrinology. Funding was provided by the Agence nationale de la recherche, the Fondation du Grand défi Pierre Lavoie, the Institut national du cancer, the Fonds de recherche du Québec-Santé, INSERM and Assistance publique-hôpitaux de Paris. About the CRCHUM The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students Media contact Jeff HeinrichUniversité de MontréalTel: 514 343-7593 Lucie DufresneCentre hospitalier de l’Université de MontréalTel: 514 890-8000 p. 15380
  3. Example: Make sure the last urine is exactly 24 hours after you started the clock (when you discard the first urine). Any 24-hour period is fine. Urinate at 7:00 am Monday morning and flush. Start your clock and collect every drop of urine up to and including 7:00 am on Tuesday morning (set an alarm if necessary). If you are doing multiple tests, they should give you a new jug when you turn the first one in. Your doctor or the lab should give you a urine "hat" - this will help with collection. If not, amazon sells them:
  4. What You Need to Know COVID-19 Vaccine booster shots are available for the following Pfizer-BioNTech vaccine recipients who completed their initial series at least 6 months ago and are: 65 years and older Age 18+ who live in long-term care settings Age 18+ who have underlying medical conditions Age 18+ who work in high-risk settings Age 18+ who live in high-risk settings Those "underlying medical conditions" include diabetes and obesity.
  5. Personal Stories: From my bio: (At the NIH in October 1987) The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrollable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don't have to keep sticking me). I got to go home for a weekend and then went back for the surgery... _____ From Karen's Story: https://cushingsbios.com/2016/11/18/doc-karen-pituitary-and-bla-bio/ At that time, there was evidence of a pit tumor but it wasn’t showing up on an MRI. So, I had my IPSS scheduled. An IPSS stands for Inferior Petrosal Sinus Sampling. It is done because 60 % of Cushing’s based pituitary tumors are so small that they do not show up on an MRI. Non Cushing’s experts do not know this so they often blow patients off, even after the labs show a high level of ACTH in the brain through blood work. An overproduction of the hormone ACTH from the pituitary communicates to the adrenal glands to overproduce cortisol. Well, the IPSS procedure is where they put catheters up through your groin through your body up into your head to draw samples to basically see which side of your pituitary the extra hormone is coming from, thus indicating where the tumor is. U of C is the only place in IL that does it. ... I was scheduled to get an IPSS at U of C on June 28th, 2011 to locate the tumor. Two days after the IPSS, I began having spontaneous blackouts and ended up in the hospital for 6 days. The docs out here had no clue what was happening and I was having between 4-7 blackouts a day! My life was in danger and they were not helping me! We don’t know why, but the IPSS triggered something! But, no one wanted to be accountable so they told me the passing out, which I was not doing before, was all in my head being triggered by psychological issues. They did run many tests. But, they were all the wrong tests. I say all the time; it’s like going into Subway and ordering a turkey sandwich and giving them money and getting a tuna sandwich. You would be mad! What if they told you, “We gave you a sandwich!” Even if they were to give you a dozen sandwiches; if it wasn’t turkey, it wouldn’t be the right one. This is how I feel about these tests that they ran and said were all “normal”. The doctors kept telling us that they ran all of these tests so they could cover themselves. Yet, they were not looking at the right things, even though, I (the patient) kept telling them that this was an endocrine issue and had something to do with my tumor! Well, guess how good God is?!!!! ... Fast forward, I ended up in the hospital with these blackouts after my IPSS. The doctors, including MY local endocrinologist told me there was no medical evidence for my blackouts. In fact, he told the entire treatment team that he even doubted if I even had a tumor! However, this is the same man who referred me for the IPSS in the first place! I was literally dying and no one was helping me! We reached out to Dr. Ludlam in Seattle and told him of the situation. He told me he knew exactly what was going on. For some reason, there was a change in my brain tumor activity that happened after my IPSS. No one, to this day, has been able to answer the question as to whether the IPSS caused the change in tumor activity. The tumor, for some reason, began shutting itself on and off. When it would shut off, my cortisol would drop and would put me in a state of adrenal insufficiency, causing these blackouts! Dr. Ludlam said as soon as we were discharged, we needed to fly out to Seattle so that he could help me! The hospital discharged me in worse condition then when I came in. I had a blackout an hour after discharge! But get this…The DAY the hospital sent me home saying that I did not have a pit tumor, my IPSS results were waiting for me! EVIDENCE OF TUMOR ON THE LEFT SIDE OF MY PITUITARY GLAND!!! _____ From Kirsty: https://cushingsbios.com/2013/06/25/kirsty-kirstymnz-ectopic-adrenal-bio/ The hardest of all these was what they call a petrusal vein sampling (this is where they insert a catheter into the groin through the femoral vein which goes up to the base of the brain to look at the pituitary, they do this while awake – I could actually feel them moving around in my head.) This test concluded that my Cushing’s was being caused by a tumor somewhere other than the pituitary (this only happens in 1% of cases, and there is about a 1 in 10 million chance of getting it). The question now was “where is the tumor?” _____ Find other bios with which mention this test at https://cushingsbios.com/tag/ipss/ __________ This topic on these message boards: https://cushings.invisionzone.com/forum/54-css-ct-ipss-ivp-mri-np-59-scan-octreoscan-pss-sonogram-ultrasound/ __________ Thoughts from Dr. James Findling: https://cushieblogger.com/2019/03/24/cushings-syndrome-expert-a-standout-in-clinical-practice/ Another defining moment in my career from a research perspective was when I was a fellow, I had to do a project. We were seeing a lot of patients with Cushing’s — of course, that’s why I went there — and in those days we had no good imaging. There were no CT scans, no MRI, there was no way to image the pituitary gland to find out whether there was a tumor. By the late ’70s it became obvious that some patients with Cushing’s syndrome didn’t have pituitary tumors. They had tumors in their lungs and other places, and there was no good way of sorting these patients from the pituitary patients. My mentor at UCSF, Blake Tyrrell, MD, had the idea of sampling from the jugular vein to see if there was a gradient across the pituitary. I took the project up because I didn’t think this is going to be helpful due to there being too much venous admixture in the jugular vein from other sources of cerebral venous drainage. We went into the radiology suite to do the first patient. As I was sampling blood from the peripheral veins, the interventional radiologist, David Norman, MD, says, “Would you like to sample the inferior petrosal sinus?” I said, “Why not? It sounds like a good idea to me.” That turned out to be helpful. We then studied several patients, and it eventually went to publication. Now everybody acknowledges it is necessary, maybe not in all patients with Cushing’s, but in many patients with Cushing’s to separate pituitary from nonpituitary Cushing’s syndrome. __________ Official information Patient information from Canterbury Health Limited Endocrine Services INFERIOR PETROSAL SINUS SAMPLING WITH CRH STIMULATION Introduction You have been diagnosed with Cushing's syndrome which results from excessive production of the hormone cortisol, made by the adrenal glands. In your case, the adrenal glands are being driven by excessive amounts of another hormone called ACTH. This test is to determine where that ACTH is coming from. Constant high levels of ACTH are usually caused by a tumor. Approximately 80% of cases are tumors of the pituitary gland while the remainder may occur in the lung, pancreas and other sites (known as "ectopic" sites). This test relies on the fact that if the source of your high ACTH is the pituitary gland blood levels taken from very near the gland will be higher than the blood level in an arm vein. Pituitary gland tumors are often tiny and can't be seen even with the most modern scanners. This test will help your endocrinologist to know with almost 100% certainty whether the pituitary gland is the source or if a search is needed elsewhere (for example in the lungs or abdomen). This guides treatment, for example the recommendation for Pituitary surgery. Procedure You are allowed water only from midnight the night before (nothing else to eat or drink). You will be given a light sedative, but will be awake during the procedure. You will be taken to the Radiology Department where the procedure will take place. The radiologist will place some local anesthetic into the groin on each side over the main vein that drains blood from each leg. Then a fine bore catheter will be passed up the vein, past the heart and into the major vein in the neck (the jugular vein). From there it is passed into a smaller vein that drains blood directly from the pituitary gland, known as the inferior petrosal sinus. The procedure is repeated for the other side. X-ray screening guides the radiologist to know where the catheters are positioned. A small butterfly needle is inserted into an arm vein. Once the catheters are in place, blood samples will be taken from the right and left petrosal sinus, and an arm vein at exactly the same time. After two baseline samples, a hormone called CRH is injected into the arm vein. This increases ACTH when a pituitary gland tumor is present, but has no effect on ectopic ACTH production. Further blood samples are taken for another 10 to 15 minutes, then the catheters are withdrawn. Pressure is applied to the groins to minimize bruising. Often sampling is continued from the arm vein only, for a total of 90 minutes. You will have to remain lying on your back for at least 2 hours afterwards. Risks This procedure is very safe when performed by an experienced radiologist. Rarely, there have been reports of people having a stroke at the time of this procedure but this was related to a catheter of faulty design which is now no longer used. Bruising, which is common in Cushing's syndrome, may occur after the catheters are pulled out. Some people notice flushing of the face after the CRH and rarely it can result in a fall in blood pressure. From: http://www.pituitarycenter.com/html/article1.html INFERIOR PETROSAL SINUS SAMPLING Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From: http://www.mc.vanderbilt.edu/pituitarycenter/html/article1.html Patients who are suspected of having a pituitary tumor resulting in Cushing's syndrome may be referred for inferior petrosal sinus sampling if findings on MRI examination of the pituitary did not reveal a tumor or are inconclusive. The inferior petrosal sinus sampling procedure is performed in the radiology department. With the patient on the angiography table both groin regions are partially shaved, sterilized, and a local anesthetic is injected into the skin to provide pain relief. A tiny incision is made within the skin and a needle is inserted to puncture the femoral vein which drains blood from the leg. A small catheter is then inserted into the vein and flushed with an intravenous solution. Longer catheters are passed into the shorter catheters and advanced through the large veins traversing the torso into the neck and then into the base of the skull. Thereafter, a microcatheter is advanced through each of these larger guiding catheters and threaded into the inferior petrosal sinuses which lie along the internal aspect of the skull base and drain blood from the pituitary gland. Once these microcatheters have been positioned, contrast dye is injected and X-rays are taken to verify their position in the inferior petrosal sinuses. Next, blood samples are collected from both catheters in the inferior petrosal sinuses and from a peripheral (usually arm) vein. Thereafter, corticotropin-releasing hormone is administered through the peripheral vein. Repeat blood samples are drawn 2, 5, and 10 minutes after the injection. Additional X-rays are taken to confirm that the catheters were not dislodged from their site during the sampling procedure. Thereafter, the catheters are removed and direct pressure is applied to the groin region to decrease the likelihood of bruising. Patients are observed for 4 hours following the procedure to ensure that no bleeding from the femoral vein puncture sites will occur. Normal non-strenuous activity may be resumed 48 hours after the procedure. Sedatives and pain relievers may be administered during the procedure as necessary. A blood thinner might be used depending on the patient's anatomy and the clinical suspicion of developing a blood clot. If a blood thinner is used, this may be counteracted with medication at the conclusion of the procedure to ensure that normal blood clotting resumes while removing the catheters. Overall, the inferior petrosal sinus sampling procedure involves minimal discomfort. The risks of the procedure are small. X-rays are used but the radiation doses are minimized. Infection is controlled by using sterile technique. Some patients might have an unexpected allergic reaction to the dye used during the study. A bruise may develop within the groin. Although rare, blood clots have developed in the groin veins following this procedure. Again, steps are taken to minimize the likelihood of each and every one of these complications. ACTH levels are measured in each of the blood samples obtained during the procedure. The ratios between the petrosal sinus sampling and the peripheral vein samples are compared. The results are used to determine whether ACTH production is due to either a pituitary or a non-pituitary source. ___ From https://www.uclahealth.org/radiology/interventional-neuroradiology/inferior-petrosal-sinus-sampling The IPSS test is done in some patients to identify if there is too much ACTH is causing the excess production of cortisol, and where it is coming from. How do we do an IPSS procedure? Typically under general anesthesia, we place small tubes (catheters) into the femoral veins (the main vein draining the legs) at the level of the groin. From there, under X-ray guidance, we navigate those catheters to the main veins which drain the Pituitary gland. These are the inferior petrosal sinuses (right and left). We then draw samples from those veins and the main vein of the abdomen and test those samples for ACTH. We also take timed samples after giving a dose of medication which would normally stimulate the production of ACTH to improve the sensitivity of the test. When we get the results, the different levels of ACTH may help the endocrinologist determine where the tumor is located that is causing the adrenal gland to produce the excess cortisol. If it is from the Pituitary gland, any difference between the right and left samples may help the surgeon determine the surgical plan to remove the tumor yet preserve the normal Pituitary gland. Example of testing results: Time Right IPS Left IPS Inf Vena Cava Cortisol Baseline 1 09:32 40 pg/ml 17 18 25 mcg/dl Baseline 2 09:34 45 18 15 24 DDAVP inj 09:38 Post 2min 09:40 72 21 18 Post 5min 09:43 157 20 19 Post 10min 09:48 161 30 25 Post 15min 09:53 162 33 26 Post 30min 10:08 124 32 29 30 This example shows elevation of ACTH in the right inferior petrosal sinus, likely indicating a tumor in the right side of the pituitary gland causing Cushing’s Disease. Picture of contrast injection of the inferior petrosal sinuses: Tips of the catheters in the inferior petrosal sinuses.
  6. Kate** on the Cushing’s support board (Cushing’s Help and Support) wrote this letter after having pituitary surgery… Dear friends and family: I am writing this letter to share with you some basic facts about Cushing’s Disease/Syndrome and the recovery process so that you will have sufficient information to form realistic expectations about me and my ability to engage in certain activities in light of this disease and its aftermath. As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress. The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol. People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc. Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne. Cushing's Symptoms http://www.cushings-info.com/images/1/12/Lady.gif A sketch of a typical Cushing’s patient. As you can see, the effects of the disease on the body are dramatic. Worse, the psychological and emotional effects of having a chronic, debilitating and disfiguring disease range from distressing to demoralizing. Imagine that, in the space of a year, you became unrecognizable to those around you and to yourself. You look in the mirror, but the person staring back a tyou is a stranger. You endure the stares and looks of pity from those who knew you before Cushing’s, fully aware that they believe you have “let yourself go” or otherwise allowed this to happen to your body. Nothing you can say or do will persuade them otherwise, so at some point, you stop trying and resolve to live your life in a stranger’s body. You feel increasingly sick, but when you explain your array of symptoms to your doctor, you are dismissed as a depressed hypochondriac who needs to diet and exercise more. Worse, your family members think the same thing — and are often quick to tell you how you need to “change your lifestyle” to overcome the effects of what you eventually will discover, once properly diagnosed, is a serious and rare disease. If only it were so simple! No one would choose to have Cushing’s. Those of us who have it would not wish it even on our worst enemy. Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher. One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease. Sometimes, as with any serious illness, performing even basic tasks of daily care such as showering and dressing can exhaust the limited reserves of energy available to a Cushing’s patient. How do we explain to you what it’s like to watch our lives slip away? What response is sufficient to express the grief and frustration over losing so much of ourselves? It is often difficult to find the strength to explain how your well-meaning words of prompting and encouragement (to diet or exercise) only serve to leave us more isolated and feeling alone. Though we wouldn’t want it, we wish our disease were as well-understood as cancer so that those who love us would have a frame of reference for what we go through. With Cushing’s, there is such limited public awareness that we are left to describe the effects of the disease from a void, often with limited understanding from those who love us most, which is disheartening. The most frustrating misconception about this disease is that we somehow are “doing this to ourselves,” or delaying recovery because we need to continue steroid replacement or lack the energy to excercise often, which is sadly false. Trust me that we would love to have that much control over such a terrible disease. Fortunately, there is a good likelihood of remission from Cushing’s in the hands of a skilled pituitary surgeon. Unfortunately, the long-term remission rate is only 56%, meaning that 44% of people with Cushing’s will require a second (sometimes third) pituitary surgery, radiation or bilateraly adrenalectomy to resolve the hypercortisolism. Without successful treatment, Cushing’s leads to death. Even with successful treatment, I will have to be monitored for possible recurrence for the rest of my life. After surgery or other treatment, the recovery period can last months or even years. Because the tumor takes over control of the body’s production of cortisol, the adrenal glands, which had lain dormant prior to surgery, require time to start functioning properly again. Until this happens, we must take synthetic steroids or else risk adrenal insufficiency or adrenal crisis, which can be quickly life-threatening. Careful monitoring of our cortisol levels is critical during the weaning period. It is a rare but sad fact that some people’s adrenal glands never return to normal, and those people must continue to take hydrocortisone or prednisone — sometimes for life — simply in order for the body to perform correctly its basic systemic functions. The physical recovery from surgery can be quick, but the withdrawal from hydrocortisone can be a lengthy and extremely painful process. As I described above, Cushing’s causes a tearing-down of muscles and bone. While there is an over-abundance of cortisol in our bodies (as a result of the tumor), we often can’t feel the effects of the muscle-wasting and bone deterioration because of the anti-inflammatory action of cortisol. Upon weaning, however, these become painfully (literally!) evident. The physical pain experienced while weaning from cortisol has been described as worse than weaning from heroin. When cortisol levels are low, one experiences the symptoms akin to a really bad flu, including severe fatigue (”like a wet cement blanket laid on top of me”); weakness and exhaustion; nausea; headache; vomiting; mental confusion. It is imperative for people who are on replacement steroids after Cushing’s surgery to carry extra Cortef (or injectable Solu-Cortef) with them at all times in addition to wearing a medic alert bracelet so that medical professionals will be alerted to the possiblity of adrenal insufficiency in the event of an adrenal crisis. People who have struggled with Cushing’s Syndrome all hope to return to “normal” at some point. Though none of us want to have Cushing’s, it is often a relief finally to have a correct diagnosis and treatment plan. For many, there is a gradual resolution of many Cushing’s symptoms within a few years of surgery or other successful treatment, and a good quality of life can be achieved. But regrettably, this is not possible in every case. Depending on the severity of the disease and the length of time before diagnosis and treatment, the prognosis can be poor and lead to shortened life expectancy and diminished quality of life. This is not a choice or something we can control, but it is the reality for some people who have suffered the consequences of long-term hypercortisolism. The best support you can give someone who is suffering from Cushing’s or its aftermath is to BELIEVE them and to understand that they are not manufacturing their illness or prolonging recovery. Ask them what they are able (and not able) to do, and then be prepared to help them in ways that matter — whether that be to bring them a meal or help them to run errands, pick up prescriptions from the pharmacy or clean their house. Because it’s these little everyday tasks, which can fall by the wayside when someone has (or has had) Cushing’s, and these are the things we miss the most: doing for ourselves. Ask us questions about the disease, and then actively listen to what we say. We know you don’t know much about Cushing’s — even our doctors sometimes lack information about this rare disease. But know we appreciate the interest and will tell you everything you want to know, because those of us who have it necessarily become experts in it just in order to survive. Thank you for caring about me and for hearing what I am saying in this letter. I know you love me and are concerned about me, and I appreciate that so much. Thank you also for taking the time to read this letter. I look forward to discussing further any questions you might have. In the meantime, I am attaching a brief article written by a woman who recently was diagnosed with Cushing’s. I hope hearing another person’s experiences will help you to understand what I’m going through so that when we talk, we will be coming from a similar starting place. Endocrinologists (doctors who specialize in Cushing's Syndrome and its related issues) realize the medical aspect and know the damaging effects that Cushing's has on the body. Family and friends see their Cushie suffering and know they are hurting physically and often times mentally and emotionally. However, understanding the debilitation of Cushing's and how it can affect every aspect of a person's life can only be truly realized by those who have experienced the syndrome. Cushings Help Organization, Inc., a non-profit family of websites maintained by MaryO, a pituitary Cushing's survivor, provides this letter for patients to provide to their family and friends in hopes of providing a better understanding Cushing's and it's many aspects. We're sorry to hear that your family member or friend has Cushing's Syndrome or suspected Cushing's. A person may feel better at times then at other times. It's common for a Cushing's patient to have burst of energy and then all of a sudden they become lethargic and don't feel like moving a muscle. There are many symptoms that are associated with Cushing's. They include weight gain, fatigue, muscle weakness, shortness of breath, feeling achy all over, headaches, blurred vision, mood swings, high blood pressure, stretch marks (straie), buffalo hump, diabetes, edema and the list goes on. Hormones affect every area of the body. It is important to note that not all patients have every symptom. Even some hallmark symptoms, such as straie or the "buffalo hump", may not be noticable on every patient. Not everyone who has Cushing's will experience the same symptoms, treatment, or recovery. Because not all "Cushies" have these symptoms, it makes diagnosis even more difficult. Cushing's can cause the physical appearance change due to weight gain, hair loss, rosacea, acne, etc. This can be very disturbing when looking in the mirror. Changes in appearance can often cause the Cushing's patient to withdraw from family and friends making it a very lonely illness. Patients often feel alone or withdrawn because few others understand. Cushing's can affect affect anyone of any age although it is more commen in women. Cushing's patients need to be able to take one day at time and learn to listen to their bodies. There will most likely be times when naps are needed during the day and often times may not be able to sleep at night due to surges of cortisol. Your Cushie doesn't expect you to understand Cushing's Syndrome completely. They do need you to be there for them and try to understand to the best of your ability what they feel and not give up on them. Often a Cushing's patient may be moody and say things that they don't mean. If this should happen with your Cushie try not to take it personally and know that it's most likely caused by the elevated cortisol and disturbances in other hormone levels caused by the Cushing's and not from the heart or true feelings of your Cushie. It can be very depressing and frustrating having so many limitations and experience things in life being taken from you. Cushing's patients are sick, not lazy, not hypochondriacs or even the newer term "Cyberchondriacs". If a Cushing's patient says they don't feel like doing something or they express how bad they feel let them know that you believe them. One of the most frustrating things to someone who is sick is to have those you love not believe you or support you. Telling a Cushie to think positive thoughts will not make him/her well and will just be aggrivating. Testing procedures can be lengthy and this can become frustrating for the patient and family. Often, it takes a while for results to come back and this can be stressful. Don't look to far ahead just take one day at a time and deal with the situation that is at hand at the present time. After a diagnosis is made then it's time for treatment. Surgery is usually the best treatment option for Cushing's that is caused by tumors. Don't be surprised if the surgeon's facility wants to run even more tests or redo some of those that have already been done. Your Cushie may have to travel a ways to find a surgeon who is trained in these delicate surgeries and who has performed many of them. Once the diagnosis has been made and treatment has finished then it's time for the recovery process. Not all patients who have surgery are cured and they have to make a choice along with the advice of their doctor as to what their next treatment option will be. The recovery from the surgery itself is similar to any other surgery and will take a while to recover. The recovery process obtained from getting a cure from Cushing's is quiet different from other surgeries. A Cushing's patients body has been exposed to excess cortisol, usually for quite a long time, and has become accustomed it. When the tumor is removed that has been responsible for the excessive cortisol and the body is no longer getting it this causes the body to have withdrawal symptoms. Withdrawal can be very hard causing an array of symptoms muscle aches, weakness, bone and joint pain, emotional disturbances etc. Thank you for reading this and we hope it will help you to understand a little more about Cushing's and the dibilating affect it can have on a person. Thank you for being there and supporting your Cushie during this time in their life. We realize that when a family member has Cushing's it not only affects the individual but other family members and those around them as well. Showing your love and support will encourage a speedy recovery for your Cushie. **Note: Kate died on on June 23, 2014. Read her In Memory page here: http://cushingsbios.com/2014/06/25/in-memory-kate-meyers/
  7. Abstract Background The most common etiologies of Cushing's syndrome (CS) are adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients. Methods A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009–2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups. Results Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, P = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, LDL-C, HDL-C, triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two. Conclusions Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics. Keywords Cushing's syndrome Pituitary Cushing's Adrenal Cushing's Metabolic disturbance From https://www.sciencedirect.com/science/article/pii/S2095882X21000669
  8. I really don't understand why they aren't removing the adrenal gland, then - is she doing testing with an endocrinologist, Bizzyusual? She would need to be diagnosed with Cushing's before they do anything with the adrenal tumor and that means testing, sometimes lots of it. I hope she sees that and gets started with endo appointments. Thanks for being good parents-in-law!
  9. https://doi.org/10.1016/j.radcr.2021.07.093 Abstract The chronic excess of glucocorticoids results in Cushing's syndrome. Cushing's syndrome presents with a variety of signs and symptoms including: central obesity, proximal muscle weakness, fatigue striae, poor wound healing, amenorrhea, and others. ACTH independent Cushing's syndrome is usually due to unilateral adenoma. A rare cause of it is bilateral adrenal adenomas. In this paper we report a case of a 43-year-old woman with Cushing's syndrome due to bilateral adrenal adenoma. Read the case report at https://www.sciencedirect.com/science/article/pii/S1930043321005690
  10. The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background. Introduction Endogenous Cushing´s syndrome (CS) is a rare disorder with an incidence of 0.2–5.0 per million people per year (1, 2). The predominant subtype (accounting for about 80%) is adrenocorticotropic hormone (ACTH)-dependent CS. The vast majority of this subtype is due to an ACTH-secreting pituitary adenoma [so called Cushing´s disease (CD)], whereas ectopic ACTH-secretion (e.g. through pulmonary carcinoids) is much less common. In contrast, ACTH-independent CS can mainly be attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease (PPNAD) may account for some of these cases as well (3, 4). Coexistence of different subtypes of endogenous CS in single individuals is even rarer but has been described in few reports. These cases were usually observed in the context of prolonged ACTH stimulation on the adrenal glands, resulting in micronodular or macronodular hyperplasia (5–9). A sequence of CD and PPNAD was also described in presence of Carney complex, a genetic syndrome characterized by the loss of function of the gene encoding for the regulatory subunit type 1α of protein kinase A (PRKAR1A) (10). Moreover, another group reported the case of a patient with Cushing's disease followed by ectopic Cushing's syndrome more than 30 years later (8). To our knowledge, however, we here describe the first case report on a single patient with a cortisol-producing adrenocortical adenoma and subsequent CD. Read the rest of the article at https://www.frontiersin.org/articles/10.3389/fendo.2021.731579/full
  11. Friday, October 8, 2021 7:45 am - 4:00 pm OVERVIEW This conference will present the newest approaches and techniques in the diagnosis and treatment of pituitary adenomas, including acromegaly and Cushing’s disease. Diagnosis and treatment will be covered from the interdisciplinary and interprofessional perspective of endocrinology, radiology, neuro-ophthalmology, neurosurgery, and radiation oncology. Didactic presentations will include case discussions. The conference format, although virtual will provide a significant opportunity for interaction with expert faculty. A simulcast of transsphenoidal surgery will occur throughout the conference with real-time discussion and case review of the progress on the day of surgery, post-op management, surveillance and follow-up care. Participants will leave with up-to-date, practical information and written resources including: DDAVP stimulation protocol for Cushing’s disease localization, perioperative glucocorticoid and salt-water monitoring protocol, clinic note templates, laboratory testing panels, "Sick Day Rules" letter for patients with adrenal insufficiency. These materials will have immediate clinical application and help streamline care of pituitary patients at the office and during hospitalizations. LEARNING OBJECTIVES – CME Upon completion of this conference, participants should be able to: Evaluate a sellar mass to determine if it is a pituitary adenoma or other lesion Identify the value and limits of MRI in evaluating a sellar mass List the potential and limits of endoscopic transsphenoidal surgery for pituitary adenoma Manage, medically, a patient following endonasal surgery List the different types of radiation, including linear accelerator (IMRT, Cyberknife), gamma radiation, (Gamma Knife) and proton beam Treat, medically, patients who have acromegaly and Cushing’s disease Apply multidisciplinary, interprofessional and interdisciplinary approach in the management of pituitary disease LEARNING OBJECTIVES – PATIENTS Upon completion of this course patients, families and advocates will be able to: Identify the latest advances in pituitary tumor treatment Demonstrate familiarity with the terminology and technical aspects of pituitary tumor care Demonstrate patient-active behavior in working with the healthcare team to make ongoing treatment decisions WHO SHOULD ATTEND This activity has been designed for endocrinologists, neurosurgeons, ophthalmologists, gynecologists, general radiologists, nurse practitioners, nurses, residents and fellows. Additionally, patients and their caregivers, family members, advocates and members of the public who may benefit from understanding current innovative approaches to pituitary tumor care are invited. For additional information please contact Hyacen Putmon. Register Now
  12. Urine Tests: These involve collecting urine, usually for periods of twenty-four hours at a time. Twenty-four Hour Urine: The doctor will give you a gallon collection jug, usually with boric acid in it. The instructions are usually printed on the side. Generally, you urinate first thing in the morning, as usual. after that, you collect the rest of the urine for the next 24 hours in the jug. The directions usually tell you to refrigerate the jug. Directions for the Twenty-four Hour Urine Test Physicians have always relied upon analysis of urine specimens in order to diagnosis and treat many disease processes. Twenty-four hour urine collections are often employed to estimate the production rates of various hormones. The accuracy of test results depends entirely on the accuracy of the urine collection technique. These instructions are provided as a guide to ensure that your 24-hour urine collection is obtained in a manner that will permit reliance upon the test results. Urine samples should be collected in a large cup, urine collection hat or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Urine collection hats can usually be purchased at medical supply stores if not provided by your physician or lab. If you should have a bowel movement while urinating the urine collection hat should keep the urine clean if used correctly. Urine samples should be collected in a large cup or other container and then poured into the large bottle. Do not try to urinate directly into the bottle. Void urine prior to bowel movements in order to avoid losing urine that might normally be passed during a bowel movement. Some patients are asked to collect more than one consecutive 24-hour urine sample. If that is the case, you should complete the first collection as instructed. Then, begin the second collection by adding any urine made in the next 24-hours to the second bottle. You should not discard any urine when starting the second or any subsequent collections. Simply change bottles at the stop and start times after adding that last sample required to complete the previous collection. The bottles for some tests contain a weak acid as a preservative. Do not discard the acid. If you accidentally get acid or urine from the bottle on your skin or clothing, rinse the effected area immediately with plenty of cold water. Collection bottles must be refrigerated. This is best accomplished by using an ice chest, cooler, or if so inclined, your refrigerator. If you forget to collect all of the urine or perform the test improperly, discard the specimen and start again on another day. If the bottle contained an acid preservative, you will need to obtain a new bottle from the laboratory or your physician's office. Otherwise, you may reuse the bottle after rinsing it with distilled water. Finally, please remember to call your physician, medical provider or nurse if you have any questions about the proper collection of a 24-hour urine sample. This Topic on the Message Boards.
  13. Cushing’s syndrome is a rare disorder that occurs when the body is exposed to too much cortisol. Cortisol is produced by the body and is also used in corticosteroid drugs. Cushing's syndrome can occur either because cortisol is being overproduced by the body or from the use of drugs that contain cortisol (like prednisone). Cortisol is the body’s main stress hormone. Cortisol is secreted by the adrenal glands in response to the secretion of adrenocorticotropic hormone (ACTH) by the pituitary. One form of Cushing’s syndrome may be caused by an oversecretion of ACTH by the pituitary leading to an excess of cortisol. Cortisol has several functions, including the regulation of inflammation and controlling how the body uses carbohydrates, fats, and proteins. Corticosteroids such as prednisone, which are often used to treat inflammatory conditions, mimic the effects of cortisol. Stay tuned for more basic info...
  14. Ieva Lase, Malin Grönberg, Olov Norlén, Peter Stålberg, Staffan Welin, Eva Tiensuu Janson First published: 13 August 2021 https://doi.org/10.1111/jne.13030 Abstract Neuroendocrine neoplasms (NENs) causing ectopic Cushing's syndrome (ECS) are rare and challenging to treat. In this retrospective cohort study, we aimed to evaluate different approaches for bilateral adrenalectomy (BA) as a treatment option in ECS. Fifty-three patients with ECS caused by a NEN (35 females/18 men; mean ± SD age: 53 ± 15 years) were identified from medical records. Epidemiological and clinical parameters, survival, indications for surgery and timing, as well as duration of surgery, complications and surgical techniques, were collected and further analysed. The primary tumour location was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). BA was performed in 37 patients. Median time from diagnosis of ECS to BA was 2 months (range 1–10 months). Thirty-two patients received different steroidogenesis inhibitors before BA to control hypercortisolaemia. ECS resolved completely after surgery in 33 patients and severe peri- or postoperative complications were detected in 12 patients. There were fewer severe complications in the endoscopic group compared to open surgery (p = .030). Posterior retroperitoneoscopic BA performed simultaneously by a two surgeon approach had the shortest operating time (p = .001). Despite the frequent use of adrenolytic treatment, BA was necessary in a majority of patients to gain control over ECS. Complication rate was high, probably as a result of the combination of metastatic disease and metabolic disorders caused by high cortisol levels. The two surgeon approach BA may be considered as the method of choice in ECS compared to other BA approaches as a result of fewer complications and a shorter operating time. 1 INTRODUCTION Endogenous Cushing's syndrome (CS) has an estimated incidence of 0.2–5.0 per million people per year.1 In 5–10% of these, it is caused by ectopic secretion of adrenocorticotrophic hormone (ACTH) or, in extremely rare cases, corticotrophin-releasing hormone, from a non-pituitary tumour.1, 2 The treatment of neuroendocrine neoplasms (NENs) with ectopic secretion of ACTH is challenging. Because of the rarity and heterogeneity of this condition, there is no established evidence-based recommendation.3 Most patients with ectopic Cushing's syndrome (ECS) have severe hypercortisolaemia leading to disrupted electrolyte and glucose levels, metabolic alkalosis, thrombosis and life-threatening infections, amongst many other manifestations. Initiation of oncological treatment is often delayed as a result of the consequences of high cortisol levels. A reduction of the cortisol level is crucial for survival and hypercortisolaemia and hypokalaemia are negative prognostic factors.4, 5 If radical surgery of the tumour is not possible because of metastatic disease, normo-cortisolaemia can be achieved either by medical treatment with steroidogenesis inhibitors (SI) or bilateral adrenalectomy (BA),6 and BA has also been considered a treatment option for patients with occult or cyclic ECS. In patients with metastatic neuroendocrine carcinomas, platinum-based chemotherapy may be applied as first-line action, combined by SI and/or followed by BA. Computed tomography-guided percutaneous adrenal ablation has been reported in several case reports as a possible therapeutic alternative for patients in whom medical treatment has failed and BA is not feasible,7-10 althhough more data is needed to recommend this method in daily practice. In the 1930s, transabdominal open access BA was introduced as a treatment option for uncontrolled cortisol secretion.11 Sixty years later, in the 1990s, laparoscopic methods were established12, 13 and are now considered as the gold standard for BA (except for adrenal carcinomas) because they result in less postoperative pain, a shorter hospitalisation time and faster recovery.14 Laparoscopic transperitoneal adrenalectomy (LTA) is the most frequently applied surgical method. However, posterior retroperitoneoscopic adrenalectomy (PRA), introduced in 1995 by Walz et al,15 is gaining popularity.16 Using PRA compared to LTA offers a more direct approach to the adrenal glands, a shorter operating time (no need for reposition of the patient), less blood loss and faster recovery, and it aso has advantages for patients with obesity or a history of previous abdominal surgery.16 There are centres where PRA is performed by a two surgeon approach; thus, a simultaneous bilateral approach offers the possibility of decreasing the surgical time by up to 50% and reducing operative stress.17-19 The present study aimed to evaluate BA as a treatment option for ECS, as well as the effects of different approaches on morbidity and mortality. We hypothesised that endoscopic surgery methods could be superior regarding complication rate, operating and hospitalisation time compared to open access surgery and also influence overall survival. 2 MATERIALS AND METHODS 2.1 Patients and data A cohort of 59 patients with ECS was identified retrospectively from medical records of 894 patients with NENs, referred to the Department of Endocrine Oncology, Uppsala University Hospital between 1984 and 2019. None of the patients had a small-cell lung cancer (SCLC) because these tumours are not treated at our centre and possibly have a different mechanism behind ACTH production compared to that of NENs. Furthermore, SCLCs have a much more severe course of disease compared to well differentiated NENs and including them in the present study could mask any results important for NEN clinical management. Six patients were from outside Sweden and were excluded from further analysis because of a lack of follow-up data; thus, in total, 53 patients were available for analysis. Diagnosis of ECS was confirmed by histopathological examination of tumour specimen (n = 48) together with the clinical and biochemical picture of ACTH-dependent Cushing’s syndrome (elevated serum and urinary cortisol, high ACTH and pathological functional tests). In five patients where neither primary tumor, nor metastatic disease was found despite several PET examinations, including 68 Ga- DOTATOC-PET, 11C-5HTP-PET and 18FDG-PET in four of the five patients, ECS was confirmed on the basis of the clinical/biochemical picture and exclusion of pituitary origin by magnetic resonance imaging, as well as inferior sinus petrosus sampling. Epidemiological data, data on clinical parameters, survival, indication and duration of surgery, complications and surgical technique were extracted and further analysed. 2.2 Surgery BA was performed either by an open access approach, LTA or PRA. PRA was performed either by one surgeon (PRA-1S) or by two surgeons operating on both sides simultaneously (PRA-2S). Some patients were operated twice (one adrenal at the time) and, for those patients, operating time was pooled from both surgeries, if both sessions were performed within 1 week. Cases where conversion from an endoscopic to an open access approach was made peroperatively were grouped as open access surgery in further analysis. Patients who died during the postoperative stage (within 30 days) were excluded from calculation of hospitalisation time. Postoperative complications were graded using the Clavien–Dindo classification where complications of Grade 1 are defined as “any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions. Allowed therapeutic regimens are drugs as antiemetics, antipyretics, analgesics, diuretics and electrolytes and physiotherapy”.20 Because almost all patients had mild, Grade 1 postoperative complications (metabolic disturbances caused by hypercortisolaemia), this variable is not described. We defined complications up to Grade 2 as mild and Grade 3–5 as severe. 2.3 Statistical analysis All parameters were analysed by descriptive statistics: normally distributed data as the mean ± SD, and data with skewed distribution and/or outliers were described as medians, accompanied by the 25th to 75th percentile ranges (Q1-Q3) or minimum-maximum (min-max). The defined event was death from any cause. Overall survival (OS) was defined as time from diagnosis of ECS or time of BA until date of death or, if the event was not found, censored at date of last observation, 31 December 2019. Kaplan-Meier plots were used for survival analysis and the log-rank test was used for comparison. Chi-squared was used for testing relationships between categorical variables. p < .05 was considered statistically significant. All statistical analyses were performed using IBM, version 27 (IBM Corp., Armonk, USA). 3 RESULTS 3.1 Studied patients ECS represented six% (n = 59) of NENs in our cohort. Six patients were excluded from further analysis, resulting in 53 ECS patients who were analysed; there were 35 females and 18 males with a mean ± SD age of 53 ± 15 years. The localisation of the primary NEN was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). Histopathological staining for Ki-67 was available in 38 patients and Ki-67 was < 2% in five patients, 3–20% in 22 patients and > 20% in 11 patients. Patient characteristics are shown in Tables 1 and 2. Twenty-two patients (41.5%) in this cohort had concomitant hypersecretion of hormones other than ACTH from their tumour (5-HIAA, n = 10; calcitonin, n = 3; 5-HIAA + calcitonin, n = 2; glucagon, n = 3, gastrin, n = 2; growth hormone, n = 1; insulin + gastrin + vasointestinal peptide, n = 1). 3.2 Surgery Adrenalectomy was performed in 37 patients (70%); 24 patients were operated at Uppsala University Hospital, nine at Karolinska University Hospital in Stockholm and four at Umeå University Hospital. Median time from diagnosis of ECS to BA was 2 months (range 1–10 months). Median Ki-67 in patients who were operated within 2 months after ECS diagnosis was higher (Ki-67 18.5%) compared to those with BA performed later in the course of disease (Ki-67 9.5%), although the difference was not statistically significant (p = .085). Thirty-two (86%) patients received different SI prior to BA to control hypercortisolaemia. Eight of those were treated with chemotherapy as well in an attempt to reduce cortisol levels. The majority of patients was treated with ketoconazole, often in combination with other drugs (Table 3). Indications for BA in our cohort included (1) persistent hypercortisolaemia despite use of SI (n = 30); (2) BA as first choice of treatment to reduce cortisol levels (n = 5); and (3) no effect combined with severe side effects from SI including liver toxicity and severe leukopenia (n = 2). In 16 patients, BA was not performed as a result of (1) good control of ECS with SI (n = 4); (2) radical surgery of the primary tumour (n = 3); (3) good control of ECS with SI followed by radical surgery of the primary tumour (n = 5) and (4) the bad condition of the patient (n = 4). 3.3 Survival analysis There was no operative mortality in this cohort. Four patients died within 1 month after adrenalectomy (on day 5, 16, 22 and 30, respectively) as a result of multiple organ dysfunction syndrome and progression of NEN. At the end of the follow-up period, 14 patients were still alive and 39 had died. Median survival after BA was 24 months (95% confidence interval [CI] = 7–41, min-max: 0–428) with a 5-year survival of 22%. Median follow-up time for all patients from time of ECS diagnosis was 26 (range 6–62) months and after BA was 19 (range 3–50) months. OS was longer in patients where ECS was treated by radical surgery of the primary tumour or where good biochemical control was achieved by SI compared to patients who underwent BA, 96 months (95% CI 0–206) vs 29 months (95% CI 7–51), respectively. However, this difference was not statistically significant (p = .086), most likely as a result of the small sample size. Multiple hormone secretion correlated with shorter OS after BA (p = .009; hazard ratio = 2.9; 95% CI= 1.3–6.7). There was no significant difference in OS after BA depending on localisation of primary tumour (thoracic NENs 24 months [95% CI = 8–40, min-max: 0–428], pancreatic NENs 19 months [95% CI = 0–43, min-max: 0–60], p = .319) or surgical approach (open access approach 24 months [95% CI = 1–47], endoscopic approach 19 months [95% CI = 1–37], p = .720). Median time from ECS diagnosis to BA was 2 months (range 1–10). Patients who underwent BA within 2 months after ECS diagnosis had shorter OS compared to those who were operated at a later stage: 6 months (95% CI = 0–18) and 45 months (95% CI = 3–86) respectively (p = .007). The former group had a slightly higher median Ki-67 level (18% vs 9%), lower potassium (2.7 mmol L-1 vs 3.0 mmol L-1) and higher hormone levels (ACTH 217 vs 120 ng mL-1, morning cortisol 1448 vs 1181 nmol L-1 and UFC 5716 vs 4234 nmol per 24 h) at diagnosis compared to those who were operated later in the course of disease. 4 DISCUSSION The present study highlights new aspects of the advantages of an endoscopic approach of BA compared to open access surgery, regarding the incidence of severe complications graded using the Clavien-Dindo classification, as well as operation- and hospitalisation time. Our results indicate that PRA performed by two surgeons simultaneously is the method of choice for patients with ECS. However, despite these advantages, the endoscopic approach did not appear to improve overall survival. Recent Endocrine Society guidelines recommend SI as primary treatment for ECS in patients with occult or metastatic ECS followed by BA.6 Although the toxicity of SI in our cohort was low (n = 2; 6%), 32 patients (73%) had persistent hypercortisolaemia despite medical treatment and proceeded to BA. BA, especially with an endoscopic approach, with a short operating time and low complication risk, appears to play a major role in the appropriate management of hypercortisolaemia in ECS, where rapid reduction of cortisol levels is very important. Prolonged exposure to high cortisol levels, in combination with high risk for hepatotoxic and nephrotoxic SI side effects, increases morbidity and risk for severe complications, and often delays the start of oncological treatment. However, the trauma caused by surgery can also postpone initiation of chemotherapy.21 Therefore, a fast and minimally invasive surgical procedure appears to be a crucial factor for the better survival in ECS. The endoscopic approach is now considered as the gold standard for BA. Our study presents fewer severe complications, as well as shorter operating and hospitalisation times, when the endoscopic approach is compared with open surgery. In line with previous studies,19, 22 we observed a significantly shorter operating time when applying PRA compared to LTA because there is no need for repositioning of the patient during PRA. PRA-2S had the shortest operating time and should be considered as the best choice of surgical approach in ECS. This result ties well with previous studies reporting the median operating time to be between 43 and 157 min in PRA-2S, which is significantly shorter compared to LTA and PRA-1S.17-19 The median time from diagnosis to BA was 2 months, which is consistent with a previous study.23 However, OS was significantly shorter in patients who were operated within 2 months after diagnosis of ECS in our cohort compared to those operated at a later stage. These early operated patients probably had a more aggressive clinical course of disease, as indicated by slightly higher median Ki-67, lower potassium and higher hormone levels at diagnosis, and they were operated as a result of more acute indications (without time to proper pre-treatment with SI) than the other group. In our previous report on patients with ACTH-producing NENs, multiple hormone secretion was identified as the strongest indicator of a worse prognosis.4 A similar pattern of results was observed in this cohort, showing that patients with NENs, with concomitant hypersecretion of other hormones than ACTH from their tumour, had a shorter OS after BA compared to those with ACTH hypersecretion only. As a result of the extremely high preoperative cortisol levels in ECS, the substitution therapy needed after successful BA may be challenging.21 Over-replacement of glucocorticoids may lead to higher morbidity24 and mortality, especially in patients with metastatic NENs, who often have impaired immune function because of oncological treatment. Many patients suffer from glucocorticoid withdrawal syndrome, despite adequate replacement therapy, and it can take ≥ 1 year to gain control over these symptoms.6 This frequently leads to high dosage of glucocorticoids. The Endocrine Society guidelines recommend glucocorticoid replacement with hydrocortisone, 10–12 mg m-2 day-1 in divided doses.6 If we assume that most of our patients have body surface area around 2 m2 or less, the daily hydrocortisone dose should not exceed 25 mg. However, 1 year after BA, only one patient received 25 mg of hydrocortisone daily, with the majority receiving 30 mg or more. One-third of the patients had residual arterial hypertension and diabetes 3 months after BA, probably partially depending on too high a dose of glucocorticoids. There was a higher complication rate in our cohort compared to other studies19, 25, 26 and five patients needed conversion from an endoscopic approach to open surgery. In particular, the outcome of BA in ECS has not previously been systematically evaluated27 because most of the reports include patients with various aetiologies of CS.19, 22, 23, 28, 29 In a systematic review of the literature published between 1980 and 2012 on BA in CS, Reincke et al23 identified 37 studies and ECS was present in 13% of the patients. There are only few papers focused on BA in ECS solely21, 25, 26, 30, 31 and only one has a cohort with > 50 patients (n = 54).26 Patients with ECS have almost always a more aggressive course and more severe metabolic disturbance than patients with other types of Cushing’s syndrome, which probably leads to higher risk for postoperative complications. Furthermore, multiple liver metastases, fibrotic processes in the abdomen as a result of previous surgery or large primary tumour in pancreas could be some of the factors influencing surgical outcome in ECS. The present study has several limitations. First, all data were collected retrospectively from patient records and not all the preferred parameters were available for all patients. Second, even if our cohort is one of the largest regarding studies on BA in ECS, the number of patients is too low for reliable statistical analysis. Finally, our study covered more than three decades, BAs were performed at different clinics and by different surgeons. Therefore, the data should be interpreted carefully. In conclusion, the present study is one of few reports focusing on BA in specifically NEN patients with ECS and includes one of the largest patient cohorts analysed in the field. PRA-2S can be considered as method of choice in ECS compared to other BA approaches. The aim is to avoid administrating too high a hydrocortisone replacement dosage postoperatively because this can worsen the metabolic disturbance. As a result of the rarity of the condition, multicentre studies are needed with large, prospective cohorts and standardised inclusion criteria, aiming to further improve our knowledge about the management of ECS. ACKNOWLEDGEMENTS This study was funded by the Swedish Cancer Society (grant number CAN 18 0576), the Lions Foundation for Cancer Research at Uppsala University Hospital, Selanders Foundation and Söderbergs foundation at Uppsala University. CONFLICT OF INTERESTS The authors declare that they have no conflicts of interest. AUTHOR CONTRIBUTIONS Ieva Lase: Conceptualisation; Data curation; Formal analysis; Investigation; Methodology; Visualisation; Writing – original draft; Writing – review & editing. Malin Grönberg: Formal analysis; Supervision; Visualisation; Writing – review & editing. Olov Norlén: Conceptualisation; Writing – review & editing. Peter Stålberg: Conceptualisation; Writing – review & editing. Staffan Welin: Conceptualisation; Supervision; Writing – review & editing. Eva Tiensuu Janson: Conceptualisation; Funding acquisition; Methodology; Supervision; Writing – review & editing. ETHICAL APPROVAL The need for informed consent was waived by the local ethics committee. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the local ethics committee, Regionala etikprövningsnämnden (EPN), in Uppsala, Sweden. PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/jne.13030. The entire article, PDF, supporting tables and more can be found at https://onlinelibrary.wiley.com/doi/full/10.1111/jne.13030
  15. This article was originally published here J Clin Endocrinol Metab. 2021 Sep 3:dgab659. doi: 10.1210/clinem/dgab659. Online ahead of print. ABSTRACT CONTEXT: Confirming a diagnosis of Cushing’s disease (CD) remains challenging yet is critically important before recommending transsphenoidal surgery for adenoma resection. OBJECTIVE: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Patients (n=105; 86% female) who underwent surgery from 2007-2020 were classified into 3 groups: Group A (n=84) pathology-proven ACTH adenoma; Group B (n=6) pathology-unproven but with postoperative hypocortisolemia consistent with CD, and Group C (n=15) pathology-unproven, without postoperative hypocortisolemia. Group A+B were combined as Confirmed CD and Group C as Unconfirmed CD. MAIN OUTCOMES: Group A+B was compared to Group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1mg dexamethasone suppression test (DST), plasma ACTH, and pituitary MRI. RESULTS: All groups had a similar clinical phenotype. Compared to Group C, Group A+B had higher mean UFC (p<0.001), LNSC(p=0.003), DST(p=0.06), ACTH(p=0.03) and larger MRI-defined lesions (p<0.001). The highest accuracy thresholds were: UFC 72 µg/24hrs; LNSC 0.122 µg/dl, DST 2.70 µg/dl, and ACTH 39.1 pg/ml. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of Group A+B versus Group C, respectively, p<0.0001. In Group A+B non-remission was strongly associated with adenoma cavernous sinus invasion. CONCLUSIONS: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing. PMID:34478542 | DOI:10.1210/clinem/dgab659
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