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LOS ANGELES — More than a century has passed since the neurosurgeon and pathologist Harvey Cushing first discovered the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure, according to a speaker here. There are several challenges clinicians confront in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, FRCP, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, said during a plenary presentation. Patients who present with Cushing’s disease typically have depression, impaired mental function and hypertension and are at high risk for stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders, Melmed said. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said. “This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.” The outlook for Cushing’s disease is now beginning to change, Melmed said. New targets are emerging for treatment, and newly discovered molecules show promise in reducing the secretion of adrenocorticotropic hormone (ACTH) and pituitary tumor size. “Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — SST5, [epidermal growth factor] receptor, cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.” Challenges in diagnosis, treatment Overall, about 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average size is only about 6 mm and 40% of them are not visible, Melmed said. In patients with Cushing’s disease, surgery is effective in only about 60% to 70% of patients for initial remission, and overall, there is about a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes. “There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said. The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term control without recurrence. “This is a difficult challenge to meet for all of us,” Melmed said. Available options Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, Melmed said, and there are several advantages, including rapid initial remission, a one-time cost and potentially curing the disease. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications. Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said. “The reality of Cushing’s disease — these patients undergo first surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to their demise,” Melmed said. “Medical therapy is appropriate at every step of the spectrum.” Zebrafish clues Searching for new options, Melmed and colleagues introduced a pituitary tumor transforming gene discovered in his lab into zebrafish, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high. Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH. In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said. “Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule (that) suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.” In a small, open-label, proof-of-principal study, four patients with Cushing’s disease who received roscovitine for 4 weeks developed normalized urinary free cortisol, Melmed said. Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial that will evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib) in patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. “Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s. Hopefully, this will light the pathway for a phase 2 trial.” ‘ Offering optimism’ Practitioners face a unique paradigm when treating patients with Cushing’s disease, Melmed said. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life. “Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.” Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy. “He was imagining this ‘elixir of youth’ (that) we could offer patients who are very ill and, in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. These Cushing’s patients are extremely ill. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer Reference: Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles. Disclosure: Melmed reports no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B585002ad-640f-49e5-8d62-d1853154d7e2%7D/new-discoveries-offer-possible-cushings-disease-cure- 3 replies
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- dr. shlomo melmed
- radiation
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A man with Cushing’s disease — caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma — who later developed metastases in the central nervous system without Cushing’s recurrence, was successfully treated over eight years with radiation and chemotherapy, according to a case report. The report, “Long-term survival following transformation of an adrenocorticotropic hormone secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma: Case report,” was published in the journal World Neurosurgery. Pituitary carcinomas make up only 0.1-0.2% of all pituitary tumors and are characterized by a primary pituitary tumor that metastasizes into cranial, spinal, or systemic locations. Fewer than 200 cases have been reported in the literature. Most of these carcinomas secrete hormones, with ACTH being the most common. Though the majority of ACTH-secreting carcinomas present with Cushing’s disease, about one-third do not show symptoms of the condition and have normal serum cortisol and ACTH levels. These are called silent corticotroph adenomas and are considered more aggressive. A research team at the University of Alabama at Birmingham presented the case of a 51-year-old Caucasian man with ACTH-dependent Cushing’s disease. He had undergone an incomplete transsphenoidal (through the nose) resection of an ACTH-secreting pituitary macroadenoma – larger than 10 mm in size – and radiation therapy the year before. At referral in August 1997, the patient had persistent high cortisol levels and partial hypopituitarism, or pituitary insufficiency. He exhibited Cushing’s symptoms, including facial reddening, moon facies, weight gain above the collarbone, “buffalo hump,” and abdominal stretch marks. About two years later, the man was weaned off ketoconazole — a medication used to lower cortisol levels — and his cortisol levels had been effectively reduced. He also had no physical manifestations of Cushing’s apart from facial reddening. In May 2010, the patient reported two episodes of partial seizures, describing two spells of right arm tingling, followed by impaired peripheral vision. Imaging showed a 2.1-by-1-cm mass with an associated cyst within the brain’s right posterior temporal lobe, as well as a 1.8-by-1.2-cm mass at the cervicomedullary junction, which is the region where the brainstem continues as the spinal cord. His right temporal cystic mass was then removed by craniotomy. A histopathologic analysis was consistent with pituitary carcinoma. Cell morphology was generally similar to the primary pituitary tumor, but cell proliferation was higher. Physical exams showed no recurrence of Cushing’s disease and 24-hour free urinary cortisol was within the normal range. His cervicomedullary metastasis was treated with radiation therapy in July 2010. He took the oral chemotherapy temozolomide until August 2011, and Avastin (bevacizumab, by Genentech) was administered from September 2010 to November 2012. At present, the patient continues to undergo annual imaging and laboratory draws. He receives treatment with hydrocortisone, levothyroxine — synthetic thyroid hormone — and testosterone replacement with androgel. His most recent exam showed no progression over eight years of a small residual right temporal cyst, a residual mass along the pituitary stalk — the connection between the hypothalamus and the pituitary gland — and a small residual mass at the cervicomedullary junction. Lab results continue to show no Cushing’s recurrence. “Our case is the first to document a patient who initially presented with an endocrinologically active ACTH secreting pituitary adenoma and Cushing’s disease who later developed cranial and spinal metastases without recurrence of Cushing’s disease and transformation to a silent corticotroph pituitary carcinoma,” the scientists wrote. They added that the report is also the first documenting “8 years of progression-free survival in a patient with pituitary carcinoma treated with radiotherapy, [temozolomide] and bevacizumab.” Adapted from https://cushingsdiseasenews.com/2019/01/03/successful-treatment-pituitary-carcinoma-radiation-chemo-case-report/
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- cushings disease
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Erica was a fellow Cushing’s Disease survivor. She had been through pituitary surgery, radiation, and a BLA in an effort to receive her cure. Read more at https://cushingsbios.com/2015/03/11/in-memory-erica-michelle-gaga-meno/
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Fabiana had transsphenoidal surgery (pituitary) July 30th 2004. She had a recurrence after seven years of being Cushing's free. A second pituitary surgery on 10/26/2011 was unsuccessful. Another Golden Oldie, this bio was last updated 9/12/2015 Fabiana will be our guest in an interview on BlogTalk Radio Wednesday, October 21 at 6:00 PM eastern. The Call-In number for questions or comments is (657) 383-0416. The archived interview will be available after 7:00 PM Eastern through iTunes Podcasts (Cushie Chats) or BlogTalkRadio. While you're waiting, there are currently 88 other past interviews to listen to! ~~~ Well it has taken me a year to write this bio...and just to give some hope to those of you just going thru this process...I have to say that after surgery I have not felt better! I am back to who i always knew I was....the depression and anxiety is gone and I am living life like a 24 year old should! I guess it all started when i was sixteen (hindsight is 20-20 i guess). My periods stopped i was tired all the time and the depression started. We all kind of just chalked it up to being sixteen. But my mom insisted something was not right. we talked with my gyno...who said nothing was wrong, I had a fungus on my head (my hair was getting really thin) and sometimes girls who had normal periods (in my case three years of normal periods) just go awry. My mom wasnt hearing that and demanded a script for an endo. I went....he did blood work...and metioned cushings. But nothing came back definitive...so they put me on birthcontol and gave me some hormones and the chushings was never mentioned again because that all seemed to work. As time went on my depression got worse, the shape of my body started to change-my face and stomach was the most noticeable- and my energy level kept going down. I kept going back to the doctors asking to be tested for mono..or something. I went to a psycologist....but i knew there was no reason for my depression. Two of them told me "i had very good insight" and that I didnt need them. I started getting more anxiety..especially about going out socially. High school ended and my typical optimistic personality started to decline. I put on a good act to my friends but my family was seeing me break down all the time. I went away for college (all the while gaining weight). My sophmore year I had a break down..I called my family crying that i needed help. I couldnt beat my depression. I didnt drink in college because i knew that would mean instant weight gain, i barely went out...i exercised everyday..hard....i joined weight watchers...i stuck with it. I was at 103 lbs....that crept up to 110...that crept up to 117...each time my weight goal would be "ohh if i could just get back to 108..112...115" with each weight gain my original weight goal would get higher and higher. Internally i felt like I was constantly under a black cloud..i knew there was no reason why i shoudl feel this way..i was doing great in school, i had a supportive family, an amazing boyfriend and great friends...why was i depressed? I was becoming emotionally draining to the people closest to me...I would go home a lot on the weekends...i was diagnosed with PMDS....like severe PMS..and was given an antidepresant...i hated it it made me feel like a zombie...i stopped taking it and just made it apoint to work on fighting the depression....and the weight gain. When i was done college i was about 120 lbs. My face was getting rounder and rounder..i was noticing more hair on my face and arms...and a hump between my shoulder blades and the bottom of my neck. My mom saw a tv show about Polycystic ovarian syndrome and felt that maybe that was what was going on with me...i went to my PCP with this and she said it was possible and that i should to talk to my gyno....I am 4'8 and at the time weighing close to 125..i talked to my gyno and she said I was not heavy..that i was just "itailan" ..i told her my periods were getting abnormal again even w/the birthcontrol and that i was so tired all the time and my arms and legs ached. I also told her that i was bruising very easily...and that the weight gain would not stop despite my exercising and following the atikins diet very strickly for over 6 weeks. My boyfriend and I decided to try the diet together..he lost 35 llbs in 6 weeks..i lost NOTHING! I went back to my PCP who ordered an ultra sound of my ovaries.....NOTHING.(i kept thinking i was going crazy and that it was all in my head)....she also decided to do some blood work...and as i was walking out the door she said.."you know what..i am going to give you this 24hr urine test too. Just so that we cover everything". I just kept thinking please let something come back ....please dont let this be all my fault...please dont let this be all in my head.....please dont let me be crazy. When i got the test results back it turned out that the 24hr urine test was the one test i needed to get on the right track to finding what was wrong. My cortisol level was 3x's the normal. I went to an endo...by the time i got to the endocronoligist i was up to 130...i could not work a full day without needing a full day of sleep and my body was aching beyond description. I was crying all the time...in my room...and was becoming more and more of a recluse...i would only hang out with my boyfriend in our houses. I looked my symptoms up on the internet and saw cushings...that was it! I went to the endo and told him..i think it is cushings....he said he had only saw it one other time and that he wanted to do more tests. I got CAT scans, x-rays, MRI's....my adrenals my pituitary my lungs....he did a CRH stimulation test which was getting blood work done every fifteen minutes for 90minutes....it took weeks to get that test scheduled..no one had ever heard of it and therefore did not know how to do it.....finally after 3 months of tests my dr. felt he had enough evidence to diagnos me with cushings disease (tumor on my pituitary) I was diagnosed in March of 2004. By this time i was about 137 lbs i had to work part time (i am an occupational therapist for children..i do home visits....i could not make it thru a whole day) In April i had to change to office work...i could not lift the children and i could barely get up off the floor. I have to say i was one of the lucky people who worked for people who were very supportive and accomidating...my boss was very willing to work with me and willing to hold my job for me. July 30th 2004 i finally had transphenodial surgery to remove my tumor (they went thru my lip and nose because they felt my nose was too small). It is now over 1 year later....i am down to 108 lbs, i have so much energy...no depression....and i dont mind looking at myself in the mirror...i am enjoying my friends and my boyfriend...(who stayed with me thru it all) And my family. I feel healthy mentally, emptionally, and physically. And i just got back into my size 2 jeans!!! It was a crappy time...(as i am sure you all can atest to) but i learned a lot.....most importantly i was bombarded by good wishes and prayers....friends requested masses for me...a nun in brazil prayed for me...people who i never thought i touched their lives...took the time to wish me well...send an email..or call....I got to experience the wonderful loving nature of human beings and i was lucky to be supported by my family (my mom, dad, and two younger brothers) and my boyfriend throughout this entire tough journey. This experience taught me to realize the strength i have as well as to appreciate the good and the bad in life. I was on hydrocortizone for about 8 months...i was lucky that my tumor was in its own little sack so my pituitary gland was not touched. In the end in took about 7 years to diagnose me..i think that if the dr. at 16 would have pursued the cushings idea nothing would have been found because it took so long for my symptoms to really peak...needless to say i love my PCP and my endo ..and that i changed gyno's... I just want to let anyone out there going thru this disease to know..you are not alone....and to take each day is stride...when you need help ask for it....and that this road can lead to a happy ending. God Bless! ps- it is ok to feel bad about what you are going thru...it is a tough thing to endure...and when the docotors tell you there is noting wrong.....follow your gut...and you keep searching for the doctor that will listen... If there is anyone in the philadelphis of south jersey area who needs someone to talk to please feel free to email me... .i will help you out the best i can! Update November 6, 2011 Well- here is an update, after seven years of being Cushings free it has returned. With in those seven years I married my college boyfriend and we now have a son- Nicholas who will be 2 in Decemeber. It has been a blessed and wonderful seven years. However right around when my son was turning 1 I started to notice symptoms again. Increase facial hair, the whole "roundness" of my body, buffalo hump. I decided I was going to work out hard, eat right, and see - I didnt just want to jump to any conclusions. I stuck to it- and nothing.....my hair started thinning again and the acne was coming back and then the missed periods.....so I went to my PCP- told them i needed the 24hr urine and wouldnt you know.....427 cortisol level (on that 0-50 scale)......here we go again. So back to endo- now at Penn Pituitary Center.....it was another journey b/c the tumor wasnt definative on MRI, and it seems to be cycling.....but I was diagnosed with Cushings again- with the option of 2nd pit surgery or BLA.......after some months of trying to make a decision I went with the 50/50 chance of the second pituitary surgery on 10/26/2011. It didnt work- my levels never came down in the hospital and I went home w/ out of range cortisol levels and no need for medication......BLURG......Sooooo on to the next step.....after I recover from this surgery I will most likely have the BLA- with the hopes of not having to deal with Cushings ever again. This time around has been a little more difficult just with being a mom and feeling sick- but I still continue to be amazingly blessed with a supportive family and husband and we are surrounded by love and support and for that I am beyond greatful. I keep all of you in my prayers for relief and health- as I ( we all) know this no easy journey. Many Blessings! Fabiana Update September 12, 2015 So to bring this up to date. My second pituitary surgery in 2011 was unsuccessful. January of 2012 I had both of my adrenal glands removed. Going to adrenal insufficiency was a very difficult transition for me. It took me nearly 2 years before I felt functional. As time went on I felt more human, but I haven't felt healthy since that day. I can and do function, but at a lower expectation of what I used to be capable of....my "new normal". My husband and I decided to try for a second child...my pituitary was damaged from the second surgery and we needed fertility...after 8 months of fertility I got pregnant and we had our second son January of 2015. In April of 2015 we discovered that my ACTH was increasing exponentially. MRI revealed a macroadenoma invading my cavernous sinus. The tumor is sitting on my carotid artery and milimeterrs away from my optic chasim. I was not a candidate for another surgery due to the tumors proximity to.both of those vital structures. So September 1st of this year I started daily radiation treatments. I spent my 34th birthday getting my brain zapped. I am receiving proton beam therapy at the Hospital of the University of Pennsylvania. I am so lucky to live so close to an institute that has some of the rarest treatment options. Again Cushing's is disrupting our life, my husband goes with me every night to radiation while family takes turns watching the kids....I am now on my 18th year of fighting this disease. I never imagined it would get to this point. But here we all are making the best of each day, fighting each day and trying to keep things as "normal" as possible. Blessings to all of you fighting this disease...my new go to saying is" 'effing Cushing's"! For you newbies...Fight, Advocate for yourselves, and find a doc who doesn't dismiss you and hang on to them for dear life. HOME | Sitemap | Adrenal Crisis! | Abbreviations | Glossary | Forums | Donate | Bios | Add Your Bio | Add Your Doctor | CushieWiki
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From Kathy's bio at http://cushingsbios.com/2014/04/25/kathy-c-pituitary-bio/ Kathy will be interviewed May 7, 2014 in BlogTalkRadio. You can listen live and ask questions or download the podcast later.
