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Cushing’s disease patients whose pituitary tumors carry a USP8 mutation are more likely to achieve remission after surgery than those without such mutations, a retrospective Italian study found. The study, “Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas,” was published in the journal Endocrine. Cushing’s disease is a condition where a tumor on the pituitary gland produces too much of the adrenocorticotropin hormone (ACTH), which will act on the adrenal gland to make cortisol in excess. While rare, the condition can be life-threatening, as excess cortisol is linked to an increased risk of infections and cardiovascular complications, along with an increased likelihood of obesity and diabetes. The reasons some patients develop these pituitary adenomas are far from understood, but researchers recently found that some of these patients show mutations in the USP8 gene. These appear to increase EGFR signaling which, in turn, has a stimulatory role for the synthesis of ACTH. But more than influencing the development of Cushing’s disease, researchers believe the USP8 mutations may also determine response to treatment. Thus, a team in Italy examined whether patients with USP8 mutations presented different clinical features and responded differently to the standard surgical procedure, called transsphenoidal pituitary surgery. The study included 92 patients with ACTH-secreting pituitary tumors who received surgery at the neurosurgical department of the Istituto Scientifico San Raffaele in Milan between 1996 and 2016. “All surgical procedures were performed by the same experienced neurosurgeon, which is one of the most important factors affecting early and late surgical outcome of pituitary adenomas,” researchers explained. Among study participants, 22 (23.9%) had mutations in the USP8 gene, but these mutations were significantly more common in women than in men — 28.7% vs. 5.3%. Researchers think estrogens — a female sex hormone — may have a role in the development of mutated pituitary tumors. Overall, the two groups had similar tumor size and aggressiveness and similar ACTH and cortisol levels before surgery. But among those with microadenomas — tumors smaller then 10 mm in diameter — USP8-mutated patients had significantly larger tumor diameters. After receiving surgery, 81.5% of patients achieved surgical remission — deemed as low cortisol levels requiring glucocorticoid replacement therapy, normal cortisol levels in urine, and normal response to a dexamethasone-suppression test. But remission rates were significantly higher among those with USP8 mutations — 100% vs. 75.7%. Also, USP8 mutation carriers required steroid replacement therapy for shorter periods, despite ACTH and cortisol levels being similar among the two groups after surgery. Among patients who entered remission, 12 (16%) saw their disease return. While more patients with USP8 mutations experienced a recurrence — 22.7% vs. 13.2% — this difference was not significant. After five years, 73.8% of UPS8-mutated patients remained alive and recurrence-free, which researchers consider comparable to the 88.5% seen in patients without the mutation. Researchers also tested sex, age at surgery, and post-surgical ACTH and cortisol levels as possible predictors of disease recurrence, but none of these factors was associated with this outcome. “ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated on by a single neurosurgeon. Recurrence rates are not related with USP8-variant status,” researchers concluded. From https://cushingsdiseasenews.com/2018/10/23/cushings-disease-patients-usp8-mutations-more-likely-achieve-remission-after-surgery/
A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary. “Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.” In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies. On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3. At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests. The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve. The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas. Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers. The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers. “A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne Disclosures: The authors report no relevant financial disclosures. From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission
MaryO posted a topic in Upcoming Speakers in VoiceChatFabiana 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