The 6th NIH Clinic for Pediatric & Wildtype GIST was held January 19th - 21st, 2011. Fourteen patients attended, including adolescents and adults, some of whom travelled from around the world.
Invitational Lecture on Skin Toxicities
The invitational lecture at the opening of the clinic was:
Skin Toxicities in Targeted Therapies by Heidi H. Kong MD
To watch a webcast of the lecture click here.
Summary of the pre-clinic science meeting on January 19th.
by Becky Bensanhaver
On Wednesday, January 19th the Gist Drs. and Specialists met to start the Clinic. This was the 6th Clinic. There were 14 Clinic participants this time, with a total of 58 patients accrued since the Inaugural Clinic. The scientific meeting included not only the Specialists and support group representatives in the room, but also a few people that were listening/contributing through a telephone conferencing system. Here is my overview report of the meeting:
Constantine Stratakis, MD (Head of Genetics and Endocrinology, NIH) said that a Succinate Dehydrogenase (SDH) germline mutation was present in 7 of the 48 Clinic participants that had been tested thus far. 5 had SDH Subunit B, 2 had SDH Subunit C defects or omissions. Dr. Stratakis is in the process of screening the original cohort of Carney-Stratakis Triad patients for B, C & D mutations now as this has not yet been performed. Some triads seem to be inherited and some sporadic (not B,C, or D related). They are looking for a different pathway as the driving etiology. Paragangliomas (PGLs) are more commonly affiliated with neurofibromas than with GIST.
Of the 7 patients with SDH mutations, 6 of 9 of their family members tested were positive for a SDH mutation.
Next Dr. Joshua Schiffman, MD (Huntsman Cancer Institute, Salt Lake City, Utah) gave a slide presentation--speaking via telephone conferencing. Dr. Schiffman is responsible for the discovery that a mutation of the tumor suppressor hSDH5 gene is responsible for hereditary PGLs (published in 2009). He said that for patients with SDHB, C, D or AF2 mutations the initial recommended protocol was for a full body MRI screen be performed once a year. He said that of the 10 patients that did this, 100% were still alive, without it only 25% were still alive. The total body MRIs utilized rapid sequences, slices every 3-5 mm. He also recommended monitoring serum catecholamines. Their initial protocol has now been revised, recommending a full body MRI every 2 years rather than every year. PET scans are only utilized if there is an abnormal finding on the MRI screen. Also, serum testing for methoxytyramine should be performed as this is usually produced by PGLs in patients with SDHB mutations. There was discussion amongst the specialists regarding the protocol of full body MRIs for Gist patients with SDH mutations--also discussion of insurance reimbursement for this. Not everyone agreed annual full body MRIs are necessary for SDH (+) GIST patients.
The second presentation was given by Karel Pacek, MD (Neuroendocrinologist, NIH). He stated that of patients with malignant PGLs 50% to 80% had SDHB mutations. There is no cure available for these patients yet, with life expectancy not statistically different between those who undergo chemotherapy and those that don't. In the cases where the PGL is located in the abdomen, there is a 40% chance of a SDHB gene mutation. About 45% die within 5 years from Dx of malignancy. 54% had SDHB/C/D mutations and 50% were younger than 36 yoa. Multiple PGLs almost always have a SDH mutation of some sort. Of those with SDHB mutations over 66% had tumors in abdomen or thorax, with a family history in only 22%. Of malignant PGLs in children over 80% have SDH defects. In his opinion plasma or urine testing for metanephrines is the best screening.
The third speaker was Dr. Marston Linehan, MD (Renal cancer specialist, NIH). He said that SDHB defects can be involved in familial renal cell carcinoma (RCC), related to Fumarate Hydrotase--the next step up on the KREBS cycle chain from the HIF-1alpha problem associated with Ped GIST.
The confluence of the 3 presentations given is that SDH mutations can be multicausative for different disorders. Maybe there should be a multi-institutional screening protocol for all patients with SDH mutations. SDHB mutations are seen sometimes in GIST, thyroid cancer, renal cancer, and paragangliomas. The question is: is there any benefit to testing family members? If so, what would the protocol be? The funding and reimbursement can be challenging for this. For the full body MRI Huntsman Cancer Institute is using a generic procedure code and a letter of explanation which they are happy to share with any institution that is interested in using it. This is what they recommend for for screening of SDH patients. They discussed that value of a publication of a discussion of the presence of (+) SDH defects in these different cancers. (Possibly something published by the NCCN, or Gene Reviews).
As you can see, the discussion was not specifically focused on GIST, but rather more generally toward the advancement of understanding the relevance of SDH mutations.