IN THE NAME OF ALLAH

1. IN THE NAME OF ALLAH GRAND ROUND 98.4.17 ShahinNosratzehi

2. PROBLEM LIST • PTC with brain metastases • Germline mutation of RET(G691S and S904S variant in himself and his children) • Germline mutation of RET(634 in his nephew) • Family history of MTC, pheochromocytoma(his brother)

3. CLINICAL QUESTIONS • Cause of low Tg in metastatic PTC? • Indication of imaging in this patient? • Survival and treatment of patients with brain metastases? • Have these codons of RET pathologic or oncogenic effect? • Pathologies associated with these codons of RET? • Indications of prophylactic thyroidectomy in these patients?

4. Li et al. Medicine (2017) 96:7

5. Cause of low Tg • aggressive pathological variant of thyroid cancer that may produce low amounts of serum Tg. • false-negative Tg determination phenomenon can be explained by the following several reasons

6. Cause of low Tg • First, technical issues might cause a false Tg-negative result. In particular, antigen levels 10 to 10,000 times the upper limit of the assay range can exceed the binding capacity of antibody for the solid support • Second, according to Brendel et al, reduced Tg synthesis and/or the release or synthesis of a Tg variant that routine radioimmunoassays cannot recognize could lead to lower Tg levels, which often occurs in marginally differentiated metastatic tumors. Alternatively, Tg might be cleared more rapidly from plasma

7. Cause of low Tg • Third, the Tg structure has changed. Part of malignant transformation can change Tg's structure by reducing the iodine content and the amounts of several amino acids and monosaccharides. • Last, small tumors are unable to secrete Tg while preserving their capability of 131I trapping.Thatreport found that 1 g of cancer tissue elevates the serum Tg by 0.5 to 1 ng/mL, which eloquently indicates that smaller cancers secrete less Tg into the blood

8. WBS or Tg level may not be helpful in establishing the clinical prognosis. • The CT or 18F-FDG PET/CT may be more helpful in this condition

9. CLINICAL QUESTION • cause of low Tg in metastatic PTC • indication of imaging in this patient • survival and Treatment of brain metastases • Are these codons of RET pathologic or oncogenic effect? • pathologies associated with these codons of RET • indication of Prophylactic thyroidectomy in these patients?

10. CT and MRI • Imaging of other organs including : • MRI brain, MR skeletal survey, • and/or CT or MRI of the abdomen • should be considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) • and negative neck and chest imaging who have symptoms referable to those organs • or who are being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be at risk for complications of tumor swelling. • (Strong recommendation, Low-quality evidence

11. 18FDG-PET scanning • (18FDG-PET/CT is primarily considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) with negative RAI imaging • sensitivity of 18FDG-PET/CT was 83% (50% - 100%) • specificity was 84% (42% - 100%) in non–131I-avid DTC • Factors influencing 18FDG-PET/CT sensitivity included • tumor dedifferentiation, larger tumor burden, and to a lesser extent, TSH stimulation

12. 18FDG-PET scanning • It is complementary to 131I WBS, even in the presence of detectable 131I uptake inmetastases, because 18FDG uptake may be present in neoplastic foci with no 131I uptake. • In patients with a TSH-stimulated Tg≤10 ng/mL, the sensitivity of 18FDG is low, ranging from <10% to 30%. • Of course, this level needs to be adapted and lowered in case of aggressive pathological variant of thyroid cancer that may produce low amounts of serum Tg.

13. CLINICAL QUESTION • cause of low Tg in metastatic PTC • indication of imaging in this patient • survival and Treatment of patients with brain metastases • Are these codons of RET pathologic or oncogenic effect? • pathologies associated with these codons of RET indication of Prophylactic thyroidectomy in these patients

14. Treatment of brain metastases • Several treatment modalities with varying results: • surgical resection • stereotactic EBRT • whole brain radiation therapy • radioiodine therapy • and chemotherapy • Although the presence of a brain metastasis is an overall negative prognostic indicator, surgical resection of brain metastases might help to significantly prolong survival in patients with DTC especially in solitary or oligometastaticlesions

15. Treatment of brain metastases • Surgical resection and stereotactic EBRT are the mainstays of therapy • RAI can be considered if CNS metastases concentrate RAI. • Stereotactic radiation therapy is preferred to whole-brain radiation • because life expectancy in patients with brain metastases may be prolonged, and stereotactic radiation induces less short- and long-term toxicity compared with whole-brain radiation • and it may be effective even in patients with multiple brain lesions

16. Treatment of brain metastases • alternative treatments :chemotherapy or biological therapy with tyrosine kinase inhibitors within the framework of clinical studies. • Kinase inhibitor therapy should be considered in RAI refractory • DTC patients with metastatic, rapidly progressive, • symptomatic, and/or imminently threatening disease • not otherwise amenable to local control using other approaches

17. Treatment of brain metastases

18. GuelhoD, et al. BMJ Case Rep 2016. doi:10.1136/bcr-2015-213824

19. PTC has a relatively benign course, with a 10-year survival rate of 90–95% • brain metastases from PTC are extremely rare (0.15-1.3)and are often associated with poor prognosis. • patients with brain metastases usually showed other secondary localisations such as in the lungs, bones or liver. • Brain metastases can be unique or numerous, clinically silent or very symptomatic

20. median survival of PTC brain metastases varies from 4 to 33 months. • surgical resection of brain metastases might help to significantly prolong survival in patients with differentiated thyroid carcinoma, especially in solitary or oligometastatic lesions • Predictive factors of survival seem to be • Advanced age • male gender • extra-thyroidal invasion • metastases at presentation • histological grade and incomplete resection of primary thyroid cancer

21. CLINICAL QUESTION • cause of low Tg in metastatic PTC • indication of imaging in this patient • survival and Treatment of brain metastases • Are these codons of RET pathologic or oncogenic effect? • pathologies associated with these codons of RET • indication of Prophylactic thyroidectomy in these patients

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29. MATERIALS AND METHODS • We ascertained 35 independent Spanish families as having individuals affected by MEN 2A. • 104 patients with oncogenic MEN 2A mutation and 94 healthy relatives • 110 patients with MTC, considered as sporadic tumor • because germ-line mutation had not been detected in exons 10, 11, or 13–16, and the patient had no familial history of the disease. • Likewise, genomic DNA was obtained from 653 unrelated healthy individuals • we analyzed the polymorphisms G691S and S904S of RET

30. RESULT • we found two variants of RET gene, G691S and S904S ,that cosegregated together as haplotype (100% Fisher’s exact test, P <0.001), suggesting that these polymorphisms are in linkage disequilibrium • The presence of the polymorphisms was independent of the specific pathogenic mutation of RET in MEN 2A families (data not shown) • we did not observe any relationship between these polymorphisms and the type of clinical presentation (MTC, phaeochromocytoma, and PHPT; data not shown).

31. RESULT • Homozygous cases were, on average, 10 years younger when they were diagnosed • Homozygous cases were, on average, 10 years younger when they were diagnosed • Homozygous had an 8-fold probability to be diagnosed at an age before 20 compared with wild-type cases (P <0.01) • Restricting the analysis to cases with RET mutation in codon 634 (the most frequent altered codon that included all homozygous in our study) still yielded a similar result, with a statistically significant OR> 6

33. In this regard, we carried out the genetic analysis in a group of 110 cases of sporadic MTC and did not detect any relationship between G691S/S904S polymorphisms and the age at onset of symptoms (data not shown) • compared with healthy controls, the prevalence of G691S/S904S homozygous state was higher among sporadic MTC patients (OR 2.36, P <0.045), suggesting that these variants may play a role as a low penetrance gene • Even though we did not find a statistically significant interaction between the effect of these variants and age, the risk • excess observed for homozygous was more noticeable among younger cases (OR 3.42, P <0.036), for whom the • influence of genetic risk factors must be stronger.

34. CONCLUSION • the authors also observed that this haplotype could modify the age of onset of MTC patients • These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset • this study were the higher prevalence of the haplotype G691S/S904S, in homozygosity, in patients with MEN 2A compared to the control group

35. J. Biosci. 36(4), September 2011, 603–611, * Indian Academy of Sciences

36. Materials and methods • The study group comprised 140 samples • 51 MTC patients • 39 first-degree relatives of 13 index cases with family history (1 to 7 members per family) • 50 healthy unrelated controls • for RET gene mutation and single nucleotide polymorphism (SNP) analysis

37. RET gene mutations were detected in 15(29.4%) patients • with MEN 2A/FMTC in 13 patients • and MEN 2B in 2 patients. • Further, 39 family members of seven index cases were analysed, where in four of the seven index cases showed identical mutations, in 13 of 25 family members

41. RESULT • SNPs at the critical RET gene exons were investigated in our study, and we observed SNPs primarily at codons • 691:GGT→AGT, • 769:CTT→CTG, • 836:AGC→AGT • 904:TCC→TCG in the patient group and healthy controls. • Significant differences in the frequency of the SNP alleles were not observed in the patient and control groups

43. Methods • In this research 293 participants were studied, Over the last ten years including • 181 patients (MTC) • 112 their relatives • In the present study, we report the frequency of G691S/S904S haplotype in Iranian MTC patients and their relatives

44. RESULT As the G691S and S904S variants were in com-plete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype

45. The analysis of G691S/S904S RET gene haplotype showed that 104 of 181 (57.45%) MTC patients • and 55 of 112 (49.1%) relatives had this haplotype • In particular, 82 MTCs and 47 relatives were heterozygous and 22 MTCs and 8 relatives were homozygous for the G691S/S904S haplotype

46. Conclusion • Even though G691S/S904S haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. • this haplotype could modify the age of onset of MTC patients • Further researches on this issue can contribute toward clarifying the prevalence of this haplotype and its probable modifying

47. CLINICAL QUESTION • cause of low Tg in metastatic PTC • indication of imaging in this patient • survival and Treatment of patients with brain metastases • Are these codons of RET pathologic or oncogenic effect? • pathologies associated with these codons of RET • indication of Prophylactic thyroidectomy in these patients

49. Material and methods • 135 patients (belonging to 17 families) with MEN 2A • Between the years 1982–2013(spain) • In 124 cases (92 %),the mutation was located at codon 634 in exon 11 (The most frequent RET mutation ) • In nine cases (7 %),the mutation was located at codon 804 in exon 14, • All the cases with V804M mutation corresponded to the same family.

50. Results • The analysis of the thyroid glands of these patients revealed PTC in two of them: • The first case was a 37-year-old male,V804M mutation in exon 14. • Total thyroidectomy was performed with central lymphadenectomy. • The examination did not reveal either CCH or MTC,multicentric PTC (9 and 5 mm), follicular variant. • B-RAF mutation (V600E) was confirmed in the 9-mm nodule. • He received a 100-mCi dose of I131, with normal control in the follow-up