A comprehensive review on MEN2B.

MEN2B is a very rare autosomal dominant hereditary tumor syndrome associated with medullary thyroid carcinoma (MTC) in 100% cases, pheochromocytoma in 50% cases and multiple extra-endocrine features, many of which can be quite disabling. Only few data are available in the literature. The aim of this review is to try to give further insights into the natural history of the disease and to point out the missing evidence that would help clinicians optimize the management of such patients. MEN2B is mainly characterized by the early occurrence of MTC, which led the American Thyroid Association to recommend preventive thyroidectomy before the age of 1 year. However, as the majority of mutations are de novo, improved knowledge of the nonendocrine signs would help to lower the age of diagnosis and improve long-term outcomes. Future large-scale studies will be aimed at characterizing more in detail the main characteristics and outcomes of MEN2B.

Surgery for lymph node metastases of medullary thyroid carcinoma: A review.

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells that occurs in hereditary and sporadic clinical settings. Metastatic spread commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine and are not sensitive to hormonal manipulation, and therefore surgery is the most effective option for curative therapy, reduction in tumor burden, or effective palliation. In patients undergoing preventative surgery for hereditary MTC, central lymph node dissection should be considered if the calcitonin level is elevated. Preservation of parathyroid function in these young patients is of paramount importance. In patients with established primary tumors, systematic surgical removal of lymph node basins (compartmental dissection) should be guided by ultrasound mapping of lymph node metastases and level of serum calcitonin. A "berry-picking" approach is discouraged. Newly approved targeted molecular therapies offer wider treatment options for patients with progressive or metastatic disease.

Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With Multiple Endocrine Neoplasia Type 2.

OBJECTIVES: Patients with multiple endocrine neoplasia type 2 (MEN2) have mutations in the RET protooncogene and virtually all of them will develop medullary thyroid carcinoma. Family members identified by genetic testing are candidates for preventive thyroidectomy. Management of the parathyroids during thyroidectomy is controversial. Some experts advocate total parathyroidectomy with autotransplantation, whereas others recommend preserving the parathyroids in situ. METHODS: Between 1993 and 2000, we performed preventive thyroidectomies on 50 patients with MEN2A (group A). All patients had a central neck dissection (CND) combined with total parathyroidectomy and autotransplantation of parathyroid slivers to the nondominant forearm or to the neck. Between 2003 and the present, we performed 102 preventive thyroidectomies attempting to preserve the parathyroid glands in situ with an intact vascular pedicle (group B). Individual parathyroids were autotransplanted only if they appeared nonviable or could not be preserved intact. Central neck dissection was done only if the serum calcitonin was greater than 40 pg/mL. RESULTS: Permanent hypoparathyroidism occurred in 3 (6%) of 50 patients in group A, compared with 1 (1%) of 102 patients in group B (P = 0.1). After total thyroidectomy, no patient in either group developed permanent recurrent laryngeal nerve injury or hyperparathyroidism. Immediate postoperative serum calcitonin levels were in the normal range (<5 pg/mL) in 100 of 102 patients in group B. No patients in either group have died. Oncologic follow-up of patients in group B is in progress. CONCLUSIONS: In patients with MEN2A treated by preventive total thyroidectomy routine total parathyroidectomy with autotransplantation and CND gives excellent long-term results. However, preservation of the parathyroids in situ during preventive thyroidectomy combined with selective CND based on preoperative basal serum calcitonin levels is an effective and safe alternative that results in a very low incidence of hypoparathyroidism.

Anaplastic Thyroid Carcinoma, Version 2.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.

Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.

INTRODUCTION: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.

BRAF mutation is not predictive of long-term outcome in papillary thyroid carcinoma.

The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1-2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1-2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1-2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan-Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy.

Neuroendocrine tumors, version 1.2015.

Neuroendocrine tumors (NETs) comprise a broad family of tumors that may or may not be associated with symptoms attributable to hormonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors discuss the diagnosis and management of both sporadic and hereditary NETs. This selection from the guidelines focuses on sporadic NETs of the pancreas, gastrointestinal tract, lung, and thymus.

Biochemical cure after reoperations for medullary thyroid carcinoma: a meta-analysis.

BACKGROUND: Despite meticulous surgical techniques, calcitonin levels remain detectable in 40 % to 66 % of patients after initial surgery for medullary thyroid carcinoma (MTC), and the optimal surgical management for persistent or recurrent disease remains controversial. Previous studies suggest that biochemical cure, defined by normalization of postoperative calcitonin measurements, predicts disease-free survival. Reoperative approaches range from targeted removal of detectable disease to comprehensive compartment-oriented lymph node clearance. METHODS: A proportional meta-analysis of clinical case series of postoperative calcitonin clearance after reoperation for MTC was performed. Studies were obtained from PubMed, Embase, Scopus, and the Cochrane Library. RESULTS: Twenty-seven articles capturing data of 984 patients met the inclusion criteria for the meta-analysis. Overall, normalization of calcitonin after reoperation for MTC occurred in 16.2 % of patients [95 % confidence interval (CI) 14.0-18.5]. Stratified by operative procedure, targeted selective lymph node removal procedures had a normalization of calcitonin in 10.5 % of patients (95 % CI 6.4-14.7), while compartment-oriented procedures had a higher rate of normalization at 18.6 % (95 % CI 15.9-21.3). CONCLUSIONS: The rate of calcitonin normalization after reoperation for MTC is enhanced through use of a meticulous compartment-oriented lymph node dissection. Compartment-oriented lymph node dissection results in calcitonin normalization in 18.6 % of reoperative MTC patients and is the procedure of choice in patients in whom the goal is biochemical cure.

Hereditary thyroid cancer syndromes and genetic testing.

This review focuses on both hereditary medullary thyroid cancer (MTC) and hereditary nonmedullary thyroid cancer (NMTC) and discusses the genetics, clinical diagnosis and evaluation, and surgical approach to treatment of these malignancies. Areas of innovation as well as areas of debate are highlighted and management recommendations are made.

Thyroid carcinoma, version 2.2014.

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.

Treatment approach, surveillance, and outcome of well-differentiated thyroid cancer in childhood and adolescence.

BACKGROUND: Well-differentiated thyroid carcinoma in children and adolescents is a rare disease with favorable prognosis despite regional and distant metastasis at presentation in many patients. Treatment recommendations are varied and there is little consensus on follow-up guidelines for these patients. METHODS: Medical records of patients less than 22 years of age treated at our institution were reviewed. One hundred twelve patients treated between 1969 and 2009 were selected for further analysis. Effects of patient and tumor characteristics on progression-free survival (PFS) were evaluated along with the predictive value of whole-body (131)I scintigraphy in the follow-up setting. RESULTS: Overall survival at 20 years and 30 years was 100% and 94.4%, respectively. PFS at 10, 20, and 30 years was 71%, 62%, and 55%, respectively. Although male patients and younger patients presented with more advanced disease, sex, and age at diagnosis had no effect on risk of PFS. Additionally, neither the presence of vascular invasion, capsular extension, positive margins, nor soft tissue invasion had an effect on PFS. Mean time to recurrence in patients who underwent immediate postoperative (131)I therapy was 3.8 years compared to 14.1 years in patients who either never received (131)I therapy or were treated in the salvage setting (p<0.0001). Negative posttreatment whole-body (131)I scintigraphy was strongly predictive for decreased risk of recurrence, especially in patients with three consecutive negative scans. CONCLUSIONS: Pediatric patients are more likely to present with advanced disease and for this reason, the majority of patients treated at our institution receive postoperative (131)I. Long-term surveillance is required in this population because of the risk of late recurrences. Whole-body (131)I scintigraphy is useful for risk stratification; after three consecutive negative scans, the risk of recurrence is low.

Adrenal myelolipoma: operative indications and outcomes.

BACKGROUND: Adrenal myelolipoma (AM) is a benign lesion for which adrenalectomy is infrequently indicated. We investigated operative indications and outcomes for AM in a large single-institution series. SUBJECTS AND METHODS: A retrospective cohort study of prospectively collected data was conducted. Patients (≥16 years of age) who underwent adrenalectomy in the Division of General Surgery at Barnes-Jewish Hospital (1993-2010) were grouped by operative indication (myelolipoma versus other pathology) and compared using nonparametric tests (α<0.05). RESULTS: Sixteen patients (4.0%) had myelolipomas resected out of 402 patients who underwent adrenalectomy. Fourteen patients with suspected AM underwent adrenalectomy, 13 (93%) of whom had AM confirmed on pathology. Indications for adrenalectomy were abdominal or flank pain, large tumor size (>8 cm), atypical radiologic appearance, and/or inferior vena cava compression. Three patients with suspected other adrenal lesions had AM confirmed on final pathology. Operative approach was laparoscopic in 15 cases and open in 1 case of a 21-cm lesion. Patients who underwent laparoscopic adrenalectomy for AM (n=15) or other adrenal pathology (n=343) were similar with respect to age, gender, American Society of Anesthesiologists classification, prior abdominal operation, tumor side, operative time, conversion rate, estimated blood loss, intraoperative complications, hospital length of stay, and 30-day morbidity. However, patients with resected AM had a higher body mass index (36.5±8.1 kg/m(2) versus 30.1±7.5 kg/m(2); P<.01) and a larger preoperative tumor size (8.4±3.0 cm versus 3.1±1.7 cm; P<.01). CONCLUSIONS: Laparoscopic adrenalectomy may be appropriate for patients with a presumptive diagnosis of AM and abdominal or flank pain, large tumor size, and/or uncertain diagnosis after imaging. Outcomes and morbidity following LA for AM and other adrenal pathology appear comparable.

Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening.

Childhood pheochromocytoma in the setting of multiple endocrine neoplasia type 2 (MEN2) remains rare and has not been reported under the age of 12. We present an 8-year-old female with known MEN 2A, C634Y RET mutation, diagnosed with a 6 cm pheochromocytoma requiring laparoscopic adrenalectomy. Given this patient's age at diagnosis, screening guidelines should recommend annual screening beginning at age 8 for patients with MEN 2B or MEN 2A codons 630 or 634 RET mutations.

Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma.

MicroRNAs are a primordial mechanism of gene expression control that appear to be crucial to cellular development and may play an important role in tumor development. Much is known about the genetics of medullary thyroid carcinomas, as approximately 25% are hereditary and harbor germ line activating mutations in the RET gene. Somatic RET mutations are also seen in roughly 50% of sporadic medullary thyroid carcinomas. Few studies, however, have evaluated the role of microRNA expression in these tumors. DNA and RNA were extracted from formalin-fixed paraffin-embedded tissue blocks of 15 medullary thyroid carcinomas [10 with RET mutations (3 hereditary) and 5 without RET mutations] and 5 non-tumor thyroid glands. miRNA expression of 754 targets was quantitated by real-time PCR using the ABI OpenArray miRNA assay. Three miRNAs showed significant differential expression and were validated in a larger cohort of 59 cases by real-time PCR. Expression of potential downstream targets and upstream regulators was also investigated by real-time PCR. miR-375 and miR-10a were significantly overexpressed, while miR-455 was underexpressed in medullary thyroid carcinomas. Expression of all 3 miRNAs was validated in the larger cohort of cases (miR-375, p=3.3×10(-26); miR-10a, p=5.6×10(-14); miR-455, p=2.4×10(-4)). No significant differences in miRNA expression were found between RET mutation positive and negative tumors nor between sporadic and hereditary tumors. Expression of the potential downstream targets of miR-375, YAP1 (a growth inhibitor) and SLC16a2 (a transporter of thyroid hormone), was down-regulated in the tumors suggesting that miR-375 is a negative regulator of the expression of these genes. Thus, differential expression of miR-375, miR-10a and miR-455 may be important for tumor development and/or reflect C-cell lineage of medullary thyroid carcinoma. Furthermore, the growth inhibitor YAP1 is identified as a potential important downstream target of miR-375.

Risk factors affecting operative approach, conversion, and morbidity for adrenalectomy: a single-institution series of 402 patients.

BACKGROUND: Risk factors for selecting patients for open adrenalectomy (OA) and for conversion are limited in most series. This study aimed to investigate variables that are important in selecting patients for OA, predict risk of conversion from laparoscopic adrenalectomy (LA), and impact 30-day outcomes of OA and LA. METHODS: A retrospective cohort study of prospectively collected data was conducted. Patients (≥ 16 years old) who underwent adrenalectomy in the Division of General Surgery at Barnes-Jewish Hospital (1993-2010) were grouped by operative approach (LA vs. OA) and compared using nonparametric tests and regression analyses (α < 0.05). RESULTS: In total, 402 patients underwent 422 adrenalectomies. Compared to LA patients, those in the OA group were older (p = 0.02), had higher ASA scores (p = 0.04), larger tumor size (p < 0.01), and fewer functioning lesions (p < 0.01). OA patients more often required concurrent procedures (p < 0.01), had a longer operative time (p = 0.04), more intraoperative complications (p = 0.02), higher estimated blood loss (EBL), and larger transfusion requirement. Preoperative factors that predicted selection for OA were higher patient age (p = 0.01), higher ASA score (p = 0.03), larger tumor size (p < 0.01), nonfunctioning lesion (p < 0.01), diagnosis of adrenocortical carcinoma (p < 0.01), and the need for concomitant procedures (p < 0.01). Conversion to open or hand-assisted approach occurred in 6.2 % of LA patients. Preoperative risks for conversion included large tumor size (>8 cm) and need for concomitant procedures (p < 0.01). Multivariate analysis revealed that large indeterminate adrenal mass, adrenocortical carcinoma, tumor size (>6 cm), an open operation, conversion, concomitant procedures, operative time >180 min, and EBL >200 mL were predictors of 30-day morbidity. CONCLUSIONS: Adrenal tumor size and need for concurrent procedures significantly impact the selection of patients for OA, the likelihood of conversion, and perioperative morbidity. These metrics should be considered when assessing operative approach and risks for adrenalectomy.

Outcomes of resection of extra-adrenal pheochromocytomas/paragangliomas in the laparoscopic era: a comparison with adrenal pheochromocytoma.

INTRODUCTION: Laparoscopic adrenalectomy (LA) is the standard for removal of adrenal pheochromocytomas (pheos), but laparoscopic (LAP) resection of paragangliomas (PGs) is controversial. This study analyzes our results of resection of PGs in the LAP era. METHODS: A retrospective record review of all patients who underwent resection of intra-abdominal PGs from 1998 to 2011 was performed. Pre- and postoperative clinical, radiologic, biochemical, and pathologic data for LAP resection of PGs were compared with patients who underwent LA for adrenal pheo (LA pheo; n = 62). Statistical analysis was performed and data are reported as mean ± SD. RESULTS: Fifteen patients had resection of PGs (6 OPEN, 9 LAP) and 62 had LA pheo. Most common PG locations were perirenal or renal hilum (n = 6) and para-aortic (n = 4). One LAP PG was converted to OPEN due to inflammation from a prior biopsy. Mean age of LAP PGs was 45.3 ± 13.2 years, and mean tumor size was 3.3 ± 2.1 cm. OPEN PGs were larger (5.1 vs. 3.3 cm), had shorter operative times (173 vs. 254 min), and longer hospitalization (5.7 vs. 2.6 days) and ICU stays (1.33 vs. 0.22 days) compared with LAP PGs (p ≤ 0.05). Compared with LA pheo, operative times for LAP PG were significantly longer (254 vs. 175 min, p = 0.001) but other outcomes were similar. Complications occurred in 5.9 % of LA pheos, 22 % of LAP PGs and 67 % of OPEN PGs. CONCLUSIONS: Patients with paragangliomas can safely benefit from LAP resection with outcomes similar to adrenal pheos. In the absence of a need for contiguous organ resection, LAP resection of paragangliomas seems to be the preferred surgical approach.

Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases.

PURPOSE: Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease. EXPERIMENTAL DESIGN: We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade. RESULTS: Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells. CONCLUSION: The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC.

Neuroendocrine tumors.

Neuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgical management of neuroendocrine tumors of the pancreas.

Racial differences in survival after surgical treatment for melanoma.

BACKGROUND: Surgical-treatment outcomes for melanoma in African Americans are poorly characterized as a result of low incidence of melanoma among African Americans. We examined differences by race in overall and melanoma-specific survival, stratified by receipt of surgical treatment and by specific types of surgical treatment. METHODS: Data from the 1973-2004 public-use Surveillance, Epidemiology and End Results Program (SEER) were analyzed by Cox proportional hazard models to compare the effects of surgical treatments on overall and melanoma-specific survival in blacks, whites, and other race, controlling for confounding demographic and tumor-related variables. RESULTS: Of 151,154 patients with first primary melanoma (148,883 whites, 789 blacks and 1,532 other race), 142,653 (94.4%) received surgical treatment. Among patients who received surgical treatment, 10-year melanoma-specific survival was lower in blacks (73%) than in whites (88%) and other race (85%); black patients were at significantly higher risk of overall and melanoma-specific mortality when compared with white (hazard ratio [HR] = 1.64, 95% confidence interval [CI] 1.44-1.86, P < 0.0001 and HR = 1.50, 95% CI 1.25-1.79, P < 0.0001, respectively) and with other race (HR = 1.55, 95% CI 1.31-1.85, P < 0.0001 and HR = 1.49, 95% CI 1.16-1.91, P = 0.0017, respectively). Blacks who underwent biopsy, wide excision and surgery not otherwise specified were at higher risk of overall mortality compared with whites with the same treatment. CONCLUSION: Overall and melanoma-specific survival was lower in blacks undergoing surgical treatment for melanoma compared to both whites and other race. Reasons for these disparities remain poorly understood.

A novel missense mutation in the MEN1 gene in a patient with multiple endocrine neoplasia type 1.

OBJECTIVE: To describe a novel germline missense mutation in exon 2 of the MEN1 gene identified in a man with multiple endocrine neoplasia type 1 (MEN 1). METHODS: We describe the patient's clinical, laboratory, and genetic data, and we review the relevant literature. RESULTS: A 41-year-old man with a history of primary hyperparathyroidism and left lower parathyroidectomy presented with nausea, vomiting, and hematemesis. Laboratory data revealed an elevated gastrin level. Computed tomography of the abdomen demonstrated a 3.5-cm mass in the head of pancreas. A functional study with a somatostatin receptor scan showed increased uptake in the region of the pancreatic mass. The patient's symptoms promptly improved after the Whipple procedure, although he was also noted to have a markedly elevated calcium concentration along with inappropriately elevated parathyroid hormone levels. Sestamibi scan identified a hyperfunctioning right upper parathyroid gland. His calcium level normalized after parathyroidectomy, and results from pituitary hormone studies were all normal. Genetic testing of the MEN1 gene identified a novel mutation: Arg52Gly. The Arg52Gly mutation replaces the normal arginine residue (CGC) with a glycine residue (GGC) at position 52 of the resultant menin protein. This mutation was present in family members from 3 generations. CONCLUSIONS: We report a novel disease-causing germline missense mutation in exon 2 of the MEN1 gene in a patient with MEN 1. Nonconservative replacement of arginine, a small, neutral amino acid, with glycine, a bulky positively charged amino acid, could potentially have a deleterious effect on the menin protein.