Genetic background influences tumour development in heterozygous Men1 knockout mice.

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5-26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.

What is Elective Oncologic Surgery in the Time of COVID-19? A Literature Review of the Impact of Surgical Delays on Outcomes in Patients with Cancer.

BACKGROUND: The impact of the COVID-19 pandemic has spread beyond those infected with SARS-CoV-2. Its widespread consequences have affected cancer patients whose surgeries may be delayed in order to minimize exposure and conserve resources. METHODS: Experts in each surgical oncology subspecialty were selected to perform a review of the relevant literature. Articles were obtained through PubMed searches in each cancer subtype using the following terms: delay to surgery, time to surgery, outcomes, and survival. RESULTS: Delays in surgery > 4 weeks in breast cancer, ductal carcinoma in situ, T1 pancreatic cancer, ovarian cancer, and pediatric osteosarcoma, negatively impacted survival. Studies on hepatocellular cancer, colon cancer, and melanoma (Stage I) demonstrated reduced survival with delays > 3 months. CONCLUSION: Studies have shown that short-term surgical delays can result in negative impacts on patient outcomes in multiple cancer types as well as in situ carcinoma. Conversely, other cancers such as gastric cancer, advanced melanoma and pancreatic cancer, well-differentiated thyroid cancer, and several genitourinary cancers demonstrated no significant outcome differences with surgical delays.

Epigenetic modifications in poorly differentiated and anaplastic thyroid cancer.

Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex. A deeper understanding of the signaling pathways affected by epigenetic dysregulation may improve prognostic testing and support the advancement of thyroid-specific epigenetic therapies. This review outlines the current understanding of epigenetic alterations observed in PDTC and ATC and explores the potential for exploiting this understanding in developing novel therapeutic strategies.

DNA Mismatch Repair Deficiency Promotes Genomic Instability in a Subset of Papillary Thyroid Cancers.

BACKGROUND: Efficient DNA damage repair by MutL-homolog DNA mismatch repair (MMR) enzymes, MLH1, MLH3, PMS1 and PMS2, are required to maintain thyrocyte genomic integrity. We hypothesized that persistent oxidative stress and consequent transcriptional dysregulation observed in thyroid follicles will lead to MMR deficiency and potentiate papillary thyroid tumorigenesis. METHODS: MMR gene expression was analyzed by targeted microarray in 18 papillary thyroid cancer (PTC), 9 paracarcinoma normal thyroid (PCNT) and 10 normal thyroid (NT) samples. The findings were validated by qRT-PCR, and in follicular thyroid cancers (FTC) and follicular thyroid adenomas (FTA) for comparison. FOXO transcription factor expression was also analyzed. Protein expression was assessed by immunohistochemistry. Genomic integrity was evaluated by whole-exome sequencing-derived read-depth analysis and Mann-Whitney U test. Clinical correlations were assessed using Fisher's exact and t tests. RESULTS: Microarray and qRT-PCR revealed reduced expression of all four MMR genes in PTC compared with PCNT and of PMS2 compared with NT. FTC and FTA showed upregulation in MLH1, MLH3 and PMS2. PMS2 protein expression correlated with the mRNA expression pattern. FOXO1 showed lower expression in PMS2-deficient PTCs (log2-fold change -1.72 vs. -0.55, U = 11, p < 0.05 two-tailed). Rate of LOH, a measure of genomic instability, was higher in PMS2-deficient PTCs (median 3 and 1, respectively; U = 26, p < 0.05 two-tailed). No correlation was noted between MMR deficiency and clinical characteristics. CONCLUSIONS: MMR deficiency, potentially promoted by FOXO1 suppression, may explain the etiology for PTC development in some patients. FTC and FTA retain MMR activity and are likely caused by a different tumorigenic pathway.

Parathyroidectomy prior to kidney transplant decreases graft failure.

BACKGROUND: Uncorrected uremic hyperparathyroidism is associated with delayed graft function after kidney transplantation. The current guidelines of the Kidney Disease Improving Global Outcomes recommend maintaining parathyroid hormone ≤9x normal in patients pre-kidney transplantation. This study explores the effect of increased levels of serum parathyroid hormone and preoperative parathyroidectomy on outcomes after kidney transplantation. METHODS: A retrospective review was performed of adult patients who underwent kidney transplantation between January 1, 2005, and December 31, 2014, at a single institution. Biochemistries and outcomes were analyzed pre-kidney transplantation and at 30 days, 6 months, and 1 year post-kidney transplantation. RESULTS: A total of 913 patients underwent kidney transplantation from 2005-2014. Graft survival 1 year post-kidney transplantation was 97.8%. Overall, 462 (50.6%) patients had a pre-kidney transplantation diagnosis of uncorrected uremic hyperparathyroidism, which was associated with complications in the first year post-kidney transplantation (odds ratio 1.44; 95% confidence interval, 1.11-1.87); no statistical association with delayed graft function or graft failure was detected. Pre-kidney transplantation parathyroid hormone ≥6x normal was associated with post-kidney transplantation graft failure (P < .05). A total of 57 (6.2%) patients underwent pre-kidney transplantation parathyroidectomy, which was associated with lesser risk of graft failure (odds ratio: 0.547; 95% confidence interval, 0.327-0.913), but no statistically significant association with delayed graft function or complications were detected. CONCLUSION: Pre-kidney transplantation parathyroidectomy decreases post-kidney transplantation graft failure and may benefit patients whose serum parathyroid hormone levels decrease into the target range of current Kidney Disease Improving Global Outcomes guidelines.

Primary hyperparathyroidism with normal baseline intraoperative parathyroid hormone: A challenging population.

BACKGROUND: Patients with primary hyperparathyroidism and baseline intraoperative parathyroid hormone levels in the normal range are challenging. This study compares the predictive value of a commonly used intraoperative parathyroid hormone algorithm, a software model for cure prediction, and surgeon judgment in this population. METHODS: This was a retrospective review of consecutive patients who underwent parathyroidectomy for primary hyperparathyroidism at a single institution from March 2013 to October 2014. RESULTS: Of 541 operative patients, 114 (21.1%) had a mean normal baseline intraoperative parathyroid hormone of ≤69 pg/mL (median 59.0 ± 10.3; range 26-69). Of the 114 patients, 93 (81.6%) were women, median age was 61 years (range 18-88). Overall, 107/108 (99.1%) patients were cured; 47 (41.2%) patients had single adenomas, 16 (14%) had double adenomas, and 51 (44.7%) had multigland hyperplasia. Using the 50% decline algorithm, a correct prediction was made in 86 (75.4%) patients. Using the computer software, a correct prediction was made in 88 (77.2%) patients. Surgeon judgment, however, was 99.1% accurate. CONCLUSION: Patients with normal baseline intraoperative parathyroid hormone have a high incidence of multigland disease (58.8%), greater than reported previously. Current software modeling and the 50% decline algorithm are insufficient to predict cure in this population; intraoperative parathyroid hormone interpretation combined with operative findings and surgical judgment yield optimal outcomes.

Dissection of Levels II Through V Is Required for Optimal Outcomes in Patients with Lateral Neck Lymph Node Metastasis from Papillary Thyroid Carcinoma.

BACKGROUND: Completeness of surgical resection is an important determinant of outcomes in patients with papillary thyroid carcinoma and regional lymph node metastasis. The extent of therapeutic lateral neck dissection remains controversial. This study aims to assess the impact of modified radical neck dissection of levels II to V in a large patient series. STUDY DESIGN: Retrospective analysis of consecutive patients with papillary thyroid carcinoma who underwent lateral neck dissection at a single institution from June 1, 2006 to December 31, 2014 was performed. RESULTS: A total of 241 lateral neck dissections were performed in 191 patients (118 [62%] women; median age 46 years [range 6 to 87 years]; median follow-up 14.3 months [range 0.1 to 107 months]). Overall, 202 initial neck dissections (195 modified radical neck dissections and 7 less extensive dissections) were performed. Among these initial dissections, 137 (68.8%), 132 (65.7%), 105 (52.0%), and 33 (16.9%) had positive lymph nodes in levels II, III, IV, and V, respectively. Ipsilateral lymph node persistence or recurrence occurred after 22 (10.9%) initial dissections, at level II in 10 (45.5%), level III in 8 (36.4%), level IV in 7 (31.8%), and level V in 3 (13.6%). Thirty-nine reoperative lateral neck dissection were performed, including 18 cases of persistence and recurrence after our initial dissections. In reoperative dissections, positive lymph nodes were confirmed in levels II, III, IV, and V in 18 (46.2%), 10 (25.6%), 13 (33.3%), and 5 (12.8%) dissections, respectively. Temporary nerve injury occurred in 6 (3.0%) initial and 4 (10.3%) reoperative dissections, respectively. There were no permanent nerve injuries. CONCLUSIONS: Omitting levels II and V during lateral neck dissection for papillary thyroid carcinoma potentially misses level II disease in two-thirds of patients and level V disease in one-fifth of patients. Formal modified radical neck dissection is necessary to avoid the morbidity of reoperative surgery.

Proliferation rates of multiple endocrine neoplasia type 1 (MEN1)-associated tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid and adrenocortical tumors, and neuroendocrine tumors (NETs) of the pancreas and pituitary. The pancreatic NETs are predominantly gastrinomas and insulinomas, and the pituitary NETs are mostly prolactinomas and somatotrophinomas. We postulated that the different types of pancreatic and pituitary NETs may be partly due to differences in their proliferation rates, and we therefore assessed these in MEN1-associated tumors and gonadal tumors that developed in mice deleted for an Men1 allele (Men1(+/-)). To label proliferating cells in vivo, Men1(+/-) and wild-type (Men1(+/+)) mice were given 5-bromo-2-deoxyuridine (BrdU) in drinking water from 1-12 wk, and tissue sections were immunostained using anti-BrdU and hormone-specific antibodies. Proliferation in the tumors of Men1(+/-) mice was significantly (P < 0.001) increased when compared with the corresponding normal Men1(+/+) tissues. Pancreatic, pituitary and adrenocortical proliferation fitted first- and second-order regression lines in Men1(+/+) tissues and Men1(+/-) tumors, respectively, R(2) = 0.999. Apoptosis was similar in Men1(+/-) pancreatic, pituitary, and parathyroid tumors when compared with corresponding normal tissues, decreased in Men1(+/-) adrenocortical tumors, but increased in Men1(+/-) gonadal tumors. Mathematical modeling of NET growth rates (proliferation minus apoptosis rates) predicted that in Men1(+/-) mice, only pancreatic ß-cells, pituitary lactotrophs and somatotrophs could develop into tumors within a murine lifespan. Thus, our studies demonstrate that Men1(+/-) tumors have low proliferation rates (<2%), second-order kinetics, and the higher occurrence of insulinomas, prolactinomas, and somatotrophinomas in MEN1 is consistent with a mathematical model for NET proliferation.

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic, and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1(+/-) mice, using a recombinant nonreplicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumors in 55 Men1(+/-) female mice received a transauricular intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdUrd) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and 4-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared with other groups. Daily proliferation rates assessed by BrdUrd incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control-treated tumors. In contrast, apoptotic rates, immune T-cell response, and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation.

An assessment of between-recti distance and divarication in patients with and without abdominal aortic aneurysm.

INTRODUCTION: The study assessed whether there is a greater incidence of divarication of the recti and whether between-recti distance is greater in patients with abdominal aortic aneurysm (AAA). PATIENTS AND METHODS: The study consisted of two parts: a radiological and a clinical assessment. All patients with a confirmed AAA on computerised tomography were included and compared with patients in whom AAA was excluded with imaging. Between-recti distance was measured using a computerised image viewer and clinical divarication was assessed by a surgical registrar or consultant. RESULTS: In the radiological part of the study, 108 patients with AAA were compared with 84 with colorectal cancer. Median between-recti distance was 38 mm (range, 25-59 mm) in the AAA group and 27 mm (range, 20-44.5 mm) in the non-AAA group (P=0.006). AAA diameter did not correlate with between-recti distance. The clinical study included 50 patients (25 AAA). The groups were well matched, with only a greater incidence of diabetes in the AAA group (20% vs 0%; P=0.018). AAA patients were more likely to have clinically detected divarication of the recti (76% vs 36%; P=0.004). CONCLUSIONS: Patients with AAA have greater radiological and clinical evidence of divarication. It is suggested that patients with divarication be screened for AAA.