Coincidental Occurrence of Multiple Endocrine Neoplasia Type 1 and Breast Cancer in a Young Saudi Girl: A Case Study and Genetic Analysis.

Multiple Endocrine Neoplasia Type 1 (MEN-1) is an autosomal dominant familial disorder associated with tumors in both endocrine and non-endocrine organs. It is uncommon for MEN-1 to coincide with breast cancer. We present a case of a 15-year-old Saudi girl who exhibited the classic symptoms of MEN-1 and subsequently developed breast cancer. The patient's breast cancer was diagnosed using ultrasonography and core biopsy, and she was treated with surgical interventions. Despite these treatments, her cancer progressed to a metastatic stage, and her overall health deteriorated, leading to cardiopulmonary arrest at a young age. Although the simultaneous appearance of MEN-1 and breast cancer in our patient may suggest a potential link, our comprehensive genetic analysis found no relationship between her MEN-1 mutation and the onset of breast cancer. This suggests that, in this case, the two conditions co-occurred by chance. Nonetheless, additional research is needed to explore potential associations between MEN-1 and breast cancer.

Limited disease progression in endocrine surgery patients with treatment delays due to COVID-19.

BACKGROUND: The COVID-19 pandemic profoundly impacted the delivery of care and timing of elective surgical procedures. Most endocrine-related operations were considered elective and safe to postpone, providing a unique opportunity to assess clinical outcomes under protracted treatment plans. METHODS: American Association of Endocrine Surgeon members were surveyed for participation. A Research Electronic Data Capture survey was developed and distributed to 27 institutions to assess the impact of COVID-19-related delays. The information collected included patient demographics, primary diagnosis, resumption of care, and assessment of disease progression by the surgeon. RESULTS: Twelve out of 27 institutions completed the survey (44.4%). Of 850 patients, 74.8% (636) were female; median age was 56 (interquartile range, 44-66) years. Forty percent (34) of patients had not been seen since their original surgical appointment was delayed; 86.2% (733) of patients had a delay in care with women more likely to have a delay (87.6% vs 82.2% of men, χ2 = 3.84, P = .05). Median duration of delay was 70 (interquartile range, 42-118) days. Among patients with a delay in care, primary disease site included thyroid (54.2%), parathyroid (37.2%), adrenal (6.5%), and pancreatic/gastrointestinal neuroendocrine tumors (1.3%). In addition, 4.0% (26) of patients experienced disease progression and 4.1% (24) had a change from the initial operative plan. The duration of delay was not associated with disease progression (P = .96) or a change in operative plan (P = .66). CONCLUSION: Although some patients experienced disease progression during COVID-19 delays to endocrine disease-related care, most patients with follow-up did not. Our analysis indicated that temporary delay may be an acceptable course of action in extreme circumstances for most endocrine-related surgical disease.

Factors Predicting Positive Sentinel Lymph Node Biopsy in Clinically Node-Negative Breast Cancer.

Purpose: Sentinel lymph node (SLN) biopsy (SLNB) is the standard tool to stage the axilla of breast cancer patients. This study aimed to identify the predictors of positive SLNB in patients with clinically node-negative breast cancer. Patients and Methods: A retrospective, single-institution cohort of patients with early-stage breast cancer without clinically identifiable axillary lymphadenopathy was chosen from January 2010 to December 2018. Logistic regression was used to identify possible predictors of positive SLNB. Results: Four hundred and seventy patients were identified; their mean age was 50±11 years. Most patients had the following characteristics: invasive ductal carcinoma (n=382, 81.3%), unilateral tumor (n=461, 98.1%), unifocal disease (n=351, 74.7%), intermediate grade (n=276, 59.0%), and estrogen and progesterone receptor positivity with human epidermal growth factor receptor 2 negativity (n=305, 64.9%). The mean size of the breast mass was 2.3±1.5 cm. SLNB was positive in 128 (27.2%) cases. The mean number of SLNs was 2±1.2. Axillary lymph node dissection was performed in 109 patients. The mean number of lymph nodes removed was 15±6. In 66 (60.6%) of the 109 patients with metastatic axillary nodes, only the SLNs were found to be positive. The number of SLNs, tumor size, tumor grade, receptor status, prominent axillary lymph nodes, and lymphovascular invasion predicted positive SLNB (P = 0.01, 0.03, 0.03, and 0.04 and <0.001 and <0.001, respectively). Conclusion: Our results suggest that a number of histopathological and radiological characteristics of breast cancer can predict SLNB positivity in clinically node-negative breast cancer patients.

Impact of the COVID-19 pandemic on the practice of endocrine surgery.

BACKGROUND: This study investigates the impact of the COVID-19 pandemic on endocrine surgeons. METHODS: A survey on the professional, educational, and clinical impact was sent to active and corresponding members of the American Association of Endocrine Surgeons (AAES) in September 2020. Chi-square and paired t-test were used for analysis. RESULTS: 77 surgeons responded (14.8 %). All reported suspension of elective surgeries; 37.7 % were reassigned to other duties during this time. The median number of cases backlogged was 30 (IQR 15-50). Most surgeons reported decreased clinical volume (74.6 %). The use of virtual platforms for clinical and educational purposes increased from pre-COVID-19 levels (all p < 0.001). Use of in-office procedures (p < 0.001) and length of observation prior to discharge for thyroid surgery (p < 0.05) decreased. CONCLUSION: The COVID-19 pandemic led to suspension of operations and decreased practice volume for endocrine surgeons. Surgeons increased use of virtual platforms, decreased in-office procedures, and decreased duration of observation for thyroid surgery in response.

Use of Adjunctive Therapy to Achieve Preoperative Euthyroidism in Graves' Disease: A Case Report.

BACKGROUND Graves' disease is an autoimmune disease of the thyroid gland and it is considered the most common cause of hyperthyroidism. It is characterized by particular eye manifestations, skin changes, and pretibial myxedema in addition to the signs and symptoms of hyperthyroidism. Graves' disease can be diagnosed based on clinical presentation and low thyroid stimulating hormone (TSH) and elevated free T4 (FT4) levels. Presence of TSH receptor antibody (TRAb) in the serum confirms the diagnosis of Graves' disease. Imaging studies like radioactive iodine scan will show a high and diffuse uptake. Graves' disease can be managed with three different treatment modalities: antithyroid medications, radioactive iodine, or surgical removal of the thyroid gland. Whenever surgery is indicated, careful preoperative management to achieve euthyroidism is needed to optimize the surgical outcome. CASE REPORT This is a case of a 37-year-old Saudi male known to have Graves' disease for 2 years who presented to the endocrine surgery clinic with neck swelling, difficulty breathing, and change in voice. After multiple attempts to control his fluctuating thyroid levels, the team eventually managed to achieve a euthyroid state in the patient with the addition of saturated solution of potassium iodide (SSKI), and thus rendering him eligible for urgent surgery. CONCLUSIONS We report this case to show that SSKI can be used as adjunctive therapy to achieve a preoperative euthyroid state in refractory Graves' disease.

Primary oral malignant melanoma metastasis to the brain and breast: A case report and literature review.

Primary oral malignant melanoma is a rare tumor, which is estimated to comprise 0.2-8.0% of all melanoma cases. This type of cancer is fairly uncommon, its prognosis is dismal, and it frequently exhibits a biologically aggressive behavior. The common location of primary oral malignant melanoma is the hard palate and maxillary alveolus. In ~85% of cases, the melanoma will metastasize to the liver, lung, bone and brain early in the course of the disease. The present study reports the case of a 50-year-old premenopausal woman who presented with primary oral malignant spindle cell melanoma (T3bN2aM0) and underwent complete surgical resection followed by an adjuvant course of radiation therapy. After 1 year, the patient presented with sudden onset slurred speech, and upon examination, was found to have left-sided hemiparesis and a hard left breast mass. Workup confirmed breast and brain metastasis. The patient developed lung metastasis 4 weeks later and was referred for palliative care.

Intraoperative Parathyroid Hormone Levels at 5 min Can Identify Multigland Disease.

BACKGROUND: Intraoperative parathyroid hormone (IOPTH) monitoring is crucial in the treatment of primary hyperparathyroidism (PHPT). Often, the 5 min IOPTH levels fall, but not by the requisite 50 %. In such cases, the surgeon must decide whether to wait for additional levels or to continue exploration. This study aimed to evaluate the 5 min drop in IOPTH for distinguishing single adenomas (SA) from multigland disease. METHODS: A retrospective analysis of a prospectively collected database was performed on PHPT patients who underwent initial curative parathyroidectomy between 2001 and 2013. Those with familial disease and those taking lithium or undergoing concomitant thyroidectomy were excluded from the analysis. For cases of double adenomas (DA) or hyperplasia (HA), the IOPTH values indicating additional glands were analyzed. RESULTS: The inclusion criteria were met by 1021 patients: 817 patients with SA (82.2 %), 99 patients with DA (10 %), and 78 with HA (7.9 %). The SA patients exhibited a 56.6 ± 4.9 % decline in IOPTH at 5 min compared with 21.3 ± 4.5 % of the DA patients and 22.5 ± 4.3 % of the HA patients (p < 0.01). Post hoc comparisons showed that the 5 min decrease in the SA group was significantly greater than in either the DA group or the HA group (p < 0.01). A 5 min percentage decline of 35 % best distinguished SA from multiglandular disease (85.3 vs. 24.9 %). CONCLUSION: The data suggest that when IOPTH level does not drop by at least 35 % at 5 min after excision, the surgeon should consider further exploration rather than wait for additional levels.

Antiplatelet and Anticoagulant Medications Significantly Increase the Risk of Postoperative Hematoma: Review of over 4500 Thyroid and Parathyroid Procedures.

PURPOSE: Antiplatelet and/or anticoagulant medication use is common. Abstinence a week before surgery may still result in altered hemostasis. The study aim was to report on perioperative antiplatelet and anticoagulant use in thyroidectomy and parathyroidectomy patients, and to determine the association with postoperative hematoma (POH) rates. METHODS: Retrospective review of a prospective endocrine surgery database was performed. Procedure extent was defined as unilateral, bilateral, or extensive. Antiplatelets were categorized as none, 325 mg aspirin (ASA), <325 mg ASA, clopidogrel, or other. Anticoagulants were categorized as none, oral, or injectable. RESULTS: A total of 4514 patients were identified. POH developed in 22 patients (0.5 %). Rates were similar between age, gender, and reoperative status. POH were seven times more common after thyroidectomy (0.8 vs. 0.1 %, p < 0.01). Unilateral procedures had lower POH rates than bilateral or extensive (0.1 vs. 0.9 vs. 0.8 %, p < 0.01). POH rates in patients receiving 325 mg ASA (0.8 %) or clopidogrel (2.2 %) were much higher than patients not receiving antiplatelets (0.5 %) or receiving <325 mg ASA (0.1 %, p = 0.04). Oral anticoagulants (2.2 %) and injectable anticoagulants (10.7 %) had much higher POH rates than patients not receiving anticoagulants (0.4 %, p < 0.01). Target organ, patient gender, procedure extent, antiplatelet use, and anticoagulant use were included on logistic regression to determine association with POH. Bilateral procedures, thyroidectomy, clopidogrel, oral, and injectable anticoagulants were all independently associated with POH. CONCLUSIONS: POH occur more frequently after thyroidectomy and during bilateral procedures. Patients requiring clopidogrel or any anticoagulant coverage are at much higher risk for POH. These higher-risk patients should be considered for observation to ensure prompt POH recognition and intervention.

Primary hyperparathyroidism.

Primary hyperparathyroidism is a common endocrine disorder caused by overactivation of parathyroid glands resulting in excessive release of parathyroid hormone. The resultant hypercalcemia leads to a myriad of symptoms. Primary hyperparathyroidism may increase a patient's morbidity and even mortality if left untreated. During the last few decades, disease presentation has shifted from the classic presentation of severe bone and kidney manifestations to most patients now being diagnosed on routine labs. Although surgery is the only curative therapy, many advances have been made over the past decades in the diagnosis and the surgical management of primary hyperparathyroidism. The aim of this review is to summarize the characteristics of the disease, the work up, and the treatment options.

Recurrent and persistence primary hyperparathyroidism occurs more frequently in patients with double adenomas.

INTRODUCTION: The incidence of recurrent primary hyperparathyroidism (PHPT) had been reported to be between 1% and 10%. The purpose of this study was to examine if patients with multigland disease have a different recurrence rate. METHODOLOGY: A retrospective analysis of a prospectively collected database was performed on patients with PHPT who underwent parathyroidectomy at one institution between 2001 and 2013. Patients who underwent initial parathyroidectomy with at least 6 mo of follow-up were included and were divided into three groups according to operative notes: single adenoma (SA), double adenoma (DA), and hyperplasia (HP). An elevated postoperative serum calcium level within 6 mo of surgery was defined as a persistent disease, whereas an elevated calcium after 6 mo was defined as a recurrence. RESULTS: In total, 1402 patients met inclusion criteria, and the success rate of parathyroidectomy was 98.4%. The mean age was 60±14 y and 78.5% were female. Among them, 1097 patients (78%) had SA, 124 patients (9%) had DA, and 181 patients had HP (13%). The rate of persistent PHPT was higher among patients with DA (4%) versus SA (1.3%) and HP (2.2%) (P=0.0049). Moreover, the recurrence rate was higher among patients with DA (7.3%) versus SA (1.7%) and HP (4.4%) (P=0.0005) with identical median follow-up time. The median of the follow-up was 11 mo for patients with SA, 12.5 for patients with DA, and 12 for patients with HP (P=0.1603). CONCLUSIONS: Recurrent and persistent PHPT occur more frequently in patients with DA. These data suggest that DA in some cases could represent asymmetric or asynchronous hyperplasia. Therefore, patients with DA may warrant more rigorous intraoperative scrutiny and more vigilant monitoring after parathyroidectomy.

Minimal benefit to subsequent intraoperative parathyroid hormone testing after all four glands have been identified.

BACKGROUND: Modern tools, such as intraoperative parathyroid hormone (IoPTH) assay, reduce operative time and extent of parathyroidectomy. However, the utility of a subsequent final set of IoPTH after all four glands are visualized remains questionable. This study was designed to determine the added value of IoPTH assay following parathyroidectomy with four-gland visualization in patients with primary hyperparathyroidism (PHPT). METHODS: A retrospective review of patients who underwent parathyroidectomy for PHPT between July 2001 and February 2012 by two experienced endocrine surgeons was performed. Included were patients with operative reports indicating that all four parathyroid glands were identified. Following four-gland visualization a subsequent final set of IoPTH was measured to confirm cure. Cure was defined as at least 50 % fall by 5, 10, or 15 min postexcision compared with preincision levels. RESULTS: Of 1,838 patients that underwent parathyroidectomy, four glands were visualized in 238 cases (13 %). Of those patients meeting inclusion criteria with four glands visualized, the final set of IoPTH fell to cure criteria in 235 patients (98 %). An inadequate drop was documented in three (2 %) patients all of which were found to have multigland disease. Only in one patient (0.4 %) was a fifth parathyroid gland identified and resected. In all three cases, the subsequent final IoPTH did not affect the ultimate outcome or cure rate. CONCLUSIONS: When experienced surgeons visualize all four parathyroid glands, drawing a subsequent final set of IoPTH rarely changes the operative course and therefore serves a limited role.

Leflunomide suppresses growth in human medullary thyroid cancer cells.

BACKGROUND: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Leflunomide (LFN) is a disease-modifying antirheumatic drug approved for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide has been identified as a potential anticancer drug. In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells. METHODS: Human MTC-TT cells were treated with LFN (25-150 µmol/L) and Western blotting was performed to measure levels of neuroendocrine markers. MTT assays were used to assess the effect of LFN treatment on cellular proliferation. RESULTS: LFN treatment downregulated neuroendocrine markers ASCL1 and chromogranin A. Importantly, LFN significantly inhibited the growth of MTC cells in a dose-dependent manner. CONCLUSIONS: Treatment with LFN decreased neuroendocrine tumor marker expression and reduced the cell proliferation in MTC cells. As the safety of LFN in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC may be warranted.

Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: a systematic review and meta-analysis.

BACKGROUND: Transient hypocalcemia is a frequent complication after total thyroidectomy. Routine postoperative administration of vitamin D and calcium can reduce the incidence of symptomatic postoperative hypocalcemia. We performed a systematic review to assess the effectiveness of this intervention. The primary aim was to evaluate the efficacy of routine postoperative oral calcium and vitamin D supplementation in preventing symptomatic post-thyroidectomy hypocalcemia. The second aim was to draw clear guidelines regarding prophylactic calcium and/or vitamin D therapy for patients after thyroidectomy. METHODS: We identified randomized controlled trials comparing the administration of vitamin D or its metabolites to calcium or no treatment in adult patients after thyroidectomy. The search was performed in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Google Scholar, and Web of Knowledge databases. Patients with a history of previous neck surgery, calcium supplementation, or renal impairment were excluded. RESULTS: Nine studies with 2,285 patients were included: 22 in the vitamin D group, 580 in the calcium group, 792 in the vitamin D and calcium group, and 891 in the no intervention group, with symptomatic hypocalcemia incidences of 4.6%, 14%, 14%, and 20.5%, respectively. Subcomparisons demonstrated that the incidences of postoperative hypocalcemia were 10.1% versus 18.8% for calcium versus no intervention and 6.8% versus 25.9% for vitamin D and calcium versus no intervention. The studies showed a significant range of variability in patients' characteristics. CONCLUSIONS: A significant decrease in postoperative hypocalcemia was identified in patients who received routine supplementation of oral calcium or vitamin D. The incidence decreased even more with the combined administration of both supplements. Based on this analysis, we recommend oral calcium for all patients following thyroidectomy, with the addition of vitamin D for high-risk individuals.

Parathyroid cryopreservation after parathyroidectomy: a worthwhile practice?

BACKGROUND: Parathyroid cryopreservation is often utilized for patients having parathyroidectomy. This allows for future autotransplantation if a patient becomes permanently hypocalcemic after surgery. However, the practice of cryopreservation is costly and time-consuming, while the success rate of delayed autotransplantation is highly variable. We sought to determine the rate and outcomes of parathyroid cryopreservation and delayed autotransplantation at our institution to further evaluate its utility. METHODS: At our institution, 2,083 parathyroidectomies for hyperparathyroidism (HPT) were performed from 2001 to 2010. Of these, parathyroid cryopreservation was utilized in 442 patients (21 %). Patient demographics, preoperative diagnoses, and other characteristics were analyzed, as well as the rate and success of delayed autotransplantation. RESULTS: Of the 442 patients with cryopreservation, the mean age was 55 ± 1 years and 313 (70.8 %) were female. A total of 308 (70 %) had primary HPT, 46 (10 %) had secondary HPT, and 88 (20 %) had tertiary HPT. Delayed autotransplantation of cryopreserved parathyroid tissue was used in 4 (1 %) patients at an average time of 9 ± 4 months after initial surgery. Three of the 4 patients remained hypoparathyroid after this procedure. The single cured patient underwent the procedure only 4 days after the initial parathyroidectomy. CONCLUSIONS: Although cryopreservation was used in over one-fifth of patients undergoing parathyroidectomy, the need for parathyroid reimplantation was very low (1 %). Furthermore, the success rate of parathyroid autotransplantation was poor in these patients. Therefore, the continued practice of parathyroid cryopreservation is questionable.

Hereditary medullary thyroid cancer: age-appropriate thyroidectomy improves disease-free survival.

BACKGROUND: Twenty-five percent of medullary thyroid cancer (MTC) cases are hereditary. The ideal age for prophylactic thyroidectomy is based on the specific RET mutation involved. The purpose of this study was to determine whether such age-appropriate prophylactic thyroidectomy results in improved disease-free survival. METHODS: Twenty-eight patients underwent thyroidectomy for hereditary MTC at our institution. Age-appropriate thyroidectomy was defined according to the North American Neuroendocrine Tumor Society (NANETS) guidelines. Patients who had age-appropriate surgery (group 1, n = 9) were compared to those who had thyroidectomy past the recommended age (group 2, n = 19). RESULTS: The mean age was 13 ± 2 years, and 61 % were female. Patients in group 1 were younger than in group 2 (4 ± 1 vs. 17 ± 2 years, p < 0.01). There were no significant differences in gender or RET mutation types between these two groups. Group 1 patients were cured with no disease recurrence compared with group 2 patients who had a 42 % recurrence rate (p = 0.05). Subanalysis of group 2 identified that patients who underwent surgery without evidence of disease did so at a shorter period following the guidelines compared with those who underwent therapeutic surgery (2 ± 2 vs. 16 ± 2 years, p = 0.01) and had longer disease-free survival (100 vs. 27 %, p = 0.005). CONCLUSIONS: Patients with hereditary MTC should undergo age-appropriate thyroidectomy based on RET mutational status to avoid recurrence. Patients who are past the recommended age should have surgery as early as possible to improve disease-free survival.

The necessity and reliability of intraoperative parathyroid hormone (PTH) testing in patients with mild hyperparathyroidism and PTH levels in the normal range.

BACKGROUND: Intraoperative parathyroid hormone (IoPTH) testing is useful in the management of hyperparathyroidism. The successful removal of hypersecreting parathyroids is indicated by a decrease in PTH levels >50% within 15 min. A subset of patients with mild hyperparathyroidism will actually have starting PTH levels in the normal range. We sought to determine if IoPTH testing is necessary in these patients and if the 50% rule delineating surgical cure is reliable. METHODS: A retrospective review was performed on all patients who underwent parathyroidectomy for hyperparathyroidism at a single institution from 3/2001 to 8/2008. RESULTS: Of the 1,001 patients, 142 (14%) had mild hyperparathyroidism and normal baseline PTH levels (<65 pg/ml). Their mean PTH was 59 ± 1 pg/ml. During surgery, 105 (74%) had a >50% decline in PTH levels after resection of hyperfunctioning parathyroid glands, and their operations were terminated. In contrast, 37 (26%) patients did not have a >50% decline in PTH levels leading to further surgical exploration. In these 37 patients, the PTH levels fell by >50% after the removal of the additional glands in 25 patients (17.6%) and dropped after 20 min in 7 patients (4.9%). In 5 patients (3.5%) the IoPTH did not drop. Of the 142 total patients, 91 had single adenomas and 51 patients had multi-gland disease. All patients (100%) were cured (normal serum calcium after 6 months). CONCLUSIONS: Intraoperative PTH testing plays an important role in the operative management in 14% of patients with mild hyperparathyroidism. Importantly, a 50% decline in IoPTH level within 15 min of parathyroidectomy is 96.5% reliable in predicting cure in these patients with PTH starting in the normal range.

Infrared thermographic profiles of vessel sealing devices on thyroid parenchyma.

BACKGROUND: During thyroid lobectomy, division of the thyroid parenchyma has traditionally been accomplished using suture ligation. Development of hemostatic techniques in the forms of ultrasonic dissection (UD) and electronic vessel sealing (EVS) have increased the usage of these devices during thyroid operations. We sought to characterize the thermal profile of each of these devices when used to divide the parenchyma of the thyroid gland. METHODS: Using a porcine model, the parenchyma of the gland was sealed by alternating application of the UD and EVS devices. In each case, the thermal activity was recorded using infrared thermal imaging. We performed multiple seals with each instrument and then compared the thermal profiles. RESULTS: There was no significant difference in lateral thermal spread of EVS and UD above 39, 40 or 60°C (2.30 ± 0.31 mm versus 2.53 ± 0.47 mm, P = 0.26; 2.22 ± 0.27 mm versus 2.47 ± 0.47 mm, P = 0.22, and 1.37 ± 0.27 mm versus 1.54 ± 0.26 mm, P = 0.22). There was no significant difference in mean time above 39 or 40°C (35.1 ± 8.7 s versus 31.7 ± 9.3 s, P = 0.47 and 29.9 ± 8.1 s versus 27.3 ± 6.7 s, P = 0.50). UD reached a greater maximum temperature (179.12 ± 0.0008C versus 96.52 ± 5.6C, P ≤ 0.001) and stayed over 60°C for longer than EVS (9.5 ± 1.8 s versus 5.3 ± 0.97 , P ≤ 0.001). CONCLUSIONS: The amount of lateral spread of thermal energy was not significantly different between the UD and EVS devices. However, the use of UD produced a higher maximum temperature during thyroid parenchyma sealing and remained above 60°C longer than EVS. This may translate into greater thermal injury to thyroid and surrounding tissues during division.