GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism.

Context: A germline mutation can be identified in up to 10% of patients with primary hyperparathyroidism (PHPT). In 2017, a high frequency of the GCM2 [(NM_ 004752.4) c.1181A> C; p.Tyr394Ser; rs142287570] variant was reported in PHPT Ashkenazi Jews (AJ). Objective: To evaluate the presence of the GCM2 p.Tyr394Ser variant in Israeli patients addressed for genetic evaluation to characterize their phenotype and clinical management. Method: Patients with PHPT who underwent addressed for genetic screening for suspected familial hypocalciuric hypercalcemia (FHH), a family history of isolated hyperparathyroidism (FIHP), or failed parathyroidectomy with persistent PHPT were recruited. Those with normal initial selected gene sequencing or hyperparathyroid genetic panel completed the GCM2 p.Tyr394Ser variant sequencing. The prevalence of this variant was evaluated using our local genomic database. Results: A total of 42 single individuals from unrelated kindreds were evaluated. A disease-causing mutation was found in 11 (26.1%) patients: 10 were diagnosed with FHH (eight CASR and two AP2S1 mutations), and one patient had a CKN2B mutation. In 28 of the remaining patients, the GCM2 p.Tyr394Ser variant was positive in three (10.7%), and all were AJ. Within AJ (15/28, 53.5%), the rate of the p.Tyr394Ser variant was 3/15 (20%), and of those, two had a history of familial isolated hyperparathyroidism. Multi-glandular parathyroid adenoma/hyperplasia was also observed in two of these patients. No clinical or laboratory findings could discriminate patients with the GCM2 p.Tyr394Ser variant from those with FHH. Cinacalcet normalized the calcium levels in one patient. The prevalence of the GCM2 p.Tyr394Ser variant in 15,407 tests in our local genomic database was 0.98%. Conclusion: In contrast to previous observations, the GCM2 p.Tyr394Ser variant-associated phenotype may be mild in AJ with FIHP, sometimes mimicking FHH. Because surgery may be curative, surgeons should be aware of the possibility of multiple gland diseases in these patients. The clinical spectrum and clinical utility of screening for this variant warrant further investigation.

Incidental Gastric Signet Ring Cell Carcinoma: A Call for an Aggressive Approach.

BACKGROUND: Signet ring cell carcinoma (SRCC) is classified as an undifferentiated gastric carcinoma with poor prognosis. Early SRCCs are associated with improved prognosis. OBJECTIVES: To describe the outcomes of incidental SRCC. METHODS: In this case series, 900 medical charts of patients with SRCC were screened to identify patients with incidental SRCC, defined as diagnosed in random, non-focal-lesion-targeted biopsies. RESULTS: Six patients were diagnosed with incidental SRCC and underwent gastrectomy. The final pathology of five patients revealed one or more small foci of early SRCC without lymphovascular invasion. Only one patient had no evidence of malignancy. The median follow-up after surgery was 4.2 years (50 months, range 37-90 months). No deaths or recurrences were recorded during the follow-up period. These results resemble the reported survival rate for early SRCC. CONCLUSIONS: An aggressive surgical approach in incidental gastric SRCC patients is recommended, as they have a chance for long-term survival.

Higher Rates of Complicated Appendicitis During the COVID-19 Pandemic: A Year-to-Year Analysis.

INTRODUCTION: The COVID-19 pandemic impacted presentation, management strategies, and patient outcomes of numerous medical conditions. The aim of this study is to perform a year-to-year comparison of clinical outcomes of patients with acute appendicitis (AA) before and during the pandemic. METHODS: Patients treated for AA during the initial 12-mo period of the pandemic at our institute were compared to those treated for AA during the 12-mo period before. Clinical and laboratory parameters, treatment strategies, intraoperative findings, pathology reports, and postoperative outcomes were compared. RESULTS: During the study period, 541 patients presented with AA. The median (interquartile range) age was 28 (21-40) y and 292 (54%) were males. 262 (48%) patients presented during the pre-COVID-19 period, while 279 patients (52%) presented during the COVID 19 pandemic. The groups were comparable for baseline clinical data and imaging results upon index admission. There was no significant difference in rate of nonoperative treatment between the Pre-COVID-19 and During-COVID-19 eras (51% versus 53%, P = 0.6) as well as the success rate of such treatment (95.4% versus 96.4%, P = 0.3). Significantly more patients presented with a periappendicular abscess during COVID-19 (4.6% versus 1.1%, P = 0.01) and median (interquartile range) operative time was significantly longer (78 (61-90) versus 32.5 (27-45) min, P < 0.001). Pathology reports revealed a higher rate of perforated appendicitis during COVID-19 (27.4% versus 10.2%, P < 0.001). CONCLUSIONS: Patients with AA present with higher rates of perforated and complicated appendicitis during the COVID-19 pandemic. The success rates of nonoperative management in selected patients with noncomplicated AA did not change during the pandemic and is a safe, feasible, option.

Surgical aspects of small intestinal neuroendocrine tumors.

Small intestinal neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors with a predominant neuroendocrine differentiation. Although NETs are usually considered rare neoplasms, small intestinal NETs are the most common primary malignancy of the small bowel, with an increasing prevalence worldwide during the course of the past few decades. The indolent nature of these tumors often leads to a delayed diagnosis, resulting in over one-third of patients presenting with synchronous metastases. Primary tumor resection remains the only curative option for this type of tumor. In this review article, the various surgical aspects for the excision of small intestinal NETs are discussed.

A Comparison of Outcomes in Medullary Thyroid Carcinoma Patients With and Without a Preoperative Diagnosis: A Multicenter Retrospective Cohort Study.

Background: Cytological limitations pose a challenge to preoperative diagnosis of medullary thyroid carcinoma (MTC) and therefore, a significant subset of patients is only diagnosed postoperatively. The objective of this study was to investigate the impact of knowledge of a preoperative MTC diagnosis on disease management and outcomes. Methods: Multicenter, retrospective, cohort study of MTC patients treated in Israel from January 2000 to June 2021. We compared cohorts of patients according to the presence or absence of a preoperative MTC diagnosis. Results: Ninety-four patients with histologically confirmed MTC were included (mean age 56.2 ± 14.3 years, 43% males). Fifty-three patients (56%) had a preoperative MTC diagnosis (preop-Dx group), and 41 (44%) were confirmed only postoperatively (no-Dx group). The extent of surgical resection, including completion procedures, was as follows: total thyroidectomy in 83% versus 100% (p = 0.002), central lymph node dissection (LND) in 46% versus 98% (p < 0.001), ipsilateral lateral LND in 36% versus 79% (p < 0.001), and contralateral lateral LND in 17% versus 28% (NS), in the no-Dx versus the preop-Dx group, respectively. Pathology confirmed a smaller median tumor size of 16 ± 17.4 mm versus 23 ± 14.0 mm (p = 0.09), a higher proportion of micro-MTC (size ≤10 mm) 32% versus 15% (p = 0.03), and a higher rate of co-occurrence of follicular cell-derived carcinoma 24% versus 4% (p = 0.003), in the no-Dx compared to the preop-Dx group, respectively. The rates of extrathyroidal and extranodal tumor extension were not significantly different between the groups. At the last follow-up, the biochemical cure was attained in 55% [CI 0.38-0.71] compared to 64% [CI 0.50-0.77] of the no-Dx and the preop-Dx group, respectively (p = 0.41). After the exclusion of patients with micro-MTC, biochemical cure was more commonly achieved in the preop-Dx group (33% [CI 0.14-0.52] vs. 62% [CI 0.46-0.77], p = 0.04). Preop-Dx patients had improved overall survival compared to the no-Dx group (log-rank p = 0.04) over a median follow-up of 82 months (interquartile range [IQR] 30-153). Conclusions: Preoperatively, the diagnosis of MTC is often missed. An accurate preoperative diagnosis of MTC may enable guideline-concordant surgical treatment and ultimately contribute to an overall survival benefit in MTC patients.

Deliberate Compensated Vasoplegia-A Novel Pharmaceutical Approach for Controlling Blood Pressure During Surgery for Pheochromocytoma.

BACKGROUND: The most dreaded adverse event of pheochromocytoma surgery is operative severe blood pressure fluctuations. Preoperative protocols with alpha-blockade have achieved controversial results. No study to date evaluated the use of operative protocols in pheochromocytoma patients. Deliberated compensated vasoplegia (DCV) is a novel pharmaceutical regimen developed at our institution to decrease severe hypertensive events. The aim of this study is to compare outcomes of pheochromocytoma resection with and without DCV protocol. METHODS: A retrospective analysis of all pheochromocytoma resections between the years 2012 and 2021 was performed. Resections performed with and without DCV protocol were compared. The primary outcome measured was the incidence of severe hypertension (MAP > 150 mmHg) during surgery. Secondary outcomes included other abnormal blood pressure measurements as well as perioperative data and complications. RESULTS: A total of 41 resections were included, 21 performed under DCV protocol, and 20 without the protocol. Analysis demonstrated no significant difference in preoperative parameters including tumor size, catecholamine levels, and preoperative alpha-blockade protocol. The use of DCV protocol resulted in significant decrease in severe hypertension incidence from 1.95 ± 3.6 to 0.03 ± 0.13 events/h, p = 0.008. Application of the DCV protocol was not associated with any other adverse events. CONCLUSIONS: This study suggests that DCV anesthesia protocol significantly decreases the incidence of severe hypertensive episodes during pheochromocytoma resection. This is the first study that describes a highly effective protocol for controlling hypertension in pheochromocytoma patients.

Existing Scores Fail to Predict Bowel Ischemia in Patients With Adhesive Small Bowel Obstruction.

INTRODUCTION: Early recognition of bowel ischemia is critical in patients suffering from acute adhesive small bowel obstruction (ASBO). Recent studies attempted to propose a score combining clinical and radiological factors to predict the risk of bowel ischemia in patients with ASBO. This study aimed to compare and validate the existing clinical scores with a cohort of surgical patients. METHODS: We conducted a retrospective study including all ASBO cases admitted to our institution between January 1, 2005 and December 31, 2019. Based on three existing clinical scores, we calculated the risk of bowel ischemia for each patient. We then divided the cohort into groups based on the risk for bowel ischemia. For each risk-based category, the proportion of patients who underwent surgical resection and were found to have evidence of ischemic bowel was calculated. RESULTS: A total of 160 patients presenting with 217 episodes of acute ASBO were included. One hundred seventy-one (78.8%) cases were managed nonoperatively while 46 cases (21.2%) required surgery. Sixteen patients (7.3%) were eventually found to have ischemic bowel while 13 required small bowel resection (5.9%). All three clinical scores showed correlation between the calculated risk of ischemia and the intraoperative finding of ischemia. However, all three scores overestimated ischemia rates in the high-risk groups, yielding a PPV of 8.3%-28.5% and a NPV of 93.3%-94.7%. CONCLUSIONS: Current clinical scores for predicting bowel ischemia in patients with ASBO are of high value in ruling out ischemia, yet are of extremely low sensitivity, warranting an overly aggressive and unnecessary surgical approach.

Long-term Outcomes of Endoscopic Thoracoscopic Sympathectomy for Primary Focal Palmar Hyperhidrosis: High Patient Satisfaction Rates Despite Significant Compensatory Hyperhidrosis.

BACKGROUND: Endoscopic thoracoscopic sympathectomy (ETS) is the gold standard therapy for primary focal palmar hyperhidrosis (PFPH), resulting in high patient satisfaction rates. The most common side effect of ETS is compensatory hyperhidrosis (CH). Previous studies followed patients' satisfaction degree of surgery and the incidence of CH during a limited follow-up period of 1 to 3 years. The purpose of this study was to investigate the long-term outcomes and patient satisfaction after ETS. MATERIALS AND METHODS: After approval of our institutional review board, we conducted a retrospective review of all consecutive patients who underwent ETS for PFPH at our institution between 1998 and 2019. Electronic medical records were reviewed for short-term outcomes. Long-term outcomes were collected through telephone questionnaires. Primary outcome was the resolution of PFPH. Secondary outcomes were CH and long-term patient satisfaction. RESULTS: During the study period, 256 patients underwent ETS to treat primary focal palmar hyperhidrosis at our institution between the years 1998-2019. One-hundred and fifty (58.6%) patients agreed to participate in the study and were included in the final analysis. The mean age was 23.8 (17 to 58) years, 56% were females. The mean follow-up time was 11±6.1 (1 to 22) years. Ninety-four percent reported resolution of PFPH; however, CH was reported by 90% of participants. CH decreased mean patient satisfaction score from 4.8±0.5 to 3.8±2 ( P =0.009). This effect was more pronounced in patients with CH of the head and neck ( P =0.009). Patients' satisfaction decreased over time from a mean of 4.8±0.4 in the first year after surgery to a mean of 3.7±1.4 12 years or more after surgery ( P <0.001). Despite this, 79% of patients reported they would recommend ETS to other patients. CONCLUSIONS: ETS for PFPH is highly effective and results in high patient satisfaction rates even after long-term follow-up. Despite high rates of postoperative CH, nearly 80% of patients would still recommend the procedure to fellow patients, justifying its reputation as the gold standard treatment for PFPH.

Consistency of Thyroid Imaging Reporting and Data System Reporting in Community-Based Imaging Centers Versus a Large Tertiary Hospital.

OBJECTIVE: In our country, thyroid nodules are sonographically evaluated in health maintenance organization (HMO) imaging centers, and patients are referred to tertiary hospitals for ultrasound-guided fine-needle aspiration (FNA) biopsy when indicated. We evaluated the concordance in Thyroid Imaging Reporting and Data System (TI-RADS) classification reporting between these sites. METHODS: We conducted a retrospective cohort study reviewing the sonographic features of thyroid nodules evaluated both at the HMO and a large tertiary center between January 2018 and December 2019. The primary outcome was concordance between the TI-RADS classification at both sites. Additional endpoints included correlation of TI-RADS to the Bethesda category following FNA and correlation of TI-RADS with malignancy on final pathology at each site. RESULTS: The records of 336 patients with 370 nodules were reviewed. The level of concordance was poor (19.8%), with 277 (74.8%) nodules demonstrating higher TI-RADS and 20 (5.4%) lower TI-RADS at the HMO compared to the hospital (P < .001; weighted κ = 0.120). FNA results were available for 236 (63.8%) nodules. The Bethesda category strongly correlated with the hospital TI-RADS (P < .001), yet not with HMO TI-RADS (P = .123). In the surgically removed 57 nodules, a strong correlation was identified between the malignancy on final pathology and TI-RADS documented at the hospital (P < .001), yet not at the HMO (P = .259). CONCLUSIONS: There is poor agreement between TI-RADS classification on ultrasound performed in the HMO compared to a tertiary hospital. The hospital's TI-RADS strongly correlated with the Bethesda category and the final risk of malignancy, unlike the HMO.

Minimally Invasive Parathyroidectomy: Can Intraoperative Parathyroid Hormone Monitoring be Omitted?

BACKGROUND: Intraoperative PTH (ioPTH) monitoring has become widely accepted in the era of minimally invasive parathyroidectomy (MIP). The purpose of this study was to evaluate the need for ioPTH during parathyroidectomy in patients with positive preoperative imaging. METHODS: The charts of patients who underwent parathyroidectomy at three tertiary centers between the years 2012 and 2021 were retrospectively reviewed. Patients were defined as MIP candidates with either concordant preoperative imaging or a single positive imaging. Patients with negative or discordant imaging, concomitant thyroidectomy, or previous neck surgery were excluded. RESULTS: Of a total of 1013 patients who underwent parathyroidectomy, 535 (52.8%) were defined as MIP candidates and were included in the statistical analysis. Surgical success was achieved in all patients. A single adenoma that corresponded to the preoperative imaging was identified and resected in 517 (93.8%) patients. In only 18 (3.3%) patients, the ioPTH correctly changed the operative management where additional pathologic glands were identified and excised. Patients with additional lesions were significantly more likely to have decreased index adenoma size as indicated either by preoperative imaging or by intraoperative findings (15.5 ± 6.6 vs. 8.3 ± 2.5 mm, p < 0.001). None of the patients with an adenoma size greater than 13 mm had an additional pathologic gland. CONCLUSIONS: Our findings suggest that the routine use of ioPTH in MIP candidates may be omitted in patients with an index adenoma greater than 13 mm, even with only a single positive preoperative imaging study, without compromising surgical success.

Composite Criteria for Non-Operative Management of Acute Non-Complicated Appendicitis Result in Low Failure Rates.

BACKGROUND: The aim of this study is to investigate the outcomes of conservative management of non-complicated acute appendicitis (AA) using our unique institutional protocol, and to compare between these and the outcomes of operative management. METHODS: Patients admitted to our institution between March 2016 and October 2019 with non-complicated AA were grouped according to their initial management: non-operative versus surgical. Our unique protocol for non-operative management includes: pain < 3 days; afebrile upon admission; non-gravid; WBC <15,000 (× 109/L); CRP < 5 mg/dl; appendix diameter < 1 cm; no appendicolith on imaging; no prior episode of AA; no history of Inflammatory Bowel Disease; no evidence of peritonitis on physical examination. The primary outcome measured was failure of non-surgical management during the index admission. Secondary outcomes included recurrence rate, readmissions, complications, length of antibiotic treatment and length of stay (LOS). RESULTS: A total of 695 patients were included, 436 in the operative group and 259 in the non-surgical treatment group. The mean follow-up time was 1004.9 ± 205.7 days. Patients initially treated conservatively rarely required surgery during their index admission (6.9%). Recurrence rate was 19.1% after a mean follow up of 33.4 months. The overall failure rate of conservative management was documented in 20.8% of the patients. The complication rate was higher in those treated with upfront surgery (1.6% vs. 0.4%, p < 0.001). The overall LOS was not statistically different between the groups. CONCLUSIONS: Our composite protocol for non-surgical management of non-complicated AA results in a low failure rate. A well calculated patient treatment allocation in non-complicated AA can advocate for wide-spread use of the conservative approach.

Successful parathyroidectomy improves cognition in patients with primary hyperparathyroidism: A prospective study in a tertiary medical center and comprehensive review of the literature.

Context: The recent American and European guidelines on management of patients with primary hyperparathyroidism (PHPT) did not endorse neurocognitive evaluation as part of standard work-up and did not consider it as a surgery criterion.The neurocognitive deleterious effects of hyperparathyroidism and impact of parathyroidectomy on PHPT patients is yet to be elucidated. Objective: To evaluate specific neurocognitive functions in PHPT patients prior to parathyroidectomy and describe the changes during follow-up with serial evaluations. Design: A prospective case-control study including parathyroidectomy candidates evaluated at a tertiary teaching university hospital. Thorough neurocognitive evaluation was conducted before and 1- & 6-months following parathyroidectomy: Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth Complex Figure Test (ROCF), Trail Making Test A, Trail Making Test B, Addenbrooke's Cognitive Examination-III (ACE), Frontal Assessment Battery (FAB), Beck Depression Inventory (BDI). Results: 18 consecutive patients underwent successful parathyroidectomy. Various neurocognitive functions improved significantly after successful parathyroidectomy: long term auditory memory (RAVLT, p=0.008), short- and long-term visual memory (ROCF, p=0.006 and p=0.002 respectively), visual attention and complex concentration skills (trail making A, p<0.001) and executive abilities (trail making B, p=0.005). No change was identified in frontal-lobe abilities. Depression symptoms were absent or minimal prior to surgery and no significant change was observed after surgery. Conclusions: PHPT is associated with significant various neurocognitive dysfunctions when mindfully evaluated before surgery. Successful parathyroidectomy results in several neurocognitive aspect improvements. The data suggest that neurocognitive deterioration may be considered an added parathyroidectomy criterion when surgical decision is not straightforward.

Adrenal ganglioneuroma resected for suspicious malignancy: multicenter review of 25 cases and review of the literature.

PURPOSE: We reviewed the experience with adrenal ganglioneuroma (AGN) pathologically confirmed following adrenalectomy in medium- to high-volume medical centers. METHODS: The medical records of all adrenalectomy cases in 4 medical centers between 2006 and 2020 were retrospectively reviewed for demographics, clinical, radiological and laboratory findings, surgical treatment, pathology results, and outcomes. RESULTS: Twenty-five out of 875 adrenalectomy cases (2.9%) were pathologically confirmed as AGN. Those patients' average age was 40.5 years (range, 4-76 years), 13 (52.0%) were males, and 18 lesions (72.0%) were right-sided. One patient had a family history of neurofibromatosis, and another had a succinate dehydrogenase gene mutation. Abdominal/back pain attributed to mass effect was the most common symptom. All 25 patients underwent abdominal computerized tomography scanning in which the average maximal tumor diameter was 6.61 cm. The mean pre- and postcontrast Hounsfield units (HU) values were 35.2 and 59, respectively; and the mean late-phase HU value was 71.1. Twenty-two patients (88.0%) underwent minimally invasive surgery. The average tumor diameter recorded in the final pathology report was 7 cm. Isolated AGN was diagnosed in 21 cases (84.0%), and the additional components reported for the remaining 4 cases included pheochromocytoma (2), ganglioneuroblastoma (1), and neurofibroma (1). The average follow-up length was 16.8 months (range, 1-136 months), during which there was no recurrence or death. CONCLUSION: AGN is a rare, slow-growing, large benign tumor with radiological characteristics similar to those seen in malignant tumor. Final diagnosis is established by pathology after surgical resection, preferably minimally invasive, with an overall excellent prognosis.

Active Surveillance of Thyroid Microcarcinoma-Can This Approach Be Safely Implemented Worldwide?

The incidence of thyroid cancer has been increasing exponentially worldwide, mainly due to increased detection of small papillary thyroid microcarcinomas (PTMCs). Given the indolent nature of the disease, active surveillance (AS) has been suggested as an alternative approach to immediate surgery in the management of low-risk PTMCs. The decision to proceed with AS must take into account patient characteristics, tumor characteristics, and medical team characteristics. In this review, we discuss the rationale and evidence to support AS, as well as important considerations and limitations to implementing this approach for PTMC worldwide.

The Decreasing Incidence of Acute Appendicitis During COVID-19: A Retrospective Multi-centre Study.

BACKGROUND: As the novel coronavirus disease 19 (COVID-19) spreads, a decrease in the number of patients with acute appendicitis (AA) has been noted in our institutions. The aim of this study was to compare the incidence and severity of AA before and during the COVID-19 pandemic. METHODS: A retrospective cohort analysis was performed between December 2019 and April 2020 in the four high-volume centres that provide health care to the municipality of Jerusalem, Israel. Two groups were created. Group A consisted of patients who presented in the 7 weeks prior to COVID-19 first being diagnosed, whilst those in the 7 weeks after were allocated to Group B. A comparison was performed between the clinicopathological features of the patients in each group as was the changing incidence of AA. RESULTS: A total of 378 patients were identified, 237 in Group A and 141 in Group B (62.7% vs. 37.3%). Following the onset of COVID-19, the weekly incidence of AA decreased by 40.7% (p = 0.02). There was no significant difference between the groups in terms of the length of preoperative symptoms or surgery, need for postoperative peritoneal drainage or the distribution of complicated versus uncomplicated appendicitis. CONCLUSIONS: The significant decrease in the number of patients admitted with AA during the onset of COVID-19 possibly represents successful resolution of mild appendicitis treated symptomatically by patients at home. Further research is needed to corroborate this assumption and identify those patients who may benefit from this treatment pathway.

The prognostic value of lymph node ratio in Medullary thyroid carcinoma: A multi-center study.

INTRODUCTION: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC. MATERIALS AND METHODS: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated. RESULTS: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005). CONCLUSIONS: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC.

Long-term outcomes in MEN-1 patients with pancreatic neuroendocrine neoplasms: an Israeli specialist center experience.

PURPOSE: The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes. METHODS: This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed. RESULTS: Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years. CONCLUSIONS: In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

OBJECTIVE: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). METHODS: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. RESULTS: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. CONCLUSION: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients.