Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

Severe Hyponatremia in a 46-Year-Old Female With Pituitary Stalk Duplication and Primary Empty Sella Syndrome.

Pituitary duplication is a rare congenital malformation. It has been mainly reported in the pediatric and neonatal population, with few reported cases in the adult population. In this case report, we discuss the presentation of an adult female patient with pituitary stalk duplication and primary empty sella (PES). A 46-year-old South Asian female presented with severe euvolemic hyponatremia. Initial investigation showed low serum osmolality, high urine osmolality, high urinary sodium concentration, and normal chest X-ray. On physical examination, the patient had underdeveloped secondary sexual characteristics. Laboratory tests showed low follicle-stimulating hormone, luteinizing hormone, and estradiol. Prolactin was moderately elevated, morning cortisol was low, adrenocorticotropic hormone (ACTH) was within the lower normal range, ACTH dynamic test was suboptimal, and insulin-like growth factor 1 was low. MRI showed empty sella with duplication of the pituitary stalk and third ventricle sagging. Pituitary stalk duplication is a rare congenital malformation that can be associated with other craniofacial abnormalities. Here, we describe the occurrence of pituitary stalk duplication with PES. It is not known if the two conditions are associated with each other. However, we speculate that the duplication of the stalk might have altered the normal anatomy of the aperture in the sellar diaphragm creating a space for the third ventricle to sag or herniate, as well as compressing the pituitary gland.

A New Medical Therapy for Multiple Endocrine Neoplasia Type 1?

Pancreatic neuroendocrine tumours (pNETs) are a major manifestation of multiple endocrine neoplasia type 1 (MEN1), and the most significant cause of morbidity and mortality in this disorder. There is some evidence that the early use of somatostatin analogues can retard progression, especially of small non-functioning tumours, but there are no other prophylactic therapies for patients, and the treatment of metastatic disease is similar to that for sporadic pNETs. A recent study has shown that in cell line and animal models, MEN1 mutations lead to an upregulation of the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in increasing precursor metabolites for the synthesis of pyrimidines. In these studies, blockade of this pathway by various means, including the DHODH inhibitor leflunomide, attenuates cell growth and tumour progression, suggesting a critical dependence on DHODH specifically in MEN1-mutated tissue. Preliminary clinical studies in three patients with MEN1 and pNETs have indicated some therapeutic potential of this drug, which has previously been used for some years in patients with rheumatoid arthritis. It is suggested that further clinical trials of this re-purposed drug are indicated to evaluate its potential for the treatment of patients with MEN1 and pNETS. This article describes the clinical problem of MEN1 and pNETs, and reviews the recent publication reporting on these initial results.

Insulinoma: a quarter century of dietary control.

Summary: Insulinomas are rare pancreatic neuroendocrine neoplasms (NENs) that are typically sporadic and solitary, with the majority being <2 cm in diameter at diagnosis. The median duration of symptoms before diagnosis is variable; however, this is usually in the region of 12-18 months. We report on an insulinoma diagnosed some 25 years following initial symptoms, having by that stage attained a diameter of 4 cm. We present a 50-year-old man who was reported with hypoglycaemic symptoms on his wedding 25 years prior to eventual confirmation of an insulinoma. He had since learned to live with the symptoms by eating frequently to manage his hypoglycaemia. However, over recent months, he reported a substantial deterioration in his symptoms, and indeed, had collapsed on two occasions. He had a fasting glucose of 2.9 mmol/L with grossly inappropriate elevated insulin and C-peptide levels. MRI demonstrated a 4.1 cm lesion at the body of pancreas and an indeterminate 9-mm liver lesion with a negative 68Gallium-DOTATATE PET scan. Accordingly, he was initiated on diazoxide and referred to the surgical team for distal pancreatectomy: histology confirmed a 4.4-cm well-differentiated pancreatic NEN of intermediate grade (NEN G2, Grade 2, 2017 World Health Organization (WHO) pancreatic-NEN classification), with positive immunohistochemistry for insulin. His hypoglycaemia episodes have ceased, and he remains under active surveillance. Our case demonstrates the possibility of dietary control of insulinoma-induced hypoglycaemia, and the likelihood that such a prolonged delay in diagnosis has led to the uncommonly large size of the apparently benign tumour which is usually 'small and indolent'. Learning points: Most patients with insulinomas have lesions that are 1-2 cm in size, with 96% being less than 3 cm. The mean tumour size of insulinomas found in 3 of the largest reported series was 1.5 cm, with a range of 0.1-7.0 cm. It is not uncommon for patients to have symptoms for several months to years before diagnosis; however, no reported cases had the symptoms such long for 25 years, and the large size of the tumour in this case may reflect the very long history.

The Vanishing Adrenal Glands: A Transient Regression of Adrenal Lymphoma After a Single Dose of 1 mg Dexamethasone.

OBJECTIVE: Dexamethasone is a known treatment for lymphoma, but the potency and rapidity of its effect have not been recognized. We present a case of bilateral adrenal lymphoma that significantly reduced in size after a single dose of dexamethasone. METHODS: We present the clinical course and investigations, including adrenocorticotropic hormone, cortisol, short synacthen test, computed tomography (CT), and adrenal biopsy results. RESULTS: A 52-year-old man had a fall and was incidentally found to have bilateral adrenal masses (left, 6 cm; right, 5 cm) on CT. His adrenal function tests included plasma metanephrines (normetanephrine, 830 pmol/L [normal, <1180]; metanephrine, <100 pmol/L [<510]; 3-methoxytyramine, <100 pmol/L [<180]); aldosterone, 270 pmol/L( 90-700); and random cortisol, 230 nmol/L (160-550). An overnight dexamethasone suppression test with 1 mg of dexamethasone showed cortisol of <28 nmol/L (0-50). A repeat CT scan 8 days thereafter showed adrenal masses of 4.5 and 3.5 cm on the left and right, respectively. He had a follow-up CT scan 3 months later that showed adrenal lesions measuring 8 cm (left) and 9 cm (right). He subsequently presented with fatigue and dizziness. Morning cortisol of 201 nmol/L (160-550) with adrenocorticotropic hormone of 216 ng/L (10-30) indicated primary adrenal insufficiency. Mineralocorticoid and glucocorticoid replacement therapy commenced. An adrenal biopsy showed abnormal enlarged B cells, consistent with a diagnosis of diffuse large B-cell lymphoma. CONCLUSION: A diagnosis of lymphoma should be considered when adrenal lesions shrink following even a single low dose of dexamethasone administered as a part of a diagnostic test.

A Case Series of Patients with Isolated IgG4-related Hypophysitis Treated with Rituximab.

CONTEXT: The acute presentation of immunoglobulin G4 (IgG4)-related hypophysitis can be indistinguishable from other forms of acute hypophysitis, and histology remains the diagnostic gold standard. The high recurrence rate necessitates long-term immunosuppressive therapy. Rituximab (RTX) has been shown to be effective in systemic IgG4-related disease (IgG4-RD), but experience with isolated pituitary involvement remains limited. CASE DESCRIPTION: We report 3 female patients with MRI findings suggestive of hypophysitis. All patients underwent transsphenoidal biopsy and fulfilled diagnostic criteria for IgG4-related hypophysitis. Treatment with glucocorticoids (GCs) resulted in good therapeutic response in Patients 1 and 2, but the disease recurred on tapering doses of GCs. GC treatment led to emotional lability in Patient 3, necessitating a dose reduction. All 3 patients received RTX and Patients 2 and 3 received further courses of treatment when symptoms returned and B-cells repopulated. Patient 3 did not receive RTX until 12 months from the onset of symptoms. Patient 1 was not able to have further RTX treatments due to an allergic reaction when receiving the second dose. Rituximab treatment resulted in sustained remission and full recovery of anterior pituitary function in Patients 1 and 2, with complete resolution of pituitary enlargement. By contrast, Patient 3 only showed a symptomatic response following RTX treatment, but pituitary enlargement and hypofunction persisted. CONCLUSION: Rituximab treatment for IgG4-related hypophysitis resulted in sustained remission in 2 patients treated early in the disease process but only achieved partial response in a patient with chronic disease, suggesting that early therapeutic intervention may be crucial in order to avoid irreversible changes.

Improving venous thromboembolism risk assessment compliance using the electronic tool in admitted medical patients.

Sheikh Khalifa Medical City (SKMC) in Abu Dhabi is the main tertiary care referral hospital in the United Arab Emirates (UAE) with 560 bed capacity that is fully occupied most of the time. SKMC senior management has made a commitment to make quality and patient safety a top priority. Venous thromboembolism (VTE) risk assessment has been identified as a critical patient safety measure and key performance indicator. The electronic VTE risk assessment form a computerized decision support tool was introduced to improve adherence with deep venous thrombosis (DVT) prophylaxis recommendations. A multidisciplinary task force team was formed and led this quality improvement project. The purpose of this publication is to indicate the quality improvement interventions implemented to enhance compliance with VTE risk assessment and the outcomes of those interventions. We chose to conduct the pilot study in General Medicine as it is the busiest department in the hospital. The study period was from April 2014 till August 2015.The lessons learned were disseminated throughout the hospital. Our aim was to improve VTE risk assessment compliance by using the electronic form in order to ensure patient safety and reduce preventable harm. VTE risk assessment compliance improved in general medicine from 4% to 98%, and overall SKMC compliance from 21% to above 90%.