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Contains fulltext : 245825.pdf (Publisher’s version ) (Closed access) BACKGROUND: Phaeochromocytoma or paraganglioma (collectively known as PPGL) in pregnant women can lead to severe complications and death due to associated catecholamine excess. We aimed to identify factors associated with maternal and fetal outcomes in women with PPGL during pregnancy. METHODS: We did a multicentre, retrospective study of patients with PPGL and pregnancy between Jan 1, 1980, and Dec 31, 2019, in the International Pheochromocytoma and Pregnancy Registry and a systematic review of studies published between Jan 1, 2005, and Dec 27, 2019 reporting on at least five cases. The inclusion criteria were pregnancy after 1980 and PPGL before or during pregnancy or within 12 months post partum. Eligible patients from the retrospective study and systematic review were included in the analysis. Outcomes of interest were maternal or fetal death and maternal severe cardiovascular complications of catecholamine excess. Potential variables associated with these outcomes were evaluated by logistic regression. FINDINGS: The systematic review identified seven studies (reporting on 63 pregnancies in 55 patients) that met the eligibility criteria and were of adequate quality. A further 197 pregnancies in 186 patients were identified in the International Pheochromocytoma and Pregnancy Registry. After excluding 11 pregnancies due to potential overlap, the final cohort included 249 pregnancies in 232 patients with PPGL. The diagnosis of PPGL was made before pregnancy in 37 (15%) pregnancies, during pregnancy in 134 (54%), and after delivery in 78 (31%). Of 144 patients evaluated for genetic predisposition for phaeochromocytoma, 95 (66%) were positive. Unrecognised PPGL during pregnancy (odds ratio 27·0; 95% CI 3·5-3473·1), abdominal or pelvic tumour location (11·3; 1·5-1440·5), and catecholamine excess at least ten-times the upper limit of the normal range (4·7; 1·8-13·8) were associated with adverse outcomes. For patients diagnosed during pregnancy, α-adrenergic blockade therapy was associated with fewer adverse outcomes (3·6; 1·1-13·2 for no α-adrenergic blockade vs α-adrenergic blockade), whereas surgery during pregnancy was not associated with better outcomes (0·9; 0·3-3·9 for no surgery vs surgery). INTERPRETATION: Unrecognised and untreated PPGL was associated with a substantially higher risk of either maternal or fetal complications. Appropriate case detection and counselling for premenopausal women at risk for PPGL could prevent adverse pregnancy-related outcomes. FUNDING: US National Institutes of Health.

Background Immune checkpoint inhibitors (ICIs) in cancer treatment are considered one of the major breakthroughs in the past decade. Pembrolizumab (PBL) is one of the immune checkpoint inhibitors that targets the programmed cell death protein-1 (PD-1) receptor in order to block its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). By inhibition of these molecules, PBL helps increase T-cell activation against cancer cells. Unfortunately, this inhibition also enhances autoimmunity against normal cells, leading to immune-related adverse events (irAEs) including endocrinopathies. Unlike other irAEs, endocrinopathies are usually irreversible upon diagnosis. While hypophysitis, hypo/hyperthyroidism, and adrenal insufficiency are more commonly reported, type 1 diabetes mellitus (T1DM) is also seen around 0.9 to 1.9% of cases. Unfortunately, it can become fatal if not being promptly recognized. To raise awareness about this life-threatening adverse event, we are reporting a case of new onset T1DM, presenting with diabetic ketoacidosis (DKA) only after 22 days of the first PBL infusion. Clinical case A 19-year-old male was recently diagnosed with NUT (nuclear protein in testis) carcinoma of the left floor of mouth with high PD-L1 score. NUT carcinoma is a rare type of squamous cell cancer with chromosomal rearrangement in the nuclear protein in testis gene (NUTM1) that makes the cancer aggressive and resistant to standard therapy, hence requiring a multimodal approach. This patient underwent surgery followed by concurrent cisplatin-radiation and PBL. Two weeks after his first PBL infusion, he suddenly developed polydipsia, polyuria, and nausea. He continued to receive the second PBL dose on day 20 and developed DKA on day 21. His work-up revealed a plasma glucose of 856 mg/dL, anion gap of 20 (H), CO2 of 17 mEq/L (L), and beta-hydroxybutyrate of 3.35 mmol/L (H), while hemoglobin A1C of only 5.5% suggesting his fulminant progression. He was immediately treated with DKA protocol with clinical improvement. The patient was discharged on basal bolus insulin regimen. He had non-detectable C-peptide (250 IU/mL) levels, which was consistent with PBL induced T1DM. Conclusion PBL use has been linked to multiple endocrinopathies and even though rare, DKA can also be seen in setting of T-cell mediated irreversible damage to pancreas beta cells. Due to life threatening potential of DKA, clinicians should monitor patients receiving immune checkpoint inhibitors closely and should be aware symptoms of hyperglycemia for earlier intervention. | Keywords: pembrolizumab, NUT carcinoma, diabetic ketoacidosis Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Background: It is well established that malignant cells are able to metabolize glucose to lactate in the presence of oxygen, known as the Warburg effect (WE) - a rare metabolic complication of malignancies, presenting with lactic acidosis & hypoglycemia. It signifies a poor prognosis with high mortality rates. We present the case of a woman with malignancy who presented with persistent hypoglycemia requiring a dextrose drip and type B lactic acidosis. Clinical case: A 63-year-old female was referred to our institution for persistent hypoglycemia and lactic acidosis after being admitted to another hospital for a urinary tract infection. Her history was notable for generalized fatigue & weight loss. She had lactic acidosis (18-25mEq/L; Normal: 0.5–2.2mEq/L) despite stable hemodynamics that did not improve with resuscitation & antibiotics. Her hospital course was complicated by worsening mental status & non- hypoxic respiratory distress due to profound acidosis, requiring intubation. She required a dextrose infusion of up to 40g/hour to maintain normoglycemia and with the infusion, an increase in lactate level was noted. Workup to rule out insulin-dependent hypoglycemia, adrenal insufficiency, GH deficiency, MELAS, mesenteric ischemia & drug-related lactic acidosis was unremarkable. EEG was not suggestive of seizure activity. Initial labs were notable for elevated levels of CA-19-9 408U/mL (normal: 0–34), & CA 125 430U/mL (normal: 0–34) which were attributed to her newly diagnosed cirrhosis. However, the degree of her liver dysfunction was felt to be not severe enough to cause hypoglycemia. Imaging studies looking for tumors were unrevealing. A bone marrow biopsy done to rule out occult malignancy showed metastatic carcinoma with neuroendocrine features. Further treatment was not pursued by her family. Based on the diagnosis of metastatic cancer, it was felt that her persistent hypoglycemia was due to the Warburg effect. Conclusion: The Warburg effect (WE) is observed in cancers when the malignant cells utilize glycolysis over oxidative phosphorylation, regardless of oxygen content, for energy production. This involves aerobic glycolysis & lactic acid is its by-product. Cancer cells use more glucose via the glycolysis pathway to meet their demands leading to hypoglycemia & concurrent lactic acidosis despite normal oxygen levels. WE is a rare but severe complication of malignancies that signifies a poor prognosis. Patients with this complication need to be monitored closely until definitive treatment can be implemented. This case highlights the importance of maintaining a high clinical index of suspicion for diagnosing WE. Reference Elhomsy G. C., Eranki V., Albert S. G., et al. “Hyper-warburgism,” a cause of asymptomatic hypoglycemia with lactic acidosis in a patient with non-Hodgkin’s lymphoma. The Journal of Clinical Endocrinology & Metabolism. 2012;97(12):4311–4316.

Background: It is well known that delayed images from contrast-enhanced CT are useful in distinguishing adrenal adenomas from non-adenomas, with an absolute washout that exceeds 60% being most consistent with a lipid rich adenoma. We present two cases of an adrenal mass that met the criteria for a lipid rich adenoma by CT imaging, but found to be a pheochromocytoma (PCC) and paraganglioma (PGL). Clinical Case Case#1 An 82 yo woman presenting with tachycardia was found to have a 2.4 cm heterogeneously attenuating, left adrenal nodule with an absolute washout of 61% and a relative washout of 45%. The right adrenal was normal. Urinary catecholamine levels were elevated with an epinephrine (E) 38 mcg (2–24), norepinephrine (NE) 388 mcg (15–100), dopamine (DOPA) 175 mcg (52–480), metanephrine (MN) mcg 620 (90–315), normetanephrine (NMN) 1553 mcg (122–676) and vanillylmandelic acid 12.5 mg (< 6) on a 24h collection. Due to a cardiac resynchronization therapy device, an MRI could not be obtained. MIBG imaging was obtained and showed increased uptake in left adrenal gland, corresponding to the lesion identified on CT. The patient underwent laparoscopic adrenalectomy and the pathology confirmed a PCC. Case#2: A 74 yo man was found to have an incidental right adrenal nodule on CT imaging measuring 2.4 cm. Absolute washout was 83% and relative washout 68%. The left adrenal gland was normal. A follow up MRI obtained showed slight increase in T2 weighted images and no drop out on out of phase imaging, raising concern for a PCC. Urinary catecholamines were elevated including E 12 mcg (2–24), NE 280 mcg (15–100), DOPA 246 mcg (52–480), MN 175 mcg (90–315) and NMN 1298 mcg (122–676) on a 24-hr. collection. MIBG imaging further confirmed the diagnosis with increased uptake in the right adrenal gland. The patient underwent laparoscopic adrenalectomy then, converted to open right adrenalectomy through an anterior approach due to adherence of the tumor to the renal vein. The pathology revealed a PGL. Conclusion: PCC/PGL are rare but life-threatening neuroendocrine tumors that require early detection to reduce associated morbidities and mortality and improve surgical outcomes. CT is commonly used to characterize adrenal lesions and an absolute washout of >60% is most consistent with an adenoma. However, as demonstrated by these two cases, washout exceeding 60% can also be seen in non-adenomas, perhaps secondary to degeneration of the nodule causing necrotic or cystic changes or uncommonly, the presence of a high lipid content in the tumor [1]. Thus, when clinical suspicion is strong and/or there is a positive biochemical workup, confirmatory imaging should be considered to establish the diagnosis. References: [1] Blake, M. A., Kalra, M. K., Maher, M. M., Sahani, D. V., Sweeney, A. T., Mueller, P. R., ... & Boland, G. W. (2004). Pheochromocytoma: an imaging chameleon. Radiographics, 24(suppl_1), S87-S99.

Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin. Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane. References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.

Background Chronic migraine has a well-documented association with increased insulin resistance and metabolic syndrome. The hypothalamus may play a role in the progression of insulin resistance in chronic migraine through the regulation of orexigenic peptides such as neuropeptide Y. Insulin resistance may lead to increased risk of future type 2 diabetes mellitus in patients with chronic migraine, which is more likely to occur if other pathogenetic defects of type 2 diabetes mellitus, such as impaired pancreatic β-cell functions and defects in intestinal glucagon-like peptide-1 secretion after meals. We studied the relationship of fasting neuropeptide Y with insulin resistance, β-cell function, and glucagon-like peptide-1 secretion in non-obese female chronic migraine patients. We also aimed to investigate glucose-stimulated insulin and glucagon-like peptide-1 secretions as early pathogenetic mechanisms responsible for the development of carbohydrate intolerance. Methods In this cross-sectional controlled study, 83 non-obese female migraine patients of reproductive age categorized as having episodic migraine or chronic migraine were included. The control group consisted of 36 healthy females. We studied glucose-stimulated insulin and glucagon-like peptide-1 secretion during a 75 g oral glucose tolerance test. We investigated the relationship of neuropeptide Y levels with insulin resistance and β-cell insulin secretion functions. Results Fasting glucose levels were significantly higher in migraine patients. Plasma glucose and insulin levels during the oral glucose tolerance test were otherwise similar in chronic migraine, episodic migraine and controls. Patients with chronic migraine were more insulin resistant than episodic migraine or controls ( p = 0.048). Glucagon-like peptide-1 levels both at fasting and two hours after glucose intake were similar in chronic migraine, episodic migraine, and controls. Neuropeptide Y levels were higher in migraineurs. In chronic migraine, neuropeptide Y was positively correlated with fasting glucagon-like peptide-1 levels (r = 0.57, p = 0.04), but there was no correlation with insulin resistance (r = 0.49, p = 0.09) or β-cell function (r = 0.50, p = 0.07). Discussion Non-obese premenopausal female patients with chronic migraine have higher insulin resistance, but normal β-cell function is to compensate for the increased insulin demand during fasting and after glucose intake. Increased fasting neuropeptide Y levels in migraine may be a factor leading to increased insulin resistance by specific alterations in energy intake and activation of the sympathoadrenal system.

Background: The anti-programmed-death-receptor-1 (PD-1) antibody, pembrolizumab, is one of the key immunomodulators for different types of refractory cancers. It is known to cause a variety of endocrinopathies including hypothyroidism, hyperthyroidism, diabetes mellitus, hypophysitis and primary adrenal insufficiency. However, to our knowledge, there are no reports of isolated ACTH deficiency caused by pembrolizumab. Clinical Case: A 61 yo man with a history of Stage IVA (T3, N3, M1b) poorly differentiated pleomorphic NSCLC presented to hospital with 2 weeks of worsening weakness and lightheadedness. Biopsy results revealed >95% PD-L1 expression and he was started on pembrolizumab 200 mg (4.5 mg/kg) every 3 weeks, along with palliative radiation to the right upper chest. Approximately 1 week after the patient’s 6th dose of pembrolizumab, he became weak and lightheaded and was admitted for further management. BP was 95/58 mmHg and biochemical studies demonstrated hyponatremia with a Na 119 mEq/L and K 4.3 mEq/L. . Due to a high suspicion for adrenal insufficiency, an AM cortisol was checked and was undetectable (

Background: Adrenalectomy is standard of care for phaeochromocytomas, but for bilateral phaeochromocytoma, the recommendations are inconsistent. However, large studies systematically investigating long-term outcomes for total adrenalectomies compared to those for patients with adrenal-sparing operations are lacking. Methods: A multi-center consortium-based registry was established to study clinical, genetic and surgical data in 623 patients with bilateral phaeochromocytomas. Findings: Of 623 patients, median age at diagnosis was 30 (range 3-79) years and 48% were female. Synchronous bilateral phaeochromocytomas were diagnosed in 396 patients and metachronousphaeochromocytomas in 227 (36%); interval to second operations were up to 40 (median 6) years. In 96% of tested patients germline mutations were detected in the genes RET (56%), VHL (34%), and others (10%). Of 849 operations, 385 (45%) surgeries in 326 patients were planned as adrenal-sparing which was successful in 251. 372 patients became steroid-dependent. Follow-up was up to 53 (median 11) years. Adrenal crises developed in 67 patients (18%) during follow-up, and 49 (13%) had manifestations of iatrogenic Cushing syndrome. Of the steroid-independent patients, 34 (14%) had developed another phaeochromocytoma within the remnant adrenal after up to 27, median 8 years, all treated with removal of the new phaeochromocytoma. Overall survival was mainly influenced by non-phaeochromocytoma comorbidities, whereas only 1% died of metastatic phaeochromocytoma. Cortical-sparing operations did not affect survival. Interpretation: Cortical-sparing operations avert lifelong steroid-dependency without affecting survival. Preoperative genetic testing is recommended even in unilateral phaeochromocytoma presentations to identify patients at heritable risk, to guide surgical approach, and inform for gene-specific extra-adrenal morbidities. Funding Statement: Supported in part by the grant AZV 16-32665A to Sarka Dvorakova and Petr Vlcek, and the Blank Foundation to Charis Eng. Declaration of Interests: None of the authors have relevant conflicts of interest. Ethics Approval Statement: The institutional review boards for human subjects’ protection or ethical committees of all participating centers approved this study. Patients provided written informed consent according to the protocols of respective institutional review boards. In The Netherlands data were collected anonymously, and no further Institutional Review Board approval is required.

PURPOSE Report occurrence of late-onset choroidal metastasis from breast cancer. METHODS Retrospective chart review. RESULTS The authors report 3 patients with choroidal metastasis from breast cancer that presented more than 20 years after diagnosis of the primary tumor. The choroidal metastases were the presenting feature of metastatic disease in all three patients, but after imaging, all patients had metastasis elsewhere as well. Two of the patients' tumors were known, ER+, and the hormone receptor status of the third patient was unknown. All three patients were treated with aromatase inhibitors with good response. CONCLUSION Late onset of metastatic disease, an excellent response to hormonal therapy, and a prolonged survival despite presence of systemic disease suggests a milder variant within the broad category of breast cancer patients with uveal metastases. Awareness of this entity can minimize the risk of misdiagnosis and avoid potentially toxic local therapy.

In contrast to search engines for medical image databases that use age, gender, or disease classification, Query by Image search allows an image to be presented as input to the search engine. Images together with clinical reports are returned that best match the presenting image. Work on query by image systems have been ongoing for more than two decades, predominately in fields outside of medical imaging. In these fields, features are often identified and used in the search for similar images. Corresponding strategies have been taken in medical imaging, especially MRI where it is reasonable to match based on a feature. However, in brain SPECT imaging, clinicians are often interested in the global pattern of brain activity for making diagnoses such as Small Vessel Disease, Mild Cognitive Impairment, Parkinson’s or Alzheimer’s Disease, which have some commonalities as “Global Brain Impairment” patterns. By utilizing robust spatial normalization methods to transform images to a common stereo-tactic space, we are able to use simple methods for measuring and ranking the closeness between the presenting image and images in the database. Our decomposition of the Brain SPECT dataset shows that images within the dataset have very high similarity. However, subtle differences can be reliably utilized for selecting best image matches. Throughout testing, highly relevant cases were consistently returned for our image queries. Our method is fast, robust, intuitive for users, and practical.

To evaluate the effects of multiple intravitreal injections of ranibizumab on retinal nerve fiber layer (RNFL) thickness in patients with wet age-related macular degeneration (AMD).This observational, comparative study included patients with 10 or more total ranibizumab injections and involved the measurement of RNFL thickness at baseline. Twenty-nine eyes of 29 consecutive patients were evaluated via intraocular pressure (IOP) and measurements of the total and nasal RNFL thicknesses at the initial and final follow-up by using optical coherence tomography. The RNFL thickness values of the fellow eyes and 27 healthy eyes were used as the control group. The mean total and nasal RNFL thicknesses of the injection group were compared with those of the other two groups. At each visit, at every three injections, the IOP values of the study group were recorded and compared. The relationship between the number of injections and the mean RNFL thickness was assessed.The mean number of injections was 13.88 ± 3.81 (10-24). The mean RNFL thickness of the injection group was 92.3 ± 7.7 μm at baseline and 92.46 ± 8.1 μm at the last follow-up (p = 0.7). There were no statistically significant differences between the mean total and nasal RNFL thicknesses of the eyes with injections and the fellow eyes with no injections (p = 0.379, p = 0.897, respectively) or between those with injections and the healthy control group (p = 0.159, p = 0.273, respectively). There were no correlations between the number of injections and the mean total and nasal RNFL thicknesses (p = 0.854, p = 0.25, respectively). There was no statistical difference between the initial and final IOPs (p = 0.760).Long-term treatment with anti-vascular endothelial growth factor (VEGF) agents did not lead to significant changes in RNFL thickness in a patient population with wet AMD. Chronic therapy with intravitreal anti-VEGF agents does not appear to adversely affect RNFL thickness.

Background Comorbidity of migraine with anxiety and depression may play a role in the link between migraine and obesity. We examined the moderating and mediating roles of ghrelin in the relationship between depression (and anxiety) and body weight in newly diagnosed migraineurs. Methods Participants were 63 newly diagnosed migraine patients (using the ICHD-II criteria) and 42 healthy volunteers. Body mass index (BMI) was calculated by measuring height and weight. Ghrelin was assessed at fasting. Depression was assessed with the Hamilton Depression scale, and anxiety with the Hamilton Anxiety scale. Results The data did not support the mediating role of ghrelin in the relationship between depression (or anxiety) and BMI for either the migraine or the control group. The interaction between ghrelin and depression as well as anxiety was significant for the migraine group, but not for the control group. Depressed (or anxious) migraineurs had a positive association between ghrelin and BMI, whereas for the non-depressed (or non-anxious) migraineurs this association was negative. Conclusions Depression and anxiety moderated the effect of ghrelin on BMI for migraineurs. Management of anxiety and depression might be regarded as part of migraine treatment.

Purpose: To assess the possibility of determining the insertion distance from the limbus of horizontal and vertical extraocular rectus muscles with anterior segment optical coherence tomography (AS-OCT). Methods: The right eyes of 46 patients underwent AS-OCT. The horizontal and vertical extraocular rectus muscle insertion distances from the limbus were measured in a masked fashion by two pediatric ophthalmologists. Results: Forty-two lateral rectus, 43 medial rectus, 35 inferior rectus, and 40 superior rectus muscles of the right eyes of 46 patients were included. Insertion to limbus measurements (mean ± SD) were as follows: lateral rectus = mean 6.8 ± 0.7 mm, range = 4.8 to 8.4 mm; medial rectus = mean 5.7 ± 0.8 mm, range = 4.3 to 7.8 mm; inferior rectus = mean 6.0 ± 0.6 mm, range = 4.8 to 7.0 mm; superior rectus = mean 6.8 ± 0.6 mm, range = 5.5 to 8.1 mm. The intraobserver and interobserver correlation coefficients for the insertion to limbus measurements of all four rectus muscles exceeded 0.75 (excellent correlation). Conclusions: The study showed that AS-OCT is capable of imaging all four of the rectus muscle insertions and measuring the insertion to limbus distance, and is the second AS-OCT study to image the superior and inferior rectus muscle insertions. The insertion to limbus measurements between examiners and on repeat measurements were consistent and reproducible. The ability to accurately image extraocular rectus muscle insertions may have future implications for the preoperative procedure planning in patients who have had previous surgery. [ J Pediatr Ophthalmol Strabismus . 2016;53(3):141–145.]