An open-label, single-arm, multi-center, phase II clinical trial of single-dose [131I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma

Objective In this phase II study, we aimed to investigate the efficacy and safety of single-dose [131I]meta-iodobenzylguanidine (131I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL). Patients and methods This study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%). Results Seventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5–46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and 123I-mIBG scintigraphy were 5.9% (0.3%–25.0%) and 29.4% (12.4%–52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed. Conclusion A single dose 131I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.

DESCRIPTION OF CLINICAL AND PARACLINICAL RESULTS OF LAPAROSCOPIC RETROPERITONEAL RESECTION OF BENIGN ADRENAL ADENOMA AT VIET DUC FRIENDSHIP HOSPITAL IN 2018

The study was conducted with objectives: Describe the clinical and paraclinical results of laparoscopic retroperitoneal resection of benign adrenal tumors at Viet Duc Friendship Hospital in 2018 on 67 patients diagnosed as benign adrenal tumor and was treated with retroperitoneal endoscopic surgery at Viet Duc hospital in 2018. The study design was retrospective. Results: The clinical syndromes of the patients were mainly Cushing's syndrome (3%), Conn's syndrome (29,8%), Pheochromocytome (17,9%) and 49,3% of patients with nonsecretory tumors. . Specific biochemical tests: hypercortisolemia (4,48%); increased blood catecholamines (16,42%) and increased urinary catecholamines (14,93%). Ultrasound: The average tumor size was 20.37 ± 16.05mm; The diagnostic sensitivity was 74,6%. CT or MRI: The mean tumor size was 26.63 ± 12.7mm; highly sensitive and is the gold standard on diagnostic imaging. Conclusion: The clinical and laboratory results of patients undergoing laparoscopic resection of benign adrenal tumors are highly sensitive.

Identification of novel missense mutation in a patient with an asymptomatic para-aortic paraganglioma

A 31-year-old Caucasian woman underwent a standard workup as a potential kidney transplant donor. Kidney donor protocol CT showed a left para-aortic hypervascular mass suspicious for a paraganglioma. Biochemical workup revealed elevated urinary catecholamines, supporting this suspicion. The patient underwent surgical resection with histopathological evaluation that confirmed the diagnosis. Endocrine evaluation 2 years later revealed a family history of a cousin with a history of pheochromocytoma as a teenager. A genetic panel identified a missense mutation in succinate dehydrogenase C (c.202T>C; p.Ser68Pro), which was described as a variant of unknown significance. In silico analysis suggested that it may be a deleterious mutation. We concluded that this mutation may be pathogenic, considering these supporting pieces of evidence and her early-onset paraganglioma. This report highlights the importance of genetic screening in patients with paragangliomas/pheochromocytomas, since many cases are familial. Additionally, it underscores the importance of evaluating and documenting cases of variants of unknown significance.

Treatment-resistant hypertension in a post-transplant patient with cystic fibrosis: a rare case of phaeochromocytoma

Summary Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications – amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182–867) as well as elevated metanephrines (MN) of 793 pmol/L (61–377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient’s blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential. Learning points Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1–1.0% of all secondary hypertension cases. Secondary causes should be investigated in cases where: Patient is presenting <20 years of age or >50 years of age, There is refractory hypertension, or There is serious end-organ damage present. Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms. Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour. Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration. There is a possibility of relapse so high-risk patients require life-long follow-up.

Neurofibromatosis Type 1 Presenting With Adrenal Pheochromocytoma

Background: Pheochromocytomas & Paragangliomas (PCC/PGL) are amongst the rare endocrine tumours, occurring with an incidence of 0.8 per 100,0001. Though most of them have a benign nature, they are usually hormonally active causing significant cardiovascular morbidity due to the catecholamine secretion. Approximately a third of PCC/PGL have underlying germline mutations including Neurofibromatosis type 1 (NF1). Clinical Case: A 49 year old man was reviewed for symptoms of palpitation, headache, sweating, and blurred vision. physical examination revealed signs of NF1. He had multiple neurofibromas over the skin of the back, chest and neck, café-au-lait spots on the trunk and limbs. Ophthalmology assessment revealed multiple Lisch nodules bilaterally. Urinary catecholamines were significantly elevated. His initial systolic blood pressure was 190/148 mmHg. The patient’s medical history included hypertension that used to be well-controlled with Amlodipine 10 mg and Bisoprolol 5mg. however his blood pressure was harder to control during the past year. Laboratory investigations testing included measurements of urinary fractionated metanephrines which revealed high normetanephrines with a value of 690 nmol/d (N &lt; 240). metanephrines (485 nmol/d: N &lt; 275) and norepinephrines (456 nmol/d: N &lt; 440). Plasma free normetanephrines were 3.20 nmol/L (N &lt;1.20) and free metanephrines 0.4 nmol/L (N &lt; 0.48). CT scan of the abdomen showed a 1.3 x 2.4x 3.9 mass in the left suprarenal gland which showed showed moderate uptake on A meta-iodobenzylguanidine (MIBG) scan. And no evidence of metastases. The patient underwent laparoscopic adrenalectomy of the left suprarenal gland and histopathological examination was confirmatory of pheochromocytoma postoperatively. Conclusion:This is a case demonstrating the association between the germline mutation causing neurofibromatosis type 1 with the rare catecholamine secreting tumour (pheochromocytoma). Reference:1. Lefebvre M, Foulkes WD. Pheochromocytoma and paraganglioma syndromes: genetics and management update. Curr Oncol. 2014;21(1):e8-e17. doi: 10.3747/co.21.1579. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Malignant Testicular Paraganglioma: The Importance of Adequate Clinical Follow-Up

Background: Paragangliomas (PGL) are rare neuroendocrine tumors derived from neural crest cells. The presence of metastases is the only absolute criterion of malignancy. Clinical Case: A 59 y.o. male patient reports the appearance of a tumor in the right inguinal region operated in 2014 with tumor removal and right orchiectomy, with anatomopathological (AP) outcome spermatic cord adenomathoid tumor and immunohistochemistry (IHC) compatible with PGL: Ki-67 1% (S 100 diffusely positive protein), diffusely positive chromogranin A, weak positive CD99. However, no new tests were performed in the follow-up. After 5 years, the patient started to present sporadic episodes of sweating, palpitations and increased tension levels after doxazosin suspension. Investigation for reoccurrence with Urinary Catecholamines: Noradrenaline (VR&lt; 97 mcg/24h) 112/179, Adrenaline (VR&lt; 27 mcg/24h) 4/4, Dopamine (&lt; 500 mcg/24h) 184/ 342, Plasma Metanephrines: Normetanephrines (VR&lt; 196 pg/ml) 880.7/ 2402 Metanephrines (VR&lt; 65 pg/ml) 44.6/ 53.1. Tests was performed: chest CT Multiple bilateral non-calcified pulmonary nodules with contrast enhancement, measuring 1.2 cm. Abdominal CT: Two retroperitoneal solid lesions located anteriorly to the inferior vena cava and aorta, in a discretely paramedian position on the right, intense arterial enhancement, with a hypoattenuating center. The largest lesion is located just below the emergence of the renal arteries and after the head of the pancreas and third portion of the duodenal. It measures 4.4 x 3.2 x 4.4 cm (LL x AP x CC). The smallest lesion is immediately inferior to the largest and measures 3.1 x 2.6 x 3.6 cm (LL x AP x CC). The lesions have contact with retroperitoneal vascular structures, notably with the inferior vena cava and with the vascular pedicle of the right kidney. Scintigraphy with MIBG: Radiopharmaceutical hyperconcentration in focal areas in the projections of lung fields, in greater number on the left, with intensity of uptake varying from mild to moderate; two contiguous focal areas in the median projection of mesogastrics, in moderate/acentuated degree. Patient was reoperated and removed abdominal lesions with new conclusive AP for PGL whit PASS 3, currently performing therapeutic MIBG for thoracic injury control. Clinical Lesson: Patients with lesions suggestive of PGL but without confirmatory AP should request IHC and clinical follow-up will be according to the findings in it.

A food ingredient containing phytoecdysteroids and polyphenols from quinoa grain: technology and physiological and biochemical evaluation in vivo

An effective technological approach to produce adaptogenic microingredients is to concentrate plant biologically active substances via sorption on various matrices. The aim was to develop and evaluate in vivo the phytoecdysteroids and flavonoids concentrate extracted from quinoa grain and sorbed on the coagulated chicken egg protein. The consecutive extraction of phytoecdysteroids and flavonoids was conducted followed by sorption on the protein. The in vivo experiment was performed during 37 days using Wistar male rats. The developed concentrate was added into the diet of experimental animals in the dose 0.59±0.02 g/100 g of diet. As a stress model we used daily 40-min immobilization and exhaustive 3-hour immobilization at the end of the experiment. Urinary catecholamines content was determined, blood corticosterone, malon dialdehyde, glutathione reductase and superoxide dismutase content was determined. Phytoecdysteroids and flavonoids were concentrated 20 and 80 times respectively compared to the initial raw materials. The concentrate consumption neutralized negative effect of immobilization stress on anxiety level of Wistar rats. The significant decrease in urinary excretion of adrenaline and noradrenaline shows the pronounced adaptogenic effect of the concentrate, whereas phytoecdysteroids and flavonoids act as prostressors activating body antioxidant protection system, what is substantiated by significantly increased blood superoxide dismutase level of experimental animals.

Masked Uncontrolled Hypertension Is Accompanied by Increased Out-of-Clinic Aldosterone Secretion

Masked uncontrolled hypertension (MUCH) in treated patients is defined as controlled office blood pressure (BP) but uncontrolled out-of-clinic ambulatory BP. Previously, we have shown that patients with MUCH have evidence of heightened out-of-clinic sympathetic nervous system activity. The aim is to test the hypothesis that MUCH patients have higher aldosterone secretion compared with patients with true controlled hypertension. Two hundred twenty-two patients were recruited after having controlled office BP readings at ≥3 clinic visits. Patients taking MR (mineralocorticoid receptor) antagonists and epithelial sodium channel blockers were excluded. All patients were evaluated by clinic automated office BP and morning serum aldosterone and plasma renin activity. Out-of-clinic ambulatory BP monitoring and 24-hour urinary aldosterone, catecholamines, and metanephrines were also measured. Sixty-four patients had MUCH, and the remaining 48 patients had true controlled hypertension. MUCH patients had significantly higher out-of-clinic levels of 24-hour urinary aldosterone, catecholamines, and metanephrines compared with true controlled hypertension. The 2 groups did not differ in serum aldosterone, plasma renin activity, or aldosterone-renin ratio collected in clinic. In addition, 32.8% of MUCH patients had high out-of-clinic 24-hour urinary aldosterone (≥12 µg) but normal clinic serum aldosterone (<15 ng/dL) and aldosterone-renin ratio (<20). Further, in correlation matrix analysis, higher 24-hour urinary catecholamines and metanephrines were associated with higher 24-hour urinary aldosterone and plasma renin activity levels in MUCH patients. Patients with MUCH have higher out-of-clinic urinary aldosterone levels compared with patients with true controlled hypertension. This study suggests that patients with MUCH likely have higher out-of-clinic sympathetic nervous system tone increases aldosterone secretion mediated by increased renin release that may contribute to their higher out-of-clinic BP.