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St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
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Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, Australia
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Cancer Genetics Unit, Kolling Institute of Medical Research, Sydney, Australia
Northern Clinical School, University of Sydney Faculty of Medicine and Health, Sydney, Australia
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Summary
RET mutations are implicated in 60% of medullary thyroid cancer (MTC) cases. The RET-selective tyrosine kinase inhibitor selpercatinib is associated with unprecedented efficacy compared to previous multi-kinase treatments. Langerhans cell histiocytosis (LCH) is a clonal histiocytic neoplasm usually driven by somatic BRAF mutations, resulting in dysregulated MAPK signalling. We describe a 22-year-old woman with metastatic MTC to regional lymph nodes, lung and liver. Tumour tissue harboured a somatic pathogenic RET variant p.(M918T) and selpercatinib was commenced. She experienced sustained clinical, biochemical and radiological responses. Two years later, she developed rapidly progressive apical lung nodules, prompting biopsy. Histopathology demonstrated LCH with a rare BRAF variant p.(V600_K601>D). The lung nodules improved with inhaled corticosteroids. We hypothesize that selective pressure from RET blockade may have activated a downstream somatic BRAF mutation, resulting in pulmonary LCH. We recommend continued vigilance for neoplasms driven by dysregulated downstream MAPK signalling in patients undergoing selective RET inhibition.
Learning points
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Patients with RET-altered MTC can experience rapid disease improvement and sustained disease stability with selective RET blockade (selpercatinib).
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LCH is a clonal neoplasm driven by MAPK activation, for which the most common mechanism is BRAF mutation.
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Both MTC and pulmonary LCH are driven by dysregulated MAPK signalling pathway activation.
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We hypothesise that the RET-specific inhibitor selpercatinib may have caused the activation of dormant LCH secondary to selective pressure and clonal proliferation.
Innovation and Research Center of Endocrinology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia
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Summary
Symptoms of primary adrenal insufficiency (PAI) are commonly nonspecific, causing the disease to be misdiagnosed or often delayed, and patients may present to the hospital with a life-threatening crisis. Previous case reports have documented that patients in this condition often require lifelong glucocorticoid replacement therapy. This study aimed to present a noteworthy outcome of PAI caused by adrenal tuberculosis infection, demonstrating complete recovery after six months of glucocorticoid replacement therapy. A 38-year-old Indonesian man presented to the endocrinology clinic in a tertiary hospital with a chief complaint of epigastric pain. The patient experienced nausea, vomiting, loss of consciousness, weight loss, excessive sweat, decreased appetite, weakness, and dizziness in the past 2 weeks. Laboratory examinations revealed hyponatremia, elevated adrenocorticotropic hormone, and suppressed morning plasma cortisol level. A non-contrast-enhanced abdominal MRI showed unilateral right-side adrenal enlargement and calcification. The patient’s Mantoux test was positive. Corticosteroids and anti-tuberculosis therapy were administered. After 6 months, hydrocortisone was discontinued due to the patient’s good clinical condition and normal morning plasma cortisol levels. After a 1-year follow-up, the patient remained asymptomatic with normal cortisol levels. We hypothesized several reasons for this unique outcome: (i) the patient was relatively young compared to previous cases, suggesting an adequate immune system may play a role; (ii) despite a 1-month delay in diagnosis and treatment, the absence of skin hyperpigmentation suggested an acute presentation, potentially contributing to the favorable outcome; and (iii) the absence of comorbidities potentially positively impacted the patient's outcome.
Learning points
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Symptoms of adrenal insufficiency are often nonspecific and may only become apparent once significant damage has occurred to the adrenal gland.
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Clinical adjustments and a comprehensive understanding of epidemiological knowledge are necessary for diagnosing patients with endocrine diseases in limited-resource settings.
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Complete recovery in primary adrenal insufficiency caused by tuberculosis infection might be due to younger age, acute presentation, and absence of comorbidities
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Ghent University, Ghent, Belgium
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Summary
Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic–toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10–15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia.
Learning points
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TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane.
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Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels.
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In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated.
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If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.
School of Cardiovascular Medicine & Sciences, King's College London, London, UK
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School of Cardiovascular Medicine & Sciences, King's College London, London, UK
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Summary
A Caucasian man in his 60s with recent diagnosis of metastatic renal cell carcinoma presented to the emergency department with a 5-day history of severe polyuria, polydipsia and fatigue and 1-day history of confusion, abdominal pain, nausea and vomiting. Investigations revealed an overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS). He had received the first dose of immunotherapy with nivolumab and ipilimumab 3 weeks prior to this attendance. New-onset type 1 diabetes (T1DM) was confirmed based on the clinical features at presentation, seropositivity for glutamic acid decarboxylase antibodies and significant insulin deficiency. He is currently on a multiple daily injections of insulin and uses intermittent-scanned glucose monitoring. Given the irreversible impact on beta-cell function and clinical response with insulin resulting in improved diabetes control, immunotherapy was resumed for his metastatic cancer with good radiological response. Although rare, new-onset T1DM can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes.
Learning points
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Although rare, new onset of T1DM after immunotherapy can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes and normal glycaemic parameters.
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Due to the irreversible destruction of beta-cells, treatment with steroids is not indicated in contrast to other settings such as immunotherapy-induced hypophysitis.
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Presence of low c-peptide levels post-acute presentation is indicative of an irreversible impact on beta-cell function and supports resuming immunotherapy given the significant benefits on cancer prognosis.
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Clinicians must maintain a high index of suspicion in regards to diagnosis and management of new-onset type 1 diabetes and advice patients on reporting symptoms suggestive of diabetes and/or diabetes-related hyperglycaemic emergencies.
Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
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Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy
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Summary
Psoriasis is often associated with abdominal obesity and type-2 diabetes (T2D). The inflammatory process in psoriasis can target adipose tissue depots, especially those surrounding the heart and coronary arteries, exposing to an increased risk of cardiovascular diseases. A 50-year-old female patient referred to us for abdominal obesity and T2D, which were not controlled with lifestyle modifications. She had suffered from psoriasis for some years and was treated with guselkumab, without success. Epicardial adipose tissue (EAT) attenuation and pericoronary adipose tissue (PCAT) attenuation for each coronary, defined as mean attenuation expressed in Hounsfield unit (HU), were assessed by routine coronary computed tomography angiography. At baseline, EAT attenuation was −80 HU and PCAT attenuation of the right coronary artery (RCA) was −68 HU, values associated with an increased cardiac mortality risk. Psoriasis area and severity index (PASI) was 12.0, indicating severe psoriasis, while dermatology life quality index (DLQI) was 20, indicating a negative effect on the patient’s life. Semaglutide (starting with 0.25 mg/week for 4 weeks, increased to 0.50 mg/week for 16 weeks, and then to 1 mg/week) was started. After 10 months, semaglutide treatment normalized glycated hemoglobin and induced weight loss, particularly at abdominal level, also followed by a reduction in computed tomography-measured EAT volume. EAT attenuation and PCAT attenuation of RCA decreased, showing an important reduction of 17.5 and 5.9% respectively, compared with baseline. PASI and DLQI decreased by 98.3 and 95% respectively, indicating an improvement in psoriasis skin lesions and an important amelioration of the patient’s quality of life, compared with baseline.
Learning points
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Psoriasis patients affected by obesity and type-2 diabetes (T2D) are often resistant to biologic therapies.
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Psoriasis is often associated with abdominal obesity, T2D, and cardiovascular diseases (CVD), given their shared inflammatory properties and pathogenic similarities.
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Epicardial adipose tissue (EAT) inflammation can cause the distinctive pattern of CVD seen in psoriasis.
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EAT and pericoronary adipose tissue (PCAT) attenuation, assessed by routine coronary computed tomography angiography (CCTA), can be used as biomarkers of inflammation and allow monitoring of medical anti-inflammatory therapies.
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The actions of semaglutide to reduce energy intake, improve glycemic control, and produce effective weight loss, particularly at the visceral fat depot level, can diminish adipose tissue dysfunction, reduce EAT attenuation and PCAT attenuation of the right coronary artery (RCA) and concomitantly ameliorate the clinical severity of psoriasis.
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Semaglutide therapy may be considered in psoriasis patients affected by T2D and abdominal obesity, despite low cardiovascular risk by traditional risk scores, who are resistant to biologic therapies.
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Faculdade de Medicina, Universidade de Coimbra, Portugal
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Summary
We report a case of a woman with a diagnosis of breast cancer who unintentionally started gaining weight, feeling tired, and constipated 44 weeks after the initiation of trastuzumab. Hypothyroidism secondary to an autoimmune thyroiditis associated with trastuzumab was diagnosed, the first case described in Portugal and the fourth case described worldwide. Our intention regarding the publication of this case report is to alert the clinicians treating people with trastuzumab that they should ask the patients about symptoms of hypothyroidism and should screen the thyroid function of the patients before, during, and after the initiation of trastuzumab.
Learning points
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Trastuzumab is a humanized MAB used in HER2-positive breast and gastric cancer.
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Trastuzumab-associated autoimmune thyroid disease (AITD) is rare (incidence rate in an RCT of 0.3%).
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Manifestations of autoimmune thyroiditis associated with trastuzumab resemble those of hypothyroidism in other clinical contexts, but the presence of goiter is highlighted as a reason for medical evaluation. Biochemically, it is characterized by an increased thyroid-stimulating hormone (TSH) with or without a low FT4/FT3, and sonographically with a pattern of thyroiditis.
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The treatment consists of levothyroxine, in a dose of 1.6–1.8 µg/kg/day, with re-evaluation of the thyroid function in 4–6 weeks.
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We report the first case of autoimmune thyroiditis secondary to trastuzumab in Portugal.
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It is important to evaluate the thyroid function before, during, and after the initiation of this therapeutic agent.
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Summary
A patient treated with intramuscular testosterone replacement therapy for primary hypogonadism developed blurred vision shortly after receiving his testosterone injection. The symptom resolved over subsequent weeks and recurred after his next injection. A diagnosis of central serous chorioretinopathy (CSR) was confirmed following ophthalmology review. A decision was made to change the patient’s testosterone regime from this 12-weekly intramuscular injection to a daily topical testosterone gel, given the possibility that peak blood levels of testosterone following intramuscular injection were causing his ocular complaint. His CSR did not recur after this change in treatment. CSR secondary to testosterone therapy is a rare finding but has been reported previously in the literature.
Learning Points
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Blurred vision in patients treated with testosterone replacement therapy (TRT) should prompt an ophthalmology review.
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The potential for reduced risk of central serous chorioretinopathy (CSR) with daily transdermal testosterone remains a matter of conjecture.
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CSR is a rare potential side effect of TRT.
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ANZAC Research Institute, University of Sydney, Sydney, New South Wales, Australia
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Summary
We report the successful delivery of a healthy baby after intracytoplasmic sperm injection (ICSI) with frozen-thawed autologous sperm, cryostored for 26 years, the longest successful autologous sperm cryostorage reported. Sperm was cryostored for a 15-year-old boy at the time of his cancer diagnosis. Semen samples were frozen with cryoprotectant, using a graduated vapour-phase nitrogen protocol. Straws were stored in a large vapour-phase nitrogen tank until transfer for use. The couple underwent a single ICSI–in vitro fertilisation procedure using the frozen-thawed sperm with a transfer of five fertilised embryos, resulting in the live birth of a healthy baby boy. This reinforces the importance of offering sperm cryopreservation to men who have not completed their family prior to gonadotoxic treatment for cancer or other diseases. As practical, low-cost fertility insurance, it should be offered to any young man who can collect semen and it provides essentially unlimited duration of fertility preservation.
Learning points
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Gonadotoxic chemo or radiotherapy treatment for cancer or other diseases usually causes temporary or permanent male infertility.
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Sperm cryostorage serves as a practical, low-cost insurance to facilitate future paternity.
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All men who have not completed their families and are scheduled for gonadotoxic treatments should be offered sperm cryostorage.
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There is no lower age limit for young men who can collect semen.
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Sperm cryostorage offers essentially indefinite duration for the preservation of male fertility.
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Summary
A 31-year-old woman with complete androgen insensitivity syndrome (CAIS) experienced breast volume fluctuations during biphasic hormone replacement therapy consisting of estradiol and cyclical dydrogesterone, a progestin. 3D breast volume measurements showed a 100 cc volume (17%) difference between estradiol monotherapy and combined estradiol and dydrogesterone treatment. Progestogen-dependent breast volume changes have not been reported in the literature. Our findings suggest a correlation between progestogen use and breast volume. Due to the rapid cyclical changes, we hypothesize that the effect is caused by fluid retention.
Learning points
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There is limited reports available on the effects of progesterone on breast development and volume.
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3D imaging provides an easy-to-use method to quantify breast volume.
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The patient in our case description clearly showed that cyclic progesterone use might induce substantial cyclic changes in breast volume.
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In women with complete androgen insensitivity syndrome (CAIS), monotherapy with estrogen or continuous supplementation of progesterone might be preferable over cyclic progesterone use.
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Summary
A 40-year-old Japanese woman presented to the outpatient clinic with fever and palpitations 2 days after receiving the influenza vaccine (Influenza HA Vaccine ‘KMB’®) following the second dose of coronavirus disease 2019 (COVID-19) vaccine (COVID-19 vaccine Moderna intramuscular injection®). At the first visit, the patient presented with a swollen thyroid gland with mild tenderness, and she was diagnosed with subacute thyroiditis (SAT) based on the presence of thyrotoxicosis (free T3: 5.42 pg/mL; free T4: 2.34 ng/dL; and thyroid-stimulating hormone (TSH): <0.01 μIU/mL), a high C-reactive protein level (5.77 mg/dL), a negative TSH receptor antibody, and characteristic ultrasound findings. The patient’s human leukocyte antigen types were A2, A11, B35, B51, DR4, and DR1403. Prednisolone (15 mg/day) was given as an initial dose, after which the fever subsided, and the dose was tapered and discontinued after 6 weeks. The patient was thought to have developed SAT due to influenza vaccination. SAT after influenza vaccination may be overlooked. For patients with SAT, it is necessary to obtain information regarding their vaccination history.
Learning points
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After influenza vaccination, subacute thyroiditis (SAT) may develop.
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If persistent fever, anterior neck pain, swelling, tenderness of the thyroid gland, and symptoms of thyrotoxicosis are observed immediately after vaccination for several viruses, including influenza, an examination to rule out the onset of SAT is recommended.
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Human leukocyte antigen type A2 (HLA-A2) and HLA-B35 may be linked to the development of SAT following influenza vaccination.
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The two doses of the coronavirus disease 2019 (COVID-19) vaccine given before the influenza vaccine may affect the onset of SAT.
