Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.
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Sonia Moretti, Elisa Menicali, Nicole Nucci, Martina Guzzetti, Silvia Morelli and Efisio Puxeddu
Rudolf Hoermann, John E M Midgley, Rolf Larisch and Johannes W Dietrich
Cesar Luiz Boguszewski
Acromegaly is a debilitating and disfiguring chronic disease, which occurs in both sexes at any age, associated with multiple comorbidities and increased mortality. It is typically caused by a GH-secreting pituitary adenoma that promotes exposure of body tissues to increased concentrations of GH and IGF-I. The diagnosis of acromegaly is still made very late in a substantial number of patients when the disease is already in advanced stages. An epidemiological study from Sweden has elegantly demonstrated that the longer the diagnostic delay in acromegaly, the higher the number of comorbidities. Moreover, about 25% of the Swedish patients had 10 years or more of diagnostic delay and in this group mortality rate was significantly increased. These results reinforce the importance of shortening the latency period between disease onset, diagnosis and treatment to improve patient outcomes. This commentary article discusses strategies to be embraced by the endocrine community to allow early identification of acromegaly among public and health professionals, as internists, primary care clinicians, different specialists and dentists are the first point of contact for most of the patients. We emphasize that acromegaly should be presented as a sporadic, rather than rare, insidious disease, meaning that there is a considerable chance for health professionals to see a patient with acromegaly throughout their careers. The motto ‘you must know it to think of it’ is advocated in awareness efforts to reduce time to diagnosis, which results in lower rates of morbidity and mortality and might positively impact healthcare costs.
Adina F Turcu, Diala El-Maouche, Lili Zhao, Aya T Nanba, Alison Gaynor, Padma Veeraraghavan, Richard J Auchus and Deborah P Merke
The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw.
We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019.
Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls.
Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls.
Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.
Marie-Josée Desrochers, Matthieu St-Jean, Nada El Ghorayeb, Isabelle Bourdeau, Benny So, Eric Therasse, Gregory Kline and Andre Lacroix
Context: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes.
Objectives: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone(A)Contralateral(CL)/APeripheral(P) as compared to (A/Cortisol(C)CL/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. Compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure.
Methods: 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criterias.
Results: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6% and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se 63% and Sp 71%) and 6.15 (Se 84% and Sp 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure.
Conclusions: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.
Giorgio Radetti, Antonio Fanolla, Fiorenzo Lupi, Alessandro Sartorio and Graziano Grugni
Rui Zhen Tan, Tze Ping Loh and Samuel Vasikaran
France Devuyst, Paraskevi Kazakou, Danielle Balériaux, Orsalia Alexopoulou, Agnès Burniat, Sylvie Salenave, Philippe Chanson, Bernard Corvilain and Dominique Maiter
Association of central diabetes insipidus (CDI) and pituitary stalk thickening (PST) may have several etiologies (including malignancies) and differential diagnosis remains often difficult.
The purpose of this study was to identify which clinical, biochemical or radiological features could help clinicians to make an etiological diagnosis, especially distinguishing neoplastic from non-neoplastic pituitary stalk lesions.
Design and methods
We retrospectively analyzed clinical, biochemical, radiological and histological data of 38 adult patients diagnosed with CDI and PST of proven etiology.
Of the 38 pituitary stalk lesions included, 11 (29%) were neoplastic. A histopathological diagnosis was obtained in 22/38 (58%) patients. The three most frequently observed etiologies of PST were neuroinfundibulitis (34%), germinoma (21%) and histiocytosis (18%). Pituitary stalk thickness was larger for neoplastic lesions, particularly germinomas. Male gender and a very young age were statistically associated with a risk of germinoma. At least one anterior pituitary deficit was observed in nearly 60% of patients. Patients with neoplastic PST were more affected by multiple anterior pituitary dysfunction than patients with benign PST. A high serum prolactin level was individually the best predictor of a neoplastic origin (90% sensitivity and 60% specificity for a serum prolactin level 1.27-fold above the normal upper limit (ULN)).
We confirm a relatively high risk of malignancy in adult patients presenting with the association of CDI and PST. Young age, male gender, a very large thickening of the stalk, multiple anterior pituitary deficits and prolactin above 1.3× ULN increase the likelihood of a neoplastic origin.
Jandee Lee, Chan Hee Kim, In Kyung Min, Seonhyang Jeong, Hyunji Kim, Moon Jung Choi, Hyeong Ju Kwon, Sang Geun Jung and Young Suk Jo
The characteristics of metastatic lymph nodes (MLNs) have been investigated as important predictors of recurrence and progression in papillary thyroid cancer (PTC). However, clinically applicable risk stratification systems are limited to the assessment of size and number of MLNs. This study investigated the predictive value of detailed characteristics of MLNs in combination with currently used risk stratification systems.
Design and methods
We retrospectively characterized 2811 MLNs from 9014 harvested LNs of 286 patients with N1 PTC according to the maximum diameter of MLN (MDLN), maximum diameter of metastatic focus (MDMF), ratio of both diameters (MDMFR), lymph node ratio (LNR, number of MLNs/number of total harvested LNs), presence of extranodal extension (ENE), desmoplastic reaction (DR), cystic component, and psammoma body.
Factors related to the size and number of MLNs were associated with increased risk of recurrence and progression. Extensive presence of ENE (>40%) and DR (≥50%) increased the risk of recurrence/progression. The combination of MDLN, LNR, ENE, and DR had the highest predictive value among MLN characteristics. Combination of these parameters with ATA risk stratification or 1-year response to therapy improved the predictive power for recurrence/progression from a Harrell’s C-index of 0.781 to 0.936 and 0.867 to 0.960, respectively.
The combination of currently used risk stratification systems with detailed characterization of MLNs may improve the predictive accuracy for recurrence/progression in N1 PTC patients.
Kirstine Jespersen, Marie Lindhardt Ljubicic, Trine Holm Johannsen, Peter Christiansen, Niels E Skakkebaek and Anders Juul
Non-palpable testes remain a diagnostic challenge, often involving exploratory laparoscopy. We evaluated the diagnostic value of a wide range of reproductive hormones in order to distinguish between bilateral cryptorchidism and bilateral anorchia.
In this retrospective study, we identified and included 36 boys with non-palpable testes (20 with cryptorchidism, 3 with congenital hypogonadotropic hypogonadism (CHH), and 13 with anorchia) at first examination during childhood.
Information on karyotype, phenotype, surgical results from laparoscopy, and biochemistry was retrieved from patient files. We compared serum concentrations of AMH, inhibin B, FSH, LH, testosterone, estradiol, and hCG stimulation testing in cryptorchid and anorchid boys to serum concentrations in a large, age-matched control group. Receiver-operating characteristic curves were used to determine the cut-off values of each reproductive hormone as a predictor of the presence of functional testicular tissue.
Concentrations of AMH in 0–1 year olds: ≥155 pmol/L and >1–15 year olds: ≥19 pmol/L, inhibin B (≥22 pg/mL and ≥4 pg/mL), FSH (≤28.9 IU/L and ≤20.3 IU/L) and hCG-induced testosterone (>1-15 year olds: ≥2 nmol/L) were significantly sensitive and specific markers in predicting the presence of functional testicular tissue in boys with non-palpable testes. In infancy, anorchid infants had significantly elevated gonadotropin levels, while CHH had low levels.
Our findings suggest that laparoscopy may not be necessary in all boys with non-palpable testes if reproductive hormones unequivocally confirm the presence of functional testicular tissue. However, proving the absence may still be a diagnostic challenge.