Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Carbonic anhydrases III and IX are new players in the crosstalk between adrenocortical carcinoma and its altered adipose microenvironment.

PURPOSE: Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC. RESULTS/METHODS: CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (n = 14) (fold increase FI = 7.4 ± 0.1, P < 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06, P < 0.001), compared with lower stages (n = 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11, P < 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1, P < 0.01, respectively). CONCLUSION: Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. No efficacious treatment options are currently available for patients with advanced metastatic disease with disease progression to standard etoposide, doxorubicin, cisplatin and mitotane (EDP-M) therapy. We assessed the activity and tolerability of cabazitaxel as a second/third-line approach in metastatic ACC. PATIENTS AND METHODS: Patients included in this single-center, phase II study (ClinicalTrials.gov identifier NCT03257891) had disease progression to a cisplatin-containing regimen (such as EDP) plus mitotane, plus/minus a further chemotherapy line. Cabazitaxel was administered intravenously at 25 mg/m2 on day 1 of a 21-day cycle, for a maximum of six cycles. The primary endpoint was a disease control rate after 4 months. RESULTS: From March 2018 to September 2019, 25 eligible patients were enrolled. A disease control rate after 4 months was obtained in six patients (24%). No patients attained a disease response according to RECIST 1.1, 9 patients (36%) had stable disease and 16 patients (64%) progressive disease. Median progression-free survival and overall survival were 1.5 months (range 0.3-7 months) and 6 months (range 1-22.2 months), respectively. Cabazitaxel therapy was well tolerated and only three (12%) patients developed grade 3 toxicity which were nausea in one patient (4%) and anemia in two patients (8%). CONCLUSIONS: Cabazitaxel has a manageable toxicity profile but is poorly active as second/third-line treatment in advanced ACC patients. These results do not support further evaluation of cabazitaxel in this setting.

Management and outcome of metastatic pheochromocytomas/paragangliomas: a monocentric experience.

BACKGROUND: Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5-26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines. AIM: The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs. METHODS: Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27. RESULTS: Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30-55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008). CONCLUSION: Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Volumetric evaluation of CT images of adrenal glands in primary aldosteronism.

OBJECTIVES: To investigate whether adrenal volumetry provides better agreement with adrenal vein sampling (AVS) than conventional CT for subtyping PA. Furthermore, we evaluated whether the size of this contralateral adrenal was a prognostic factor for clinical outcome after unilateral adrenalectomy. METHODS: We retrospectively analyzed volumes of both adrenal glands of the 180 CT-scans (88/180 with unilateral and 92/180 with bilateral disease) of the patients with PA included in the SPARTACUS trial of which 85 also had undergone an AVS. In addition, we examined CT-scans of 20 healthy individuals to compare adrenal volumes with published normal values. RESULTS: Adrenal volume was higher for the left than the right adrenal (mean and SD: 6.49 ± 2.77 ml versus 5.25 ± 1.87 ml for the right adrenal; p < 0.001). Concordance between volumetry and AVS in subtyping was 58.8%, versus 51.8% between conventional CT results and AVS (p = NS). The volumes of the contralateral adrenals in the patients with unilateral disease (right 4.78 ± 1.37 ml; left 6.00 ± 2.73 ml) were higher than those of healthy controls reported in the literature (right 3.62 ± 1.23 ml p < 0.001; left 4.84 ± 1.67 ml p = 0.02). In a multivariable analysis the contralateral volume was not associated with biochemical or clinical success, nor with the defined daily doses of antihypertensive agents at 1 year follow-up. CONCLUSIONS: Volumetry of the adrenal glands is not superior to current assessment of adrenal size by CT for subtyping patients with PA. Furthermore, in patients with unilateral disease the size of the contralateral adrenal is enlarged but its size is not associated with outcome.

Management and outcome of metastatic pheochromocytomas/paragangliomas: an overview.

BACKGROUND: Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5-26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines. AIM: The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs. RESULTS: Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using 90Y or 177Lu-DOTATATE, could be a promising therapy. In addition, high specific 131I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable 131I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials. CONCLUSIONS: The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.

Adrenocortical carcinoma: the dawn of a new era of genomic and molecular biology analysis.

Over the last decade, the development of novel and high penetrance genomic approaches to analyze biological samples has provided very new insights in the comprehension of the molecular biology and genetics of tumors. The use of these techniques, consisting of exome sequencing, transcriptome, miRNome, chromosome alteration, genome, and epigenome analysis, has also been successfully applied to adrenocortical carcinoma (ACC). In fact, the analysis of large cohorts of patients allowed the stratification of ACC with different patterns of molecular alterations, associated with different outcomes, thus providing a novel molecular classification of the malignancy to be associated with the classical pathological analysis. Improving our knowledge about ACC molecular features will result not only in a better diagnostic and prognostic accuracy, but also in the identification of more specific therapeutic targets for the development of more effective pharmacological anti-cancer approaches. In particular, the specific molecular alteration profiles identified in ACC may represent targetable events by the use of already developed or newly designed drugs enabling a better and more efficacious management of the ACC patient in the context of new frontiers of personalized precision medicine.

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers.

To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors.

Kikuchi-Fujimoto disease with lateral neck localisation: a case report.

The case is described of a Kikuchi-Fujimoto disease, in a 22-year-old female, onset of which was characterised by rapidly evolving lateral neck lymphadenopathy. Since clinico-radiological findings suggested a lymphoproliferative disease, it was mandatory, in order to establish the diagnosis and programme a suitable treatment protocol, to collect a lymph node biopsy specimen. The histological pattern was characteristic of Kikuchi-Fujimoto disease necrotizing lymphadenitis. Bearing in mind the difficulties encountered in the diagnosis of Kikuchi-Fujimoto disease, due not only to lack of a characteristic clinical pattern but also to the generic and aspecific findings emerging from radiological evaluation, the Authors stress the important role of histological examination in establishing the nature of the disease. In their opinion, onset of a rapidly evolving lateral neck lymphadenopathy, in a young patient, in the absence of well-defined disorders possibly responsible for the condition, and in order to establish a correct diagnostic approach, should induce the ENT specialist to take into consideration the possible presence of Kikuchi-Fujimoto disease, even if this is to be considered a rare finding.

Aggressive congenital fibromatosis of the small intestine in the newborn. Report of a case and review of the literature.

A case of so-called congenital fibro(leio)myosarcoma of the small intestine in a 18-day-old female baby, treated only with surgical resection, was studied by immunohistochemistry and electron microscopy in order to investigate the proliferating cell type. The tumour cells showed positivity only for vimentin and CD 34 and were negative for smooth muscle actin, desmin, alpha-sarcomeric actin, factor VIIIR: Ag and S-100 protein. Ultrastructural findings showed oval nuclei with prominent nucleoli, rare intracytoplasmic mitochondria and well developed rough endoplasmic reticulum. According to histoimmunological and electron microscopy findings the proliferating cells were likely to be of fibroblastic origin. A 7-year follow-up showed a favourable clinical evolution thus confirming that surgical resection can be a sufficient therapeutic approach. The morphological findings and clinical behaviour suggest that more appropriate terminology for this tumour would be "aggressive congenital fibromatosis" which better highlights its local progressive invasion without metastases.

[Mucoepidermoid carcinoma and mucoepidermoid cyst of the jaw bones in the same patient. A clinical case and discussion of their histogenesis]. / Carcinoma mucoepidermoide e cisti mucoepidermoide delle ossa mascellari nello stesso paziente. Caso clinico e discussione sulla loro istogenesi.

The association between a so-called mucoepidermoid cyst and a central mucoepidermoid carcinoma in a 29-year-old man is reported. Since the two lesions are in continuity and the morphologic appearances are very much alike, a close relationship between these entities is suggested.

[Sutures without sutures in digestive surgery. Experimental study of the rat intestine]. / Suture senza suture in chirurgia digestiva. Studio sperimentale sull'intestino del ratto.

The aim of the experimental study was to evaluate the possibility of performing an end-to-end anastomosis by using fibrin adhesive as the only means of suture. To this end, 24 Wistar rats were used, of which 16 underwent ilear resection and 8 underwent colotomy, and they were divided respectively into two groups. On the rats of the first group the anastomosis was performed by using only fibrin adhesive; on the rats of the second group operated the anastomosis was performed by using fibrin adhesive in association with non adsorbable suture material, while on those operated of colectomy the anastomosis was performed by fibrin adhesive and adsorbable suture material. The anatomo-phatological studies on the anastomosis have shown a similar healing process in the cases treated only with fibrin adhesive and by using absorbable material and has demonstrated the trange material from the suture, which are a possible causes of complication.

[A morphological study of ciliary abnormalities in patients with immotile cilia syndrome]. / Studio morfologico delle anomalie ciliari in pazienti affetti da sindrome delle ciglia immobili.

The present study has the aim of studying the morphological aspects of ciliary abnormalities in patients affected by immotile-dyskinetik cilia syndrome. Five patients affected by primary ciliary dyskinesia have been studied, examining by TEM the cells obtained by bronchial brushing during fiberoptic bronchoscopy. Many types of anomalies have been observed, and a morphologic classification was proposed. The frequency of abnormal cilia appears to be correlated to the severity of respiratory pathology. The morphological anomalies are not specific for this pathology.

[Mechanical and antibiotic preparation and infections in colorectal surgery. Comparison of 2 methods of orthograde lavage]. / Preparazione meccanico-antibiotica e infezioni in chirurgia colorettale. Confronto tra due metodi di lavaggio ortogrado.

The efficacy of two methods of orthograde lavage preparation in elective colorectal surgery was tested in 133 consecutive patients: the results obtained with whole gut irrigation (50 patients, group A) were compared with the results of oral lavage solution (83 patients, group B). All patients received a parenteral association of antibodies (clindamycin in combination with a broad spectrum antibiotic, mainly II or III generation cephalosporins). Bacterial cultures were carried out at the end of the lavage in the rectal effluent (no statistically significant differences between the two groups) and in the intraoperative aspirate from the colon (the bacterial concentration was higher in group B). The total number of infections was 12 (9%), with 6 (12%) in group A and 6 (7.2%) in group B. The infectious complications involved perineal wound in 9 cases (in 2 patients in combination with abdominal wound infection), abdominal drainage in 2 and abdominal wound in 1. The type of broad spectrum antibiotic did not affect the infection rate significantly. Perioperative and infection site bacteriological cultures grew the same type of organism only in one case. The surgeons' judgement of the adequacy of the cleansing favored whole gut irrigation, although the results of the study revealed that both methods were safe and provided equally adequate bowel cleansing.