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Adrenocortical carcinomas (ACCs) are rare and aggressive malignancies of adrenal cortex, associated with largely unknown mechanisms of biological development and poor prognosis. Currently, mitotane is the sole approved drug for treating advanced adrenocortical carcinomas (ACCs) and is being utilized more frequently as postoperative adjuvant therapy. Although it is understood that mitotane targets the adrenal cortex and disrupts steroid production, its precise mechanism of action requires further exploration. Additionally, mitotane affects cytochrome P450 enzymes, causes the depolarization of mitochondrial membranes, and leads to an accumulation of free cholesterol, ultimately resulting in cell death. Many patients treated with mitotane develop disease progression over time, underlying the need to understand the mechanisms of primary and acquired resistance. In this manuscript, we provide an overview on the intracellular mechanisms of action of mitotane, exploring data regarding predictive factors of response and evidence associated with the development of primary and acquired resistance mechanisms. In this discussion, mitotane is considered a real target therapy.

In elderly patients with high-risk classic Hodgkin lymphoma (c-HL), we evaluated the impact of a new modality treatment without bleomycin, that is, liposomal doxorubicin (NPLD)-based regimen plus consolidation radiotherapy of residual nodal masses (RNMs), on overall survival (OS) and progression free survival (PFS). In this retrospective study (2013-2023) conducted in tertiary hospitals in the bay of Naples (Italy), 50 older adults (median age, 69 years; range, 60-89) with advanced stage c-HL received frontline treatment with MVD ± irradiation. MVD consisted of 25 mg/m 2 of NPLD along with standard Vinblastine and Dacarbazine for a total of 6 cycles (twelve iv administrations, every 2 weeks) followed by radiation of RNMs with size ≥ 2.5 cm at computed tomography. Patients underwent MVD with a median dose intensity of 92%. At 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography (FDG-PET), 90% of patients (45/50 patients; one failed to perform final FDG-PET due to early death) reached complete responses. Altogether, 17 patients (34%) received consolidation radiotherapy of RNMs with Deauville score ≥ 3. At 5-year median follow-up, the OS and PFS of the entire population were 87.5% (95% confidence interval [CI], 78.7-97.4) and 81.6% (95% CI, 71.4-93.2), respectively. Eleven patients (22%) experienced grade ≥ 3 adverse events, and 4 of them required hospitalization. Our data suggest that in older adults with high-risk c-HL NPLD-driven strategy (without bleomycin) plus consolidation radiotherapy (if needed) may be a promising up-front option, to test in phase II clinical trials for improving survival incidence., (© 2024 The Author(s). Hematological Oncology published by John Wiley & Sons Ltd.)

Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics., Objective: The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO., Methods: On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria., Results: Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate., Conclusion: The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim of the Study: The aim of this study was to analyze the popularity of surgery first among orthodontists as well as the protocols used for its implementation and to collect the opinions (favorable or unfavorable) of practitioners and patients regarding it., Materials and Methods: A questionnaire was sent to a population of dental surgeons qualified in Dentofacial Orthopedics or in the process of specialization (residents) practicing in France. The questionnaire consisted of a total of 27 questions. There were 10 open-ended questions and 17 closed-ended questions (8 binary and 9 multiple choices). The conditional pathway allows the respondent's path through the form to be modified based on their answers. This survey was conducted using Google Forms online survey software., Results: On average, the responding practitioners had 15.9 years of experience, and most of them (78.2%) work in private practice. Most treated between 200 and 400 cases per year, of which 7% were surgical cases. Orthodontists who are familiar with and practice the surgery first protocol use it on average for 7 cases per year. The most frequent indication for the surgery first protocol was: transverse maxillary defects., Conclusions: Surgery first protocol is a preferred option in cases of high severity since it prevents respiratory worsening during the pre-surgical orthodontic phase. The lack of a standardized protocol for this approach, at the pre-surgical and post-surgical levels, requires an increase in the number of high-level evidence publications to clarify the methods of application of this protocol., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

We investigated the role of Coefficient of Variation (CoV), a first-order texture parameter derived from 18 F-FDG PET/CT, in the prognosis of Non-Small Cell Lung Cancer (NSCLC) patients. Eighty-four patients with advanced NSCLC who underwent 18 F-FDG PET/CT before therapy were retrospectively studied. SUVmax, SUVmean, CoV, total Metabolic Tumor Volume (MTV TOT ) and whole-body Total Lesion Glycolysis (TLG WB ) were determined by an automated contouring program (SUV threshold at 2.5). We analyzed 194 lesions: primary tumors ( n = 84), regional ( n = 48) and non-regional ( n = 17) lymph nodes and metastases in liver ( n = 9), bone ( n = 23) and other sites ( n = 13); average CoVs were 0.36 ± 0.13, 0.36 ± 0.14, 0.42 ± 0.18, 0.30 ± 0.14, 0.37 ± 0.17, 0.34 ± 0.13, respectively. No significant differences were found between the CoV values among the different lesion categories. Survival analysis included age, gender, histology, stage, MTV TOT , TLG WB and imaging parameters derived from primary tumors. At univariate analysis, CoV ( p = 0.0184), MTV TOT ( p = 0.0050), TLG WB ( p = 0.0108) and stage ( p = 0.0041) predicted Overall Survival (OS). At multivariate analysis, age, CoV, MTV TOT and stage were retained in the model ( p = 0.0001). Patients with CoV > 0.38 had significantly better OS than those with CoV ≤ 0.38 ( p = 0.0143). Patients with MTV TOT ≤ 89.5 mL had higher OS than those with MTV TOT > 89.5 mL ( p = 0.0063). Combining CoV and MTV TOT , patients with CoV ≤ 0.38 and MTV TOT > 89.5 mL had the worst prognosis. CoV, by reflecting the heterogeneity of glycolytic phenotype, can predict clinical outcomes in NSCLC patients.

Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15-30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r  = -0.45, p  = 0.0002, 95% confidence interval [CI] -0.63 to -0.23; Ala/Thr r  = -0.39, p  = 0.0012, CI -0.60 to -0.67; and Ala/Ala r  = -0.30, p  = 0.2347; CI -0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients ( p  = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO 2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21).

Background/aim: Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment: however, their role has not yet been fully clarified., Patients and Methods: In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy., Results: Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR=3.26, 95%Cl=2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS; furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS=3.8 months)., Conclusion: NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features., Competing Interests: The Authors have no conflicts of interest to declare in relation to this study., (Copyright 2023, International Institute of Anticancer Research.)

Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.