Spontaneous Mandibular Dentoalveolar Changes after Rapid Maxillary Expansion (RME), Slow Maxillary Expansion (SME), and Leaf Expander-A Systematic Review.

BACKGROUND: This systematic review aims to analyze the spontaneous dentoalveolar changes in the mandibular arch after maxillary expansion in growing patients obtained with different expansion protocols: Rapid Maxillary Expansion (RME), Slow Maxillary Expansion (SME), and Leaf Expander. METHODS: The study adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Eligibility criteria were established in the PICO format, involving patients who underwent slow, rapid, or leaf maxillary expansion during the mixed or early permanent dentitions. A comprehensive search of electronic databases and manual searches was conducted up to December 2023. The outcome measures included inter-mandibular first permanent molar width, inter-deciduous molar and canine width, arch perimeter, and arch length; both short- and long-term results were considered. The articles that met the inclusion criteria were included in this systematic review and were qualitatively evaluated using a methodological quality scoring system with a 13-point scale. To assess the inter-examiner agreement concerning the article selection and the qualitative assessment of the included studies, Kappa statistics were computed. RESULTS: A total of 1184 articles were identified through electronic and manual searches. After the removal of duplicates and the initial examination of the titles and abstracts, 57 articles were considered for the full text analysis, and according to the eligibility and exclusion criteria, 22 studies were finally selected, composed of 8 randomized controlled trials (RCTs) and 14 retrospective/case-control studies. The qualitative assessment of the included studies showed the following scores: 6 papers have high research quality, 5 have moderate quality, and 11 have low quality. SME demonstrated negligible mandibular changes, with less than 1 mm variation on average (range 0.46-2.00 mm) in the selected parameters and relapses observed in the long term. RME induced more significant increases, particularly in intermolar width greater than 1 mm, which ranged between 0.93 and 3.3 mm, and good stability over the long term. Leaf Expander exhibited promising short-term lower intermolar width increases greater than 1 mm and ranged from 0.5 to 1.69 mm, but long-term stability was not thoroughly evaluated. CONCLUSIONS: SME results in negligible short- and long-term effects, while RME, especially with Haas-type appliances, exhibits significant intermolar width increases that remain stable over the years. Leaf Expander shows short-term lower intermolar width increases, requiring further investigation into long-term stability.

RETROSPECTIVE ANALYSIS OF THE PATIENT-REPORTED ADVERSE DRUG REACTIONS IN AN ITALIAN ALLERGY UNIT: ALLERG-RAF STUDY.

INTRODUCTION: The Italian Medicines Agency indicates that about 5% of hospital admissions are due to Adverse Drug Reactions (ADRs). Several factors are recognized to be associated with an increased risk for ADRs, such as the female gender and polytherapy. The aim of this study was to retrospectively analyze the suspected ADRs reported by patients during the anamnestic interview at the Allergy Unit. PATIENTS AND METHODS: ALLERG-RAF study is a retrospective analysis of the medical records of patients evaluated in the Allergy Unit of ASST Spedali Civili and University of Brescia from 2000 to 2016. The inclusion criteria were age >18 years and medical consultation requested for suspected ADRs. Data relating to the patient's intrinsic characteristics, the drug supposed to be the cause and the prescribed pharmacological therapy were collected. Pseudonymized data from each patient were collected in an informatics database. RESULTS: From 2000 to 2016, 35817 accesses to the Allergy Unit were made and 2171 unique events related to a suspected ADR were collected in 1840 patients. More than two thirds of the reports concerned females (70.4%). Antibiotics were involved in the majority of the self-reported suspected ADRs (48.7%), particularly beta-lactams (61.1%). Anti-inflammatory drugs, mainly NSAIDs, were second in incidence and suspected in 25.2% of reports. As a site of ADR manifestation, most of the reported reactions involve the skin. No clinical sequelae were reported. CONCLUSIONS: Our results underline the importance of patient reporting in Pharmacovigilance. Furthermore, gender gap data emphasizes the importance of the gender-specific medicine approach.

The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study.

BACKGROUND: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.

Comparison of Mechanical Behavior of Clear Aligner and Rapid Palatal Expander on Transverse Plane: An In Vitro Study.

(1) Background: This study aims to investigate, within a controlled laboratory environment, the magnitude of the transversal load and the force decay over time produced by clear aligners in comparison to a Rapid Palatal Expander (RPE). (2) Methods: Resin models of a dental maxillary arch, additively manufactured from an intraoral scan, were inserted in a testing machine with uniaxial load cells to measure the force trend over time expressed by RPE and clear aligners. The mechanical load was recorded during a certain timeframe for both appliances. (3) Results: The force expressed by the RPE ranged from 30 to 50 N for each activation, decreasing with a nonlinear pattern over time. The force expressed by the clear aligner ranged from 3 to 5 N, decreasing with a linear pattern over time. In contrast, the force generated by the clear aligner fell within the range of 3 to 5 N, showing a linear reduction in force magnitude over the observed period of time. (4) Conclusions: The RPE exerted a force magnitude approximately ten times greater than that generated by clear aligners. Nevertheless, it is essential to acknowledge that the oral environment can significantly influence these results. These limitations underscore the need for caution when applying these findings to clinical settings.

Novel cellular systems unveil mucosal melanoma initiating cells and a role for PI3K/Akt/mTOR pathway in mucosal melanoma fitness.

BACKGROUND: Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. METHODS: Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. RESULTS: This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. CONCLUSIONS: Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Correction: Sigala et al. A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma. Cells 2022, 11, 1439.

The authors made the following changes to their paper [...].

Feasibility and Activity of Megestrol Acetate in Addition to Etoposide, Doxorubicin, Cisplatin, and Mitotane as First-Line Therapy in Patients with Metastatic/Unresectable Adrenocortical Carcinoma with Low Performance Status.

(1) Background: The standard first-line therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane). Progestins have shown cytotoxic activity both in vitro and in vivo on ACC; better EDP-M tolerability and efficacy have been hypnotized due to the association with progestins. (2) Methods: The feasibility and tolerability of EDP-M combined with oral megestrol acetate (EDP-MM) were tested in 24 patients (pts) affected by metastatic ACC with a low performance status (PS); the case group was compared with a 48 pts control group according to the propensity score. The secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). (3) Results: Thirteen pts (54.2%) in the EDP-MM population experienced progestin-related toxicities; in particular, five pts experienced vaginal bleeding (20.8%); four pts experienced weight gain (16.7%); and thromboembolic events, worsening of hypertension, skin rashes, and hyperglycemia were registered in one patient each (4.2%). This led to the discontinuation of megestrol acetate in four pts (16.7%). EDP-M-related toxicities were similar in both groups. No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) Conclusions: The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS.

Comparison of the skeletal, dentoalveolar, and periodontal changes after Ni-Ti leaf spring expander and rapid maxillary expansion: a three-dimensional CBCT based evaluation.

BACKGROUND: The aim of the present study was twofold:(1) three-dimensionally evaluate the quantitative skeletal and dentoalveolar changes after Ni-Ti leaf spring expander (leaf expander) and rapid maxillary expansion (RME) in mixed dentition patients;(2) analyze the modifications of the buccal alveolar bone plate of the maxillary first permanent molars. METHODS: Patients who underwent CBCT scans before and after maxillary expansion were randomly selected from the records archived at the Department of Biomedical Surgical and Dental Sciences, University of Milan, Italy. Inclusion criteria were the following: no systemic disease or syndromes; maxillary transverse deficiencies (difference between the upper intermolar width and the lower intermolar width of at least 3 mm and/or clinical need based on radiographic evaluation), early mixed dentition with ages between 7 to 10 years old; cervical vertebra maturation stage (CVMS) 1 or 2; no pathologic periodontal status; skeletal class I or II; maxillary expander cemented on the upper second deciduous molars. Exclusion criteria were the following: patients with pubertal or post-pubertal stage of development (CVMS 3-6); late deciduous or late mixed dentition, impossibility to use the second primary molar as anchorage; skeletal class III malocclusion; craniofacial syndromes; patients unable to be followed during the treatment period. Twenty-three patients treated with Leaf Expander, 11 males (mean age 7.8 ± 0.6 years) and 12 females (mean age 8.1 ± 0.8 years), met the inclusion criteria and constituted the case group. Twenty-four (control group) treated with conventional RME, 12 males (mean age 8.4 ± 0.9 years) and 12 females (mean age 8.1 ± 0.7 years). The paired-sample T test was used for intra-group comparison to evaluate the difference between before (T1) and after (T2) maxillary expansion. Independent sample t-test was computed to perform between groups comparison of the skeletal, dentoalveolar, and periodontal changes. RESULTS: The Leaf Expander and RME group showed a significant increase between T1 and T2 for most of the skeletal and dentoalveolar variables. Concerning the skeletal variables only the RME demonstrated a significant increase at the level of the posterior nasal (PNW) and apical base width (PABW) and maxillary mid-alveolar width (MMW). Despite this, when compare with the Leaf Expander, the RME group exhibited a statistically larger width increase for only two skeletal parameters: PNW (p = 0.03) and MMW (p = 0.02). No significant changes at the periodontal level were found in either group. CONCLUSIONS: According to the current research, the authors confirm the effectiveness of the Leaf Expander and RME to produce similar skeletal and dentoalveolar effects in mixed dentition subjects. Moreover, the devices anchored to deciduous teeth did not reduce the thickness and height of the buccal bone at the level of the maxillary permanent first molars in either of the two groups.

Preclinical Evidence of Progesterone as a New Pharmacological Strategy in Human Adrenocortical Carcinoma Cell Lines.

BACKGROUND: Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. METHODS: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. RESULTS: Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. CONCLUSION: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.

Three-dimensional evaluation of the maxillary sinus in patients with different skeletal classes and cranio-maxillary relationships assessed with cone beam computed tomography.

The objective was to evaluate the relationship between the dimensions of the maxillary sinuses (MSs) and various cephalometric parameters. MS volume (MSV), MS surface (MSS), linear maximum depth (LMD), linear maximum width (LMW), and linear maximum height (LMH) were calculated on CBCT scans of 99 adults. Two sets of two-way (ANOVA) assessed the influence respectively of ANB and SNA angles and of the gender on MS dimensions. Pearson's correlation was calculated between MS dimensions and different cephalometric variables. Reliability and accuracy of the proposed method was tested with intra-operator and inter-operator intraclass correlation coefficient (ICC). Two-way ANOVA showed no statistically significant difference in MSV, MSS and LMH between ANB groups, whilst males were associated with bigger sinuses. LMW showed statistically significant difference in both ANB and gender groups. LMD showed no statistically significant difference. The second Two-way ANOVA showed significantly larger MSV, MSS and LMD in patients with increased or reduced SNA angle but not between genders. LMW and LMH also showed a significant difference between genders. All linear measurements showed a significant interaction of the two factors. The intra-observer and inter-observer ICC scored high for all the tested measurements. MSV and MSS showed a positive correlation with S-N, PNS-A, S-Go, N-Me, N-Ans and the distance between Mx points. LMW had a negative correlation with Ba-S-N angle and N-Me, LMH with Ba-S-N angle, S-Go and Mx r-Mx l and LMD with N-Me and N-ANS. LMW had a positive correlation with Mx r-Mx l, LMH with S-N, S-N^Ans-Pns, N-Me, N-Ans and LMD with S-N, Ba-S-N, PNS-A, S-Go and distance between Mx points. In conclusion, MSV and MSS did not differ between the three skeletal classes, males showed significantly larger MS than in females. Concerning the influence of the cranio-maxillary relationship (SNA) and gender on MS dimension, subjects with a retrusion (SNA < 80°) or protusion (SNA > 84°) of the maxillary alveolar bone had larger MSV, MSS, LMW, LMH and LMD than subjects with a normal cranio-maxillary relationship (SNA 82 ± 2°). A statistically significant high positive correlation was observed between S-N, Pns-A, S-Go, Mx-R/Mx-r and MS dimension. Further studies that evaluate similar outcomes in different races may be able to enrich our knowledge on this topic.

Evaluation of Masticatory Muscles in Adult Patients with Maxillary Hypoplasia Treated with Surgically Assisted Rapid Maxillary Expansion (SARME): A Retrospective Study.

Aim: The aim of the present study was to investigate modifications in electromyographic activity of temporal and masseter muscles before and after surgically assisted rapid maxillary expansion (SARME) in adult subjects. Materials and Methods: Data from 20 patients with unilateral posterior crossbite were selected retrospectively from the Orthodontics Department of the University of Genoa and the Department of Biomedical Surgical and Dental Sciences of the University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan. Inclusion criteria were set as skeletal class I; adult patients (age > 18); good general health; patients with a transverse maxillary deficiency with unilateral posterior crossbite and maxillary constriction ≥ 5 mm; Superficial electromyographic (EMG) examinations at T0 and T1. Exclusion criteria were smoking, metabolic bone diseases (e.g., hyperparathyroidism, vitamin C deficiency), chronic use of corticoids before or during treatment, parafunctional habits (e.g., bruxism), and temporomandibular joint dysfunction. The Shapiro−Wilk test was performed to check whether the data were normally distributed. Differences for each variable before and after SARME were analyzed with a paired t-test (p < 0.05). Results: The statistical analysis demonstrated no statistically significant differences between the EMG values taken before and after SARME regarding the standardized electrical activity of the masticatory muscles (masseter and anterior temporalis (p > 0.05)). Conclusions: Considering the specific conditions of this study, it can be concluded that SARME did not alter the EMG activity of the masseter and temporal muscles. The present study has shown that the masticatory musculature evaluated after approximately 8 months of therapy can adapt well to SARME.

Trabectedin impairs invasiveness and metastasis in adrenocortical carcinoma preclinical models.

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells' invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

The limitations for expression recognition in computer vision introduced by facial masks.

Facial Expression recognition is a computer vision problem that took relevant benefit from the research in deep learning. Recent deep neural networks achieved superior results, demonstrating the feasibility of recognizing the expression of a user from a single picture or a video recording the face dynamics. Research studies reveal that the most discriminating portions of the face surfaces that contribute to the recognition of facial expressions are located on the mouth and the eyes. The restrictions for COVID pandemic reasons have also revealed that state-of-the-art solutions for the analysis of the face can severely fail due to the occlusions of using the facial masks. This study explores to what extend expression recognition can deal with occluded faces in presence of masks. To a fairer comparison, the analysis is performed in different occluded scenarios to effectively assess if the facial masks can really imply a decrease in the recognition accuracy. The experiments performed on two public datasets show that some famous top deep classifiers expose a significant reduction in accuracy in presence of masks up to half of the accuracy achieved in non-occluded conditions. Moreover, a relevant decrease in performance is also reported also in the case of occluded eyes but the overall drop in performance is not as severe as in presence of the facial masks, thus confirming that, like happens for face biometric recognition, occluded faces by facial mask still represent a challenging limitation for computer vision solutions.

Method Presentation of a New Integrated Orthodontic-Conservative Approach for Minimally Invasive Full Mouth Rehabilitation: Speed Up Therapy.

The materials available today allow for extensive oral rehabilitations in a non-invasive way, and often an orthodontic preparation is useful and, thanks to the use of clear aligners, is predictable and comfortable. A preliminary study of the wax-up, mock-up, and set-up allow the clinician to plan every aspect of the treatment in detail. Furthermore, the procedure offers the patient an intuitive and understandable view of the expected final result. The new proposed method, called "speed up therapy", allows for the integration of the orthodontic set-up with the mock-up technique, simulating the occlusal and aesthetic components of the planned restoration, in all details. The clinical case presented, demonstrates step by step the predictability and clinical reliability of the proposed procedure. The final clinical result coincides exactly with the initial mock-up and demonstrates that the proposed method is predictable and reliable. The correct execution of the technique is rigorously customized, and its success is operator dependent, both for the clinical aspects and for the dental laboratory. Thus, the visualization of the objectives of the treatment constitutes a decisive support for the clinician and provides the patient with the possibility of benefiting from an immediate improvement by making it easier for them to accept a treatment plan. The visualization also includes an orthodontic phase that potentially lengthens the treatment but makes the realization more conservative and predictable.

A PNU-Based Methodology to Improve the Reliability of Biometric Systems.

Face recognition is an important application of pattern recognition and image analysis in biometric security systems. The COVID-19 outbreak has introduced several issues that can negatively affect the reliability of the facial recognition systems currently available: on the one hand, wearing a face mask/covering has led to growth in failure cases, while on the other, the restrictions on direct contact between people can prevent any biometric data being acquired in controlled environments. To effectively address these issues, we designed a hybrid methodology that improves the reliability of facial recognition systems. A well-known Source Camera Identification (SCI) technique, based on Pixel Non-Uniformity (PNU), was applied to analyze the integrity of the input video stream as well as to detect any tampered/fake frames. To examine the behavior of this methodology in real-life use cases, we implemented a prototype that showed two novel properties compared to the current state-of-the-art of biometric systems: (a) high accuracy even when subjects are wearing a face mask; (b) whenever the input video is produced by deep fake techniques (replacing the face of the main subject) the system can recognize that it has been altered providing more than one alert message. This methodology proved not only to be simultaneously more robust to mask induced occlusions but also even more reliable in preventing forgery attacks on the input video stream.

Advances in adrenocortical carcinoma pharmacotherapy: what is the current state of the art?

INTRODUCTION: Surgery, followed or not by adjuvant mitotane, is the current mainstay of therapy for patients with early-stage adrenocortical carcinoma (ACC). Mitotane, either alone or in association with EDP (Etoposide-Doxorubicin-Cisplatin) combination chemotherapy, is the standard approach for patients with metastatic ACC. AREAS COVERED: The activity of newer cytotoxic drugs, radioligands, targeted therapies, and immunotherapy, both in preclinical and clinical studies, will be reviewed in this paper. EXPERT OPINION: ADIUVO trial revealed that the administration of adjuvant mitotane is not advantageous in patients with good prognosis. Future strategies are to intensify efforts in adjuvant setting in patients with high risk of relapse. In patients with advanced/metastatic disease, modern targeted therapies have shown significant cytotoxicity in preclinical studies; however, studies in ACC patients reported disappointing results so far. The absence of targeted agents specifically inhibiting the major molecular pathways of ACC growth is the main cause of the failure of these drugs. Since ACC is often antigenic but poorly immunogenic, the results of immunotherapy trials appeared inferior to those achieved in the management of patients with other malignancies. Radioligand therapy may also be a promising approach. Combination of chemotherapy plus immunotherapy could be interesting to be tested in the future.

Cytotoxic effects of targeted agent alone or with chemotherapy in the treatment of adenoid cystic carcinoma: a preclinical study.

Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.

An update on adrenocortical cell lines of human origin.

Adrenocortical carcinoma (ACC) is a rare, heterogenous and highly malignant disease. Management of ACC is dependent on disease stage with complete surgical resection as the only potentially curative option. However, advanced, un-resectable, metastatic stages and also recurrences often require systemic treatments, which are unfortunately nowadays still unsatisfactory. The scarcity of preclinical models reflecting patient heterogeneities and furthermore drug-resistant phenotypes, has hampered the progress and development of new therapies in recent years. In this review, we provide an overview on the classical models and substantial progress which has been made over the last years in context of this aggressive disease.

Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen.

PURPOSE: The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is the standard regimen. However, it is quite toxic, so an adequate supportive therapy is crucial to reduce as much as possible the side effects and maintain the dose intensity of cytotoxic agents. METHODS: We describe the main side effects of the EDP-M scheme and the best way to manage them based on the experience of the Medical Oncology Unit of the Spedali Civili of Brescia. We also deal with the administration of EDP-M in specific frail patients, such as those with huge disease extent and poor performance status (PS) and those with mild renal insufficiency. RESULTS: In patients with hormone secreting ACC the rapid control of Cushing syndrome using adrenal steroidogenesis inhibitors such as metyrapone or osilodrostat is mandatory before starting EDP-M. Primary prophylaxis of neutropenia with Granulocyte-Colony Stimulating Factors is crucial and should be introduced at the first chemotherapy cycle. Possible mitotane induced hypoadrenalism should be always considered in case of persistent nausea and vomiting and asthenia in the interval between one cycle to another. In case of poor PS. A 24 h continuous infusion schedule of cisplatin could be an initial option in patients with poor PS as well as to reduce the risk of nefrotoxocity in patients with mild renal impairment. CONCLUSION: A careful and accurate supportive care is essential to mitigate EDP-M side effects as much as possible and avoid that, due to toxicity, patients have to reduce doses and or postpone cytotoxic treatment with a negative impact on efficacy of this chemotherapy regimen.

A Comprehensive Investigation of Steroidogenic Signaling in Classical and New Experimental Cell Models of Adrenocortical Carcinoma.

Adrenocortical carcinoma is a heterogeneous and aggressive cancer that originates from steroidogenic cells within the adrenal cortex. In this study, we have assessed for the preclinical gold standard NCI-H295 in direct comparison with the more recently established MUC-1 and a here newly reported ACC cell line (TVBF-7) the mutational status of important driver genes (TP53, MEN1, PRKAR1A, CTNNB1, APC, ZNRF-3, IGF-2, EGFR, RB1, BRCA1, BRCA2, RET, GNAS and PTEN), Wnt-signaling specificities (CTNNB1 mutation vs. APC mutation vs. wildtype), steroidogenic-(CYP11A1, CYP17A1, HSD3B2, HSD17B4, CYP21A2, CYP11B1, CYP11B2, MC2R, AT1R) and nuclear-receptor-signaling (AR, ER, GCR), varying electrophysiological potentials as well as highly individual hormone secretion profiles (Cortisol, Aldosterone, DHEA, DHEAS, Testosterone, 17-OH Progesterone, among others) which were investigated under basal and stimulated conditions (ACTH, AngII, FSK). Our findings reveal important genetic and pathophysiological characteristics for these three cell lines and reveal the importance of such cell-line panels reflecting differential endocrine functionalities to thereby better reflect clinically well-known ACC patient heterogeneities in preclinical studies.