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Abstract Nowadays, treatment of metastatic breast cancer (MBC) has been enriched with novel therapeutical strategies. Metronomic chemotherapy (mCHT) is a continuous and frequent administration of chemotherapy at a lower dose and so whit less toxicity. Thus, this strategy could be attractive for elderly MBC patients. Aim of this analysis is to provide insights into mCHT’s activity in a real-life setting of elderly MBC patients. Data of patients ≥ 75 years old included in VICTOR-6 study were analyzed. VICTOR-6 is a multicentre, Italian, retrospective study, which collected data on mCHT in MBC patients treated between 2011 and 2016. A total of 112 patients were included. At the beginning of mCHT, median age was 81 years (75–98) and in 33% of the patients mCHT was the first line choice. Overall Response Rate (ORR) and Disease Control Rate (DCR) were 27.9% and 79.3%, respectively. Median PFS ranged between 7.6 and 9.1 months, OS between 14.1 and 18.5 months. The most relevant toxicity was the hematological one (24.1%); severe toxicity (grade 3–4) ranged from 0.9% for skin toxicity up to 8% for hematologic one. This is a large study about mCHT in elderly MBC patients, providing insights to be further investigated in this subgroup of frail patients.

Con il termine Sleep disorder breathing (SDB) sintendono tutte quelle difficoltà respiratorie che si verificano durante il sonno. Si può osservare una grande variabilità nella sintomatologia dei pazienti affetti da SDB, direttamente proporzionale alla resistenza che le vie aeree superiori offrono al passaggio dellaria quando queste sono ostruite. LSDB rappresenta un ampio ventaglio di disturbi che vanno dal russamento primario fino ad arrivare alle apnee ostruttive del sonno. I bambini con problemi respiratori tendono a compensare lostruzione delle vie aeree assumendo posizioni caratteristiche, tali da garantire il mantenimento della pervietà delle vie aeree durante il sonno. Unanomalia di posizione nel sonno, durante la fase di crescita e sviluppo, si ripercuote in unalterazione dello sviluppo occlusale e in una modifica del pattern di crescita. Le principali alterazioni sono a carico del mascellare superiore, dellaltezza facciale, del tono muscolare e della posizione mandibolare; nei bambini con SDB, infatti, è spesso presente un pattern scheletrico di Classe II, con lunghezza mandibolare ridotta ed overbite aumentato. Lo scopo del presente studio è stato quello di valutare i cambiamenti craniofacciali indotti dalla terapia funzionale di avanzamento mandibolare con particolare riferimento alla dimensione sagittale delle vie aeree, superiori ed inferiori, alla posizione dellosso ioide e alla posizione della lingua in soggetti con SDB e malocclusione di Classe II, messi a confronto con un gruppo controllo in Classe II non trattato. 51 soggetti (24 femmine, 27 maschi; età media 9,9 ± 1,3 anni) con malocclusione dentoscheletrica di Classe II e SDB trattati con il dispositivo funzionale Monoblocco Modificato (MM) sono stati messi a confronto con un gruppo controllo non trattato di 31 soggetti (15 maschi, 16 femmine; età media 10,1 ± 1,1 anni) presentanti la stessa malocclusione senza SDB. Il gruppo di studio è stato valutato da uno specialista in otorinolaringoiatria per la definizione del tipo di respirazione ed è stato sottoposto ad un esame fisico completo. I genitori di tutti i pazienti hanno completato un questionario per valutare la presenza di sintomi notturni e diurni prima e dopo il test clinico (versione italiana in 22 punti del Pediatric sleep questionnaire, ideato da Ronald Chervin). Le teleradiografie in proiezione latero laterale sono state analizzate allinizio e alla fine del trattamento con MM. Tutte le misurazioni cefalometriche dei due gruppi sono state analizzate attraverso dei test per la valutazione statistica dei cambiamenti avvenuti durante il trattamento. I risultati hanno evidenziato dei cambiamenti scheletrici favorevoli nel gruppo trattato a tempo T2. La terapia funzionale di avanzamento mandibolare ha indotto dei cambiamenti statisticamente significativi nella dimensione sagittale delle vie aeree, nella posizione dellosso ioide e nella posizione della lingua in soggetti di Classe II affetti da SDB rispetto ai controlli non trattati. Dopo la terapia ortodontica in 45 pazienti del gruppo di studio è stata osservata una riduzione dei sintomi diurni di SDB. Il trattamento con apparecchiature funzionali, non solo migliora i rapporti tra mascellare superiore e mandibola, ma riduce anche il rischio del collasso delle vie aere superiori. La logica terapeutica si basa sul concetto che tutte le anomalie, legate ad un retroposizionamento mandibolare, beneficiano della terapia funzionale di avanzamento mandibolare, che è in grado di ampliare lo spazio posteriormente alla lingua ed allo stesso tempo promuovere lavanzamento linguale. Lo spostamento anteriore della mandibola influenza la posizione dellosso ioide e la posizione della lingua, aumentando lo spazio intermascellare in cui questultima alloggia e migliorando la morfologia delle vie aeree superiori. Ne consegue sia la risoluzione della malocclusione scheletrica di Classe II che il miglioramento dei rapporti retrofaringei, eliminando quei fattori predisponenti per lo sviluppo di disturbi respiratori in età adulta.

The current retrospective controlled trial aimed to compare the dentoskeletal effects of the Bite-Jumping (BJ) and the Twin- Block Appliance (TB) in the treatment of skeletal Class II malocclusion. The sample was screened for eligibility criteria including skeletal and dental Class II malocclusion; Cervical Vertebral Maturation at Stage 3 at treatment start, and Functional orthopedic treatment with either a TB or BJ appliances. Twenty-three patients treated with TB, and twenty-three treated with BJ were included. Cephalometric data were compared with a control group of 15 untreated subjects retrieved from the American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection. Baseline characteristics were similar between groups. A significant increase for the AO-BO dimension, and a significant decrease in the overjet, were registered for both study groups respect to controls. TB was more effective than BJ in increasing the mandibular length (Co-Gn), in reducing the ANB angle and changing the SNB angle. The resulting differences between the two groups could be attributed to the different appliances. In conclusion, both appliances demonstrated a clinical efficacy in treating Class II. TB seems therefore better indicated, respect to BJ, in Class II cases with a predominant component of mandibular hypoplasia. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was to analyze the prevalence of infraocclusion of deciduous molars and the pattern of associations with other dental anomalies. Methods. Digital panoramic radiographs of 5005 subjects were initially randomly selected from the files of the Department of Orthodontics of the University of Rome "Tor Vergata". According to the exclusion criteria, the final sample was composed of 4706 subjects. Each panoramic radiograph was examined to evaluate the presence of infraocclusion and other common dental anomalies. Prevalence and pattern of associations were studied between the anomalies. Results. The prevalence rate of infraocclusion of deciduous molars was 2.8% with a male/female ratio of 1.5:1. The most frequent infraocclusion was mandibular second deciduous molars (48.4%). Considering the magnitude of infraocclusion, 68.4% of the affected molars were classified as mild infraocclusion, 27.1% as moderate and 4.4% as severe. The prevalence of mandibular infraocclusion was higher than maxillary infraocclusion (189:36). Subjects with infraocclusion of deciduous molars exhibited an association with impacted teeth, supernumerary teeth and with displacement of maxillary canine. Conclusion. The findings of our study support infraocclusion of deciduous molars as a factor of a common genetic condition associated with other dental anomalies. [ABSTRACT FROM AUTHOR]

Breast cancer stands as the most frequently diagnosed cancer and the primary cause of cancer-related mortality among women worldwide, including Italy. With the increasing number of survivors, many are enrolled in regular follow-up programs. However, adherence to recommendations from scientific societies (such as ASCO, ESMO, AIOM) for breast cancer follow-up management varies in daily clinical practice across different cancer centers, potentially resulting in unequal management and escalating costs. To address these concerns, the Italian Association of Multidisciplinary Oncology Groups (AIGOM) orchestrated a Consensus on early Breast Cancer follow-up utilizing the Estimate-Talk-Estimate methodology. Following the identification of 18 Items and 38 statements by a select Board, 46 out of 54 (85.1%) experts comprising a multidisciplinary and multiprofessional panel expressed their degree of consensus (Expert Panel). The Expert Panel underscores the potential for the multidisciplinary team to tailor follow-up intensity based on the individual risk of recurrence. In selected cases, the general practitioner may be recommended as the clinical lead for breast cancer follow-up, both after completion of adjuvant treatment and at early initiation of endocrine therapy in low-risk patients. Throughout follow-up, and alongside oncologic surveillance, the expert panel advises osteometabolic, cardiologic, and gynecologic surveillance for the early detection and management of early and late treatment toxicities. Moreover, preserving quality of life is emphasized, with provisions for psycho-oncologic support and encouragement to adopt protective lifestyle behaviors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: None of the authors has any interests to report directly related to this manuscript. Outside the scope of this manuscript: Stefania Gori, Fiorenza De Rose, no conflict of interests to declare. Antonella Ferro, honoraria from Novartis, MDS, Daiichi Sankyo, Astra Zeneca, Ely Lilly, Gentili. Alessandra Fabi grants from Astra Zeneca (steering committee); consulting fees from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; honoraria from Astra Zeneca, Roche, Lilly, Novartis, Gilead, Pfizer, Daiichi Sankyo Exact Sciences; travel grants from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini; advisory board from Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Menarini. Catia Angiolini, Giuseppe Azzarello, Maurizio Cancian, Michela Cinquini, Luca Arecco no conflict of interests to declare. Cynthia Aristei, grants from PRIN 2023, from the Ministry of University and Research. Project title “The microbiome in breast cancer therapy and its potential for pRobIOtics to improve treatment outcome. Acronym: BARRIO”. Daniela Bernardi, Laura Biganzoli, Anna Cariello no conflict of interests to declare. Laura Cortesi, report grants from Astra Zeneca, MSD, Pfizer; consulting fees and honoraria from Astra Zeneca, Gilead, MSD, Roche, Pfizer, Daijchii Sanchio, Novartis; travel grants from Gilead, Pfizer, Daijchi Sanchio; Advisory Board from Astra Zeneca, MSD, Novartis. Elisabetta Cretella no conflict of interests to declare. Carmen Criscitiello, grants from Seagen, Gilead; consulting fees and honoraria from Pfizer, Novartis, Lilly, MSD; Seagen, Daiichi Sankyo, Gilead, AstraZeneca, Roche. Ugo De Giorgi consulting fees from Amgen, Astellas Pharma, Astrazeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck KGaA, MSD, Novartis, Pfizer; travel grants from Pfizer, Ipsen, Astrazeneca. Maria Carmen De Santis, Giuseppe Deledda, Massimo Dessena, Sara Donati, Arianna Dri, Gianluigi Ferretti no conflict of interests to declare. Jennifer Foglietta, honoraria from Novartis; travel grants from Roche, Sophos, Pfizer; Advisory Board from Menarini Stem Line. Davide Franceschini, Pierfrancesco Franco, Alessio Schirone no conflict of interests to declare. Daniele Generali, grants from LILT, University of Trieste, Novartis, Roche; consulting fees from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo; honoraria from Lilly, Novartis, Pfizer, Roche, Accord, Daiichi Dankyo, Astrazeneca, Istituto Gentili; travel grants from Roche, Menarini; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Mednote. Lorenzo Gianni, travel grants from Novartis, Lilly, Pfizer; Advisory Board from Astra Zeneca, Novartis, Seagen. Stefano Giordani, Giovanni Grandi, Maria Cristina Leonardi, Stefano Magno, no conflict of interests to declare. Luca Malorni, consulting fees from Menarini, Pfizer, Lilly, Novartis, Roche; travel grants from Roche, Menarini, Celgene, IT Health Fusion; Advisory Board from Novartis. Carlotta Mantoan no conflict of interests to declare. Federica Martorana honoraria from Lilly, Daychii-Sankyo, Pfizer, Astra-Zeneca, Novartis; travel grants from Gilead, Roche, Pfizer, Lilly; advisory board from Amgen. Icro Meattini consulting fees from Pfizer, Astra Zeneca, Daiichi Sankyo, Novartis, Eli Lilly, Seagen, Gilead, Menarini StemLine. Bruno Meduri, Laura Merlini, Federica Miglietta, Alessandra Modena, Fabrizio Nicolis, Isabella Palumbo, no conflict of interests to declare. Pietro Panizza honoraria and travel grants from Bayer AG. Francesca Angela Rovera, Piermario Salvini, Armando Santoro, Mario Taffurelli, no conflict of interests to declare. Angela Toss consulting fees and grants from Lilly, Pfizer, Novartis, MSD, Astrazeneca, Gilead, Seagen, Daiichi Sankyo; travel grants from Gilead, Daiichi Sankyo, Menarini, Astrazeneca. Paolo Tralongo, Monica Turazza, Matteo Valerio, Matteo Verzè no conflict of interests to declare. Patrizia Vici consulting fees from Lilly, Daiichi-Sankyo, Pfizer, MSD, Novartis; honoraria from EISAI, Daiichi-Sankyo, Lilly, Novartis, Pfizer; travel grants from Roche, Pfizer, Daiichi-Sankyo, Novartis, IPSEN; advisory board from Pfizer, Novartis. Claudio Zamagni no conflict of interests to declare. Giuseppe Curigliano advisory board from Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daichii Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, Menarini. Giovanni Pappagallo no conflict of interests to declare. Alberto Zambelli consulting fees Pfizer, Lilly, Novartis, Roche, AstraZeneca, DaiichiSankyo, Seagen, ExactSciences, MSD, Gentili, Gilead; travel grants from Roche, DaiichiSankyo, AstraZeneca, Novartis; advisory board from Roche., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Although younger age has been negatively associated with persistence to adjuvant endocrine therapy (ET), factors contributing to non-persistence remain poorly understood. We assessed factors associated with non-persistence to ET and described the 5-year trajectories of quality of life (QoL) and symptoms in young women (≤40 years) with hormone receptor-positive breast cancer (BC)., Methods: We retrieved data on clinical characteristics and non-persistence from the medical annual records in the European cohort of the "Helping Ourselves, Helping Others: The Young Women's BC Study" (IBCSG 43-09 HOHO). Women completed surveys at baseline, biannually for three years, and annually for another seven years. Data collection included sociodemographic information, QoL aspects assessed by the Cancer Rehabilitation Evaluation System-Short Form and symptoms assessed by the Breast Cancer Prevention Trial symptom scales. Cox regression models were applied to identify factors associated with non-persistence., Results: The cumulative risk of interrupting ET within 5 years was 27.7 % (95 % CI, 21.5-35.2). The QoL subscale scores remained stable over 5 years, with slight improvements in the physical subscale. Hot flashes decreased (p < 0.001), while vaginal problems intensified (p < 0.001) over time. Being married without children and having difficulties interacting and communicating with the medical team were significantly associated with non-persistence., Conclusions: Discussing the desire to conceive with partnered childless women and establishing a good relationship with the medical team may be important in addressing the non-persistence in young BC survivors. As recent data suggests the safety of pausing ET to conceive, this approach may be a reasonable future option to limit non-persistence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Eraldo Oreste Bucci reports a relationship with AstraZeneca R&D that includes: consulting or advisory and travel reimbursement. Eraldo Oreste Bucci reports a relationship with Astellas Pharma Europe Ltd that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Bristol Myers Squibb Co that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Eli Lilly and Company that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Merck Serono that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Roche that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Takeda Oncology that includes: travel reimbursement. Lorenzo Gianni reports a relationship with AstraZeneca that includes: consulting or advisory. Lorenzo Gianni reports a relationship with Seagen Inc that includes: consulting or advisory. Lorenzo Gianni reports a relationship with Pfizer and Novartis that includes: travel reimbursement. Alberto Farolfi reports a relationship with from Janssen Oncology, GSK-Tesaro, Astrazeneca, Clovis that includes: paid expert testimony. Rossana Berardi reports a relationship with AZ, BI, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, EISAI, Seage that includes: consulting or advisory. Anne Patridge reports a relationship with Wolters Kluwer, Novartis that includes: equity or stocks and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The aim of the present retrospective study was to compare the changes resulting from treatment using the MA and the TB with special regard to the oro-and naso-pharyngeal sagittal airway dimensions in subjects with dentoskeletal Class II malocclusions and positive history of Sleep Disorder Breathing (SDB) diagnosed through the Pediatric Sleep Questionnaire (PSQ)., Materials and Methods: This retrospective study involved 2 groups of subjects: patients treated with Twin Block (TB group: n  = 22, 10 males, 12 females; mean age 12.0 ± 1.3 years) and patients treated with Mandibular Advancement (MA group: n  = 23, 11 males, 12 females; mean age 12.2 ± 1.1 years). Pretreatment (T1) and posttreatment (T2) lateral cephalograms were analyzed. All patients underwent the PSQ to diagnose SDB., Results: In both treated groups there was an increase in the airways dimensions and an improvement in symptoms related SDB. The statistical comparison of the changes between T1 and T2 in the TB group showed a significant increment in upper airway size (PNS-AD2, +1.50 mm + -3.30; McNamara's upper pharynx dimension, +2.21 + -4.21) after active treatment. The MA group showed similar results during active treatment with a significant increase in both upper (PNS-AD2, +2.72 + -2.65; McNamara's upper pharynx dimension, +2.97 + -3.07) and lower (PNS-AD1, +2.17 mm + -3.54) airway size., Conclusions: Despite the different structure of these two devices and the different advancement protocols, both appliances were valuable as a suitable treatment option for Class II patients with respiratory disorders, inducing an increase of upper and lower airway size and a significant reduction in diurnal symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cretella Lombardo, Lugli, Cozza, Lione, Loberto and Pavoni.)

Background: Interproximal enamel reduction (IPR) is a clinical procedure which involves reduction and anatomic recontouring of interproximal surfaces of enamel as a method of gaining space. The biological effects related to this clinical procedure have long been discussed. Thus, the aim of this study was to evaluate the enamel reduction efficiency and the effects on enamel surfaces of the oscillating mechanical system for interproximal enamel reduction (IPR)., Methods: Fifteen complete oscillating IPR sequences included one opener (0.1 mm), two metallic strips for active IPR phase (0.2 and 0.3 mm), three resin strips for active and initial polishing phases (0.4 and 0.5 mm), and one resin strip for polishing phase (0.15 mm). Sequences were selected and tested on fifteen freshly extracted teeth by means of tribological tests with alternative dry-sliding motion (Linear Reciprocating Tribometer; C.S.M. Instruments, Peseaux, Switzerland). A 3D analysis of treated surfaces was performed by using a TayMap software. Then, enamel surfaces were qualitatively evaluated before and after the tribological analysis, with a FEI Quanta 200 (FEI, Hillsboro, OR, USA) in high vacuum at 30.00 kV. Images were acquired at a 30×, 100× and 300× magnification., Results: Minimum surface irregularities were observed on all treated enamel surfaces when compared with untreated ones. The 3D analysis showed a uniform wear pattern after tribological tests. Meanwhile, the SEM analysis revealed smooth and regular wear lines on treated surfaces after the entire mechanical IPR sequence. The macroscopic irregularities illustrated can be considered similar to those of untreated surfaces., Conclusions: The adoption of a standardized oscillating IPR sequence allows an efficient reduction of the interproximal enamel, leaving regular and harmonious surfaces. Adequate polishing procedures should always be performed at the end of active IPR phases in order to guarantee a good long-term prognosis and proper respect of biological structures.

Purpose: Despite extensive research on cancer and work-related outcomes, evidence from longitudinal cohort studies is limited, especially in young women with breast cancer (BC). We aimed to investigate employment trajectories in young BC survivors and to identify potential factors associated with changes in work activity., Methods: The HOHO European prospective multicenter cohort study enrolled 300 young women (≤ 40 years) with newly diagnosed BC. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years to assess, among other variables, employment status, sociodemographic, medical, and treatment data. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Univariable and multivariable multinomial logistic regression analyses identified factors associated with changes in employment status., Results: Among the 245 women included in this analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). At 5 years, women had a 29.4% probability (95% CI: 23.6-35.5) of experiencing any reduction and a 14.9% probability (95% CI: 10.6-19.9) of experiencing any increase in work activities. Being enrolled in Switzerland (vs. Italy) and reporting more trouble in performing daily activities were significantly associated with work reduction., Conclusion: Our results suggest that most young BC survivors remain employed in the long-term., Implications for Cancer Survivors: Regular evaluation of symptoms which may interfere with daily life and identification of financial discomfort is critical in providing timely and individually tailored interventions and in limiting unwanted reductions in work activities., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The aim of the present prospective study was to detect the effects on vertical dentoskeletal dimension produced by molar distalization with Clear Aligners in a group of subjects with Class II malocclusion., Methods: The Clear Aligners Group (CAG) comprised 20 patients (13 females, seven males) with a mean age of 17.2±3.2 years. The same standardized protocol of sequential distalization was applied in all subjects. For each patient lateral cephalograms have been analyzed before treatment (T1) and at the end of the therapy (T2)., Results: At the end of treatment, clear aligners were effective in the correction of Class II dental relationship with the correction of the overjet (-1.3 mm). The treated group showed statistically significant reduction in FMA angle (-1.3°) associated with a counterclockwise rotation of the occlusal plane (POccl^PF -3.1°; SN^POccl -4.2°) and a slight intrusion of maxillary first molars to palatal plane (-0.9 mm). Finally, statistically significant differences were detected in anterior facial height (N-Me) and in the ArGo^GoMe angle (-1.2 mm and -3.4°, respectively)., Conclusions: Upper molar distalization with clear aligners represents a valid alternative to non-extraction treatment of Class II malocclusion, reducing the extrusion of maxillary first molars and improving the control of the occlusal plane and of the vertical dimension.

Background: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab., Methods: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD)., Results: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms., Conclusions: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response., Trial Registration Number: NCT03144947, and EudraCT number: 2016-000435-41., Competing Interests: Competing interests: BP reports research grants from Lilly, Pfizer, Novartis; and personal fees from MSD outside the submitted work. EC reports travel grants from Pfizer and Ipsen outside the submitted work. EB reports research grants from Roche, AstraZeneca; personal fees from MSD, AstraZeneca, BMS, Roche, Novartis, Pfizer, Lilly; and travel grants from Roche and AstraZeneca outside the submitted work. LC reports personal fees from AstraZeneca, Novartis and Lilly outside the submitted work. LG reports personal fees from Daiichi, Seagen; and travel grants from Ipsen, Novartis, Pfizer outside the submitted work. AZ reports personal fees from AstraZeneca, Lilly, Pfizer, Daiichi, MSD, Roche, Seagen, Exact Sciences, Gilead and Istituto Gentili outside the submitted work. FM reports personal fees from Roche, Novartis, AstraZeneca, Daiichi, Seagen, MSD, Lilly, Pfizer, Pierre Fabre; and travel grants from Roche and AstraZeneca outside the submitted work; from May 15th 2023, FM is Roche employee. AM reports research grants from Lilly; personal fees from Seagen, Daiichi, Gilead, Novartis, AstraZeneca; and travel grants from Gilead and Novartis outside the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent., Objective: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography., Design, Setting, and Participants: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023., Intervention: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group)., Main Outcomes and Measures: The primary end point of the study was distant disease-free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations., Results: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor-positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group., Conclusions and Relevance: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan., Trial Registration: ClinicalTrials.gov Identifier: NCT02167490.

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

Importance: In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy., Objective: To compare the efficacy of the oral vinorelbine plus cyclophosphamide plus capecitabine (VEX) regimen vs weekly IV paclitaxel among patients with ER+/ERBB2- MBC who are candidates for chemotherapy., Design, Setting, and Participants: This phase 2 randomized clinical trial including 140 women 18 years and older (randomized 1:1) with ER+/ERBB2- MBC was carried out from September 13, 2017, to January 14, 2021 at 15 centers in Italy. Eligible patients could have received 1 prior line of chemotherapy for MBC and/or 2 lines of endocrine therapy (including CDK4/6 inhibitors)., Interventions: In 4-week cycles, patients received either metronomic oral VEX or weekly IV paclitaxel., Main Outcomes and Measures: The primary end point was investigator-assessed time to treatment failure (TTF) defined as the interval between the date of randomization to the end of treatment (because of disease progression or lack of tolerability or because further trial treatment was declined). Secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (complete or partial response or stable disease lasting for at least 24 weeks)., Results: In total, 133 patients received either VEX (n = 70) or paclitaxel (n = 63) in 4-weekly cycles. The median age was 61 (range, 30-80) years. The VEX treatment significantly prolonged TTF vs paclitaxel (hazard ratio [HR], 0.61; 95% CI, 0.42-0.88; P = .008), median TTF was 8.3 (95% CI, 5.6-11.1) months for VEX vs 5.7 (95% CI, 4.1-6.1) months for paclitaxel, and the 12-month TTF was 34.3% for VEX vs 8.6% for paclitaxel. The median PFS was 11.1 (95% CI, 8.3-13.8) months vs 6.9 (95% CI, 5.4-10.1) months favoring VEX (HR, 0.67; 95% CI, 0.46-0.96, P = .03). The 12-month PFS was 43.5% for VEX vs 21.9% for paclitaxel. No difference in OS was found. The TF event for 55.6% of patients was progression of disease; for 23% it was AEs. More patients assigned to VEX had at least 1 grade 3 or 4 targeted adverse event (VEX, 42.9%; 95% CI, 31.1%-55.3% vs paclitaxel, 28.6%; 95% CI, 17.9%-41.3%), but essentially no alopecia., Conclusion and Relevance: This randomized clinical trial found significantly prolonged TTF and PFS for oral VEX but no improvement in OS compared with intravenous paclitaxel, despite increased but still manageable toxic effects. The VEX regimen may provide more prolonged disease control than weekly paclitaxel for ER+/ERBB2- MBC., Trial Registration: ClinicalTrials.gov Identifier: NCT02954055.

Purpose: Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients., Methods: We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities., Results: From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts., Conclusion: Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fabbri, Nelli, Botticelli, Giannarelli, Marrucci, Fiore, Virtuoso, Scagnoli, Pisegna, Alesini, Sini, Orlandi, Fabi, Piacentini, Moscetti, D’Auria, Gamucci, Mazzotta, Pizzuti, Vici, Cretella, Scavina, La Cesa, Persano, Atzori and Ruggeri.)

Background: One goal of orthodontic treatment in mixed dentition is to expand the maxillary arch to allow proper tooth alignment and a correction of sagittal and vertical malocclusions. However, for most treatment protocols, expected outcome is not really clear to allow for a standardization of phase I orthodontic treatments. This lack of information makes it difficult for clinicians to predict tooth movements, including transverse expansion efficacy with Invisalign® (Align Technology, Santa Clara, CA, USA) in children. Therefore, the aim of the present study was to evaluate the transverse maxillary arch development with the Invisalign First System® in growing subjects., Methods: The study group included 23 subjects (9 females, 14 males, mean age 9.4 ± 1.2 years). Patients were treated nonextraction with Invisalign First System® clear aligners with no auxiliaries other than Invisalign® attachments. Transverse interdental widths were measured only in the upper arch on each model at the start (T1) and at the end (T2) of treatment. A paired t‑test was chosen to compare T2-T1 changes. The level of significance was set at 5%., Results: The greatest increase of maxillary width was detected at the level of the upper first deciduous molars (+3.7 ± 1.4 mm; P < 0.001), followed by the level of the second deciduous molars (+3.4 ± 1.6 mm; P < 0.001) and by the deciduous canine (+2.6 ± 2.0 mm; P < 0.001). Upper first molars showed a greater expansion in the intermolar mesial width (+3.2 ± 1.2 mm; P < 0.001) than in the intermolar distal (+1.7 ± 1.2 mm; P < 0.001) and transpalatal width (+1.2 ± 1.2 mm; P < 0.01)., Conclusions: The Invisalign First System® can be considered effective in growing patients who require maxillary arch development. The greatest net increase was detected at the level of upper first deciduous molars, whereas the upper first molars showed a greater expansion in the intermolar mesial width due to a rotation that occurs around its palatal root., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses on prolonging patients' (pts) overall survival (OS) and improving their quality of life. Eribulin is a microtubule inhibitor that increases OS in pre-treated MBC pts. The most common adverse events (AEs) are asthenia, neutropenia and peripheral neuropathy (PN)., Methods: PAINTER is a single arm, phase IV study, aimed at evaluating the tolerability of eribulin in MBC pts. Secondary objectives were the description of treatment efficacy and safety, the assessment of the incidence and severity of PN and its association with genetic polymorphisms. Genomic DNA was isolated from blood samples and 15 Single Nucleotide Polymorphisms (SNPs) were genotyped by Taqman specific assays. The association between PN and SNPs were evaluated by Fisher exact test., Results: Starting from May 2014 until June 2018 180 pts were enrolled in this study by 20 Italian centers. 170 of these pts could be evaluated for efficacy and toxicity and 159 for polymorphisms analysis. The median age of pts was 60 years old and the biological subtypes were luminal type (64.7%), Her2 positive (18.3%) and triple negative (17%). Pts were pretreated with a median of 5 lines for MBC. The median follow up of this study was 15.4 months with a median number of 4.5 cycles administered (minimum-maximum 1-23). The median overall survival was 12 months. 48.8% of pts experienced a dose reduction, mainly for neutropenia (23.9%) and liver toxicity (12%). 65 pts (38.2%) reported at least one severe toxicity. Neutropenia and neurotoxicity were the most frequent severe AEs (15.3% and 14.7%, respectively); other reported toxicities were osteo-muscular, abdominal or tumor site pain (19.4%), liver toxicity (6.6%), pulmonary toxicity (6.5%) and dermatological toxicity (3.6%). Among the 15 evaluated SNPs, an association with PN was found for rs2233335 and rs7214723., Conclusions: Eribulin is a well-tolerated treatment option in MBC. Schedule and dosage modifications were common, but toxicity rarely led to treatment discontinuation. SNPs rs2233335 (G/T and T/T) in the NDRG1 gene and rs7214723 (CC and CT) in the CAMKK1 gene were associated with PN. These findings, if validated, could allow a tailored treatment with eribulin in cancer patients., Trial Registration: ClinicalTrials.gov ID: NCT02864030., (© 2022. The Author(s).)

The aim of the study was to assess modifications of gingival morphology at the end of Phase I treatment with Invisalign First. Eighteen subjects (ten females, eight males, mean age nine years) treated with Invisalign First were selected. The following parameters were measured on intraoral photographs before treatment (T0) and after the first set of aligners (T1) at level of permanent incisors, deciduous canines and molars: gingival margin height (GMH) and deciduous canine inclination (DCI). A paired t-test was used to evaluate T1-T0 changes. The level of significance was established at 5%. Deciduous canines' GMH showed a major reduction between T1 and T0 accounting for 0.87 mm and 0.86 mm, respectively on the right and left sides. DCI increased for all patients in the interval T0-T1 on both sides, +7.11° on the right and +7.5° on the left. Tooth movement during Invisalign First induced significant modifications of gingival contour resulting in a more harmonious smile.

Background: The objective of this retrospective study was to analyze the morphological changes of the upper arch after two protocols of expansion, the Invisalign® First system and rapid maxillary expansion (RME), in mixed dentition by means of geometric morphometric analysis (GMM). Methods: Digital dental casts of 32 children treated either with RME (RME group: 17 subjects; mean age 8.1 years) or the First system (First group: subjects; mean age 8.4 years) were collected. For both the RG and FG, pre-(T1) and post-treatment(T2) digital models were created. A total of 14 landmarks were digitized and GMM was applied. Procrustes analysis and principal component analysis (PCA) were performed. Results: The PC1 resulting from the T2-T1 comparison in the RG g showed statistically significant morphological changes in the posterior region of the upper arch shape, without significant variations in the anterior region. The comparison of the T2-T1 changes in the FG showed an increase in the transverse dimension at the level of the canine and the first deciduous molar widths, with morphological variation in the anterior region due to frontal teeth alignment. Conclusions: The First system induced shape modifications of the upper arch during expansion in contrast to RME. The FG presented an improvement in the maxillary arch shape, while the RG maintained the initial triangular shape.

KAT Gcn5 and DUB Ubp8 are required for respiration and mitochondria functions in budding yeast, and in this study we show that loss of respiratory activity is acquired over time. Interestingly, we show that absence of Ubp8 allows cells to grow in hypoxic conditions with altered mitophagy. Comparatively, the aggressive glioblastoma (GBM) multiforme tumor shows survival mechanisms able to overcome hypoxia in the brain. Starting from yeast and our findings on the role of Ubp8 in hypoxia, we extended our analysis to the human ortholog and signature cancer gene Usp22 in glioblastoma tumor specimens. Here we demonstrate that Usp22 is localized and overexpressed in the pseudo-palisade tissue around the necrotic area of the tumor. In addition, Usp22 colocalizes with the mitophagy marker Parkin, indicating a link with mitochondria function in GBM. Collectively, this evidence suggests that altered expression of Usp22 might provide a way for tumor cells to survive in hypoxic conditions, allowing the escape of cells from the necrotic area toward vascularized tissues. Collectively, our experimental data suggest a model for a possible mechanism of uncontrolled proliferation and invasion in glioblastoma.

Purpose: Triple-negative breast cancer (TNBC) represents a subtype of breast cancer which lacks the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2): TNBC accounts for approximately 20% of newly diagnosed breast cancers and is associated with younger age at diagnosis, greater recurrence risk and shorter survival time. Therapeutic options are very scarce. Aim of the present analysis is to provide further insights into the clinical activity of metronomic chemotherapy (mCHT), in a real-life setting., Methods: We used data included in the VICTOR-6 study for the present analysis. VICTOR-6 is an Italian multicentre retrospective cohort study, which collected data of metastatic breast cancer (MBC) patients who have received mCHT between 2011 and 2016. Amongst the 584 patients included in the study, 97 were triple negative. In 40.2% of the TNBC patients, mCHT was the first chemotherapy treatment, whereas 32.9% had received 2 or more lines of treatment for the metastatic disease. 45.4% out of 97 TNBC patients received a vinorelbine (VRL)-based regimen, which resulted in the most used type of mCHT, followed by cyclophosphamide (CTX)-based regimens (30.9%) and capecitabine (CAPE)-based combinations (22.7%)., Results: Overall response rate (ORR) and disease control rate (DCR) were 17.5% and 64.9%, respectively. Median progression free survival (PFS) and overall survival (OS) were 6.0 months (95% CI: 4.9-7.2) and 12.1 months (95% CI: 9.6-16.7). Median PFS was 6.9 months for CAPE-based regimens (95% CI: 5.0-18.4), 6.1 months (95% CI: 4.0-8.9) for CTX-based and 5.3 months (95% CI: 4.1-9.5) for VRL-based ones. Median OS was 18.2 months (95% CI: 9.1-NE) for CAPE-based regimens and 11.8 months for VRL- (95% CI: 9.3-16.7 and CTX-based ones (95%CI: 8.7-52.8). Tumour response, PFS and OS decreased proportionally in later lines., Conclusion: This analysis represents the largest series of TNBC patients treated with mCHT in a real-life setting and provides further insights into the advantages of using this strategy even in this poor prognosis subpopulation., (© 2021. The Author(s).)

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen-adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N-desmethyl-tamoxifen (ND-TAM), Z-4OH-tamoxifen (4OH-TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log-transformed ENDOss (log-ENDOss). Genotype-derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log-ENDOss. Genotype-phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R 2  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss., (© 2020 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Protein ubiquitylation regulates not only endocellular trafficking and proteasomal degradation but also the catalytic activity of enzymes. In Saccharomyces cerevisiae , we analyzed the composition of the ubiquitylated proteomes in strains lacking acetyltransferase Gcn5p, Ub-protease Ubp8p, or both to understand their involvement in the regulation of protein ubiquitylation. We analyzed His6Ub proteins with a proteomic approach coupling micro-liquid chromatography and tandem mass spectrometry (μLC-MS/MS) in gcn5 Δ, ubp8 Δ and ubp8 Δ gcn5 Δ strains. The Ub-proteome altered in the absence of Gcn5p, Ubp8p, or both was characterized, showing that 43% of the proteins was shared in all strains, suggesting their functional relationship. Remarkably, all major glycolytic enzymes showed increased ubiquitylation. Phosphofructokinase 1, the key enzyme of glycolytic flux, showed a higher and altered pattern of ubiquitylation in gcn5 Δ and ubp8 Δ strains. Severe defects of growth in poor sugar and altered glucose consumption confirmed a direct role of Gcn5p and Ubp8p in affecting the REDOX balance of the cell. IMPORTANCE We propose a study showing a novel role of Gcn5p and Ubp8p in the process of ubiquitylation of the yeast proteome which includes main glycolytic enzymes. Interestingly, in the absence of Gcn5p and Ubp8p glucose consumption and redox balance were altered in yeast. We believe that these results and the role of Gcn5p and Ubp8p in sugar metabolism might open new perspectives of research leading to novel protocols for counteracting the enhanced glycolysis in tumors., (Copyright © 2020 De Palma et al.)

(1) Background: The nature of the changes that contribute to Class II correction with functional appliances is still controversial. A broad variation in treatment responses has been reported. The purpose of this study was to find cephalometric predictors for individual patient responsiveness to twin-block treatment in patients with Class II Division 1 malocclusion; (2) Methods: The study was performed on a sample of 39 pubertal patients (21 females, 18 males) treated with the twin block appliance. Lateral cephalograms were available at the start of the treatment (T1) and at the end of functional therapy (T2). The outcome variable was the T2-T1 change in the sagittal position of the soft tissue pogonion with respect to the vertical line perpendicular to the Frankfort plane and passing through point subnasale. The predictive variables were age, gender at T1, and all the cephalometric parameters measured T1. Forward stepwise linear regression with p value to enter 0.05 and p value to leave 0.10 was applied; (3) Results: The only significant predictive variable that was selected was the Co-Go-Me angle ( p = 0.000); (4) Conclusions: A greater advancement of the soft tissue chin on the profile is expected with smaller pretreatment values of Co-Go-Me angle.

Objective: The aim of this investigation was to analyze the effects of RME and FM on the airway dimensions in Class III patients compared with untreated controls., Methods: A sample of 47 Class III patients treated with RME and FM was analyzed. The treated group was compared with 18 untreated controls. Lateral cephalograms for each patient at T1, T2, and T3 were digitized., Results: At long-term evaluation a significant increase in airway size and a significant decrease in adenoid size were found in the treated group as well as an improvement in the pharynx dimension. During active treatment the treated group showed a significant improvement in lower airway size and in lower pharynx dimension. A significant decrease in adenoid size was also found., Conclusion: The treatment with RME and FM produced favorable stable changes in the airway dimensions in Class III subjects when compared with untreated controls., Competing Interests: Declaration of competing interest The authors have no competing interests., (Copyright © 2019. Published by Elsevier B.V.)

Aims and Objectives: To assess the effectiveness of a specific home care nursing programme in addition to standard care in patients (pts) receiving oral anticancer treatments., Background: Oral anticancer therapy present challenges for pts since treatment is a home-based therapy. This study evaluates the potentiality of a home care nursing programme in decreasing hospital accesses for not severe toxicity., Methods: This is an open-label, multicentre, randomised trial including pts who were receiving an anticancer oral drug. The study complies with the CONSORT checklist published in 2010. Concomitant use of radiation therapy, intravenous or metronomic therapies, or the intake of previous oral drugs was not allowed. Pts were randomly assigned to home care nursing programme (A) or standard care (B). In arm A, dedicated nurses provided information to pts, a daily record on which pts would take note of drugs and dosages and a telephone monitoring during the first two cycles of therapy. The primary outcome was the reduction in improper hospital accesses for grade 1-2 toxicity according to CTCAE v4.0., Results: Out of 432 randomised pts, 378 were analysed (184 pts in arm A and 194 in arm B). Hospital accesses were observed in 41 pts in arm A and in 42 pts in arm B (22.3% vs. 21.6%, respectively). No difference was detected in proportion of improper accesses between arm A and arm B (29.3% vs. 23.8%, respectively)., Conclusions: Our experience failed to support the role of a specific home care nursing programme for pts taking oral chemotherapy. An improved attention to specific educational practice and information offered to pts can explain these results., Relevance to Clinical Practice: Our results underline the role of nurse educational practice and information offered to patients. A careful nurse information of patients about drugs is essential to reduce toxicities avoiding the opportunity of a specific home monitoring., (© 2019 John Wiley & Sons Ltd.)

Background: There is no sufficient evidence to establish a standard of care for patients with brain metastases (BM) from HER2 + breast cancer (BC). The aim of this study was to assess the impact of local and systemic treatments on the outcome of patients diagnosed with BM from HER2 + BC over a period of 10 years, from 2005 to 2014., Patients and Methods: Data of 154 patients were retrospectively collected at 14 Italian institutions through a specifically designed database., Results: Median overall survival (OS) was 24.5 months. Patients receiving surgery/stereotactic radiosurgery experienced longer OS compared to those receiving whole-brain radiotherapy or no treatment (33.5 vs. 11.4 months; hazard ratio = 0.34; 95% confidence interval, 0.22-0.52; P < .001). Interestingly, whole-brain radiotherapy did not improve OS compared to no treatment (11.4 vs. 9.8 months; hazard ratio = 0.99; 95% confidence interval, 0.62-1.62; P = .99). HER2-targeted therapy was associated with better OS compared to systemic therapy without HER2-targeted therapy or no systemic therapy (27.5 vs. 5.4 months; hazard ratio = 0.26; 95% confidence interval, 0.17-0.41; P < .001). At multivariate analysis stratified by local treatments, systemic therapy, Karnofsky performance status, and neurologic symptoms significantly affected OS. Age, number of BM, steroid therapy, number of previous lines of systemic therapy, status of extracranial disease, and period of diagnosis had no significant impact on OS., Conclusion: Patients with BM from HER2 + BC treated with surgery/stereotactic radiosurgery as local treatment and HER2-targeted therapy as systemic treatment experienced the best outcomes. Patients with low Karnofsky performance status and neurologic symptoms had poor survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival., Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility., Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively., Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the relationship between the severity degree of OSA (apnea/hypopnea index AHI>1) and palatal area and volume, measured by 3D analysis of digital casts in Marfan children., Methods: Twenty children with a clinical diagnosis of MS were recruited from a tertiary medical center. All the subjects underwent standard nocturnal polygraphy testing. Sixteen Marfan patients (7F,9 M; mean age 8.8yy ± 1.5yy) with AHI>1 were enrolled. Marfan Group (MG) was compared with a control group (CG) of 17 children without Marfan syndrome (9F,8 M; mean age 8.5yy ± 1.7yy) presenting with nose-breathing pattern. For each subject maxillary digital casts were taken and palatal area and volume were measured. Unpaired t-test was used to test significant differences between MG and CG for area and volume measurements. Pearson correlation coefficient (PCC) was used to measure the linear correlation between the degree of OSA (AHI index) and palatal volume and palatal area., Results: 80% of Marfan children presented an AHI>1 and a diagnosis of OSA. MG presented statistically significant lower values of palatal surface area (662.68 mm 2 ; P < 0.0001) and palatal volume (2578.1 mm 3 ; P < 0.0001) with respect to CG (923.0 mm 2 and 3756.6 mm 3 , respectively). Correlation analysis showed that AHI index had no linear correlation with palatal area (r = - 0,07) and with palatal volume (r = - 0,11)., Conclusion: OSA is highly prevalent in children with Marfan's syndrome (80%). Marfan children present a reduction of palatal area and volume when compared to healthy subjects. OSA in Marfan children is not linear correlated to the palatal morphology and it shows a multifactorial aetiology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To evaluate the craniofacial changes induced by functional appliances with special regard to the oro and nasopharyngeal sagittal airway dimensions in subjects with dentoskeletal Class II malocclusions when compared with an untreated Class II control group immediately after therapy and at long-term observation., Methods: A group of 40 patients (21 females and 19 males) with Class II malocclusion treated consecutively either with a Bionator or an Activator followed by fixed appliances was compared with a matched control group of 31 subjects (16 females and 15 males) with untreated Class II malocclusion. The treated sample was evaluated at T1, start of treatment (mean age: 9.9 ± 1.4 years); T2, end of functional treatment and prior to fixed appliances (mean age: 11.9 ± 1.3 years); and T3, long-term observation at the end of growth (mean age: 18.2 ± 2.1 years). Statistical comparisons were performed with independent sample t tests at T1 (baseline characteristics) and for the T1-T2, T2-T3, and T1-T3 changes., Results: During active treatment the treated group showed a significant increment in lower airway dimension (PNS-AD1), as well as a significant improvement in the upper airway dimension (PNS-AD2). A significant decrease in the upper adenoid size (AD2-H) was also found. In the longterm evaluation, a significant increase in both lower and upper airway thickness (PNS-AD1; PNS-AD2) and a significant decrease in the upper adenoid thickness were still present in the treated group., Conclusion: The treatment with functional appliances produced significant favorable changes during active treatment in the oro- and nasopharyngeal sagittal airway dimensions in dentoskeletal Class II subjects when compared with untreated controls, and these changes were stable in the long-term., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The management of pT1a-b pN0 HER2-positive breast cancer is controversial and no data about the efficacy of trastuzumab in this setting are available from randomized clinical trials. The aims of this retrospective study were to assess how patients are managed in clinical practice in Italy, which clinical or biological characteristics influenced the choice of adjuvant systemic therapy and the outcome of patients., Methods: Data of consecutive patients who underwent surgery from January 2007 to December 2012 for HER2-positive, pT1a-b pN0 M0 breast cancer were retrospectively collected from 28 Italian centres. Analysis of contingency tables and multivariate generalized logit models were used to investigate the association between the baseline clinical and biological features and the treatment strategy adopted., Results: Among 303 enrolled patients, 204 received adjuvant systemic therapy with trastuzumab, 65 adjuvant systemic therapy without trastuzumab and 34 did not receive adjuvant systemic therapy. At the multivariate analysis age, tumor size, proliferation index and hormone receptor status were significantly associated with the treatment choice. Five-year disease-free survival (DFS) probability was 95%, 94.3% and 69.6% for patients treated with adjuvant systemic therapy and trastuzumab, with adjuvant systemic therapy without trastuzumab and for patients who did not receive adjuvant systemic therapy, respectively (p<0.001)., Conclusions: The majority of patients (66%) with pT1a-b pN0 HER2-positive breast cancer enrolled in this retrospective study received adjuvant systemic therapy with trastuzumab, whereas only 11% patients did not receive any adjuvant systemic therapy. It should be emphasized, however, that in the adjuvant systemic therapy without trastuzumab group 94% of tumors were hormone receptor positive and 89% of patients were treated with endocrine therapy only [corrected]. The 5-year DFS probability was significantly higher for patients receiving adjuvant systemic therapy with trastuzumab compared with patients not receiving adjuvant systemic therapy or receiving adjuvant systemic therapy without trastuzumab.

Aim: This observational study investigates the use of adjuvant trastuzumab (AT) in HER2-positive breast cancer patients in a real-life setting, focusing on relapse and discontinuation rates., Patients & Methods: Data on a group of HER2-positive patients collected from 13 oncology centers of northeast Italy were analyzed., Results: In total, 1245 patients were analyzed. 13.1% of patients were excluded from AT because of comorbidities, age, tumor stage, refusal or other reasons; 8.2% of patients who received AT interrupted the therapy, mainly for toxicity. Overall the relapse rate was 10.9% in the AT-treated population versus 22.6% in nontreated patients (follow-up: 37.4 and 62.1 months, respectively). Disease-free survival (DFS) was lower in AT-relapsed patients than in not-relapsed. Statistical analysis showed a correlation between DFS and estrogen receptor status in AT-treated patients., Conclusion: Relapse rates are lower in clinical setting compared to clinical trials. Overall, AT is effective in HER2-positive early-stage breast cancer patients.

Aim: This observational study evaluated the behavior and outcome of cutaneous breast cancer metastasis treated with eribulin., Patients & Methods: From November 2012 to January 2013, oncologists completed a database with patient, tumor and treatment characteristics from 14 Italian cancer centers. Skin lesions were assessed by Response Evaluation Criteria In Solid Tumors and cutaneous symptoms by present/absent criteria., Results: A total of 23 metastatic breast cancer patients with skin metastasis who were treated with eribulin were analyzed. After treatment, 43% of patients exhibited a partial response, 35% stable disease and 22% progressive disease. Regarding only the skin response, 26% obtained a complete response, 22% a partial response, 39% stable disease and 13% progressive disease. We found an improvement in symptoms, infiltration and ulceration. With a median follow-up of 6 months, median progression-free survival was 4.3 months and median overall survival was 9.1 months., Conclusion: The response rate of skin metastasis to eribulin treatment was coherent with systemic responses. The good clinical response in most patients reflected symptom improvement.

As mice carrying mutations of the DNA mismatch repair genes MSH2 and MSH6 often develop lymphoid neoplasms, we addressed the prevalence of the replication error (RER(+)) phenotype, a manifestation of an underlying defect of DNA mismatch repair genes, in human lymphoid tumors. We compared microsatellite instability (MSI) at 10 loci in 37 lymphoid tumors, including 16 acute lymphoid leukemias (ALL) and 21 non-Hodgkin's lymphomas (NHL), and in 29 acute myeloid leukemias (AML). Significant differences in MSI prevalence between AMLs and ALLs emerged, and MSI occurrence was more frequent in the NHLs versus AMLs. Indeed, only 3 of 29 (10%) AMLs exhibited MSI, thus confirming its paucity in myeloid tumors, while 10 of 37 (27%) lymphoid tumors, 6 ALLs and 4 NHLs, disclosed an RER(+) phenotype. In 1 ALL patient, the same molecular alterations were observed in correspondence with a relapse, but were not detected during remission over a 14-month follow-up; in another ALL patient, findings correlated with impending clinical relapse. These results suggest that the study of MSI in lymphoid tumors might provide a useful molecular tool to monitor disease progression in a subset of ALLs. To correlate MSI with other known genetic abnormalities, we investigated the status of the proto-oncogene, bcl-2, in the lymphoma patients and found that 4 of 4 NHL patients with MSI carried bcl-2 rearrangements, thus linking genomic instability to enhanced cell survival in NHL; moreover, no p53 mutations were found in these patients. Finally, we addressed the putative cause of MSI in hematopoietic tumors by searching for both mutations and deletions affecting DNA repair genes. A limited genetic analysis did not show any tumor-specific mutation in MLH1 exons 9 and 16 and in MSH2 exons 5 and 13. However, loss of heterozygosity (LOH) of markers closely linked to mismatch repair genes MLH1, MSH2, and PMS2 was demonstrated in 4 of 6 ALLs and 1 of 3 AMLs with MSI. These observations indicate that chromosomal deletions might represent a mechanism of inactivation of DNA repair genes in acute leukemia.