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OBJECTIVE: Approximately 50% of cancer patients develop bone metastases in their natural disease history. The management of metastatic bone disease requires a multidisciplinary approach. Both radiofrequency ablation (RFA) and radiation therapy (RT) were safe and effective in the management of painful metastases, even if they rely on totally different action mechanisms. A synergistic combination of RT and RFA seems to result in a better pain control. A systematic review was performed to describe the feasibility and effectiveness of the association between RFA and RT in the treatment of metastatic bone pain in oligo-metastatic patients, evaluating its role in alleviating bone pain, reducing the risk of fractures, and consequently ensuring a better quality of life. MATERIALS AND METHODS: A systematic database search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This systematic review included studies that reported populations meeting the following inclusion criteria: (I) confirmed bone metastases in adult patients; (II) active bone metastases pain; (III) patients treated with combined RFA-RT; (IV) Original studies. RESULTS: Three papers that evaluated the combined treatment with doses ranging from moderately hypofractionated three-dimensional conformal RT (3D-CRT) and stereotactic body radiation therapy (SBRT) schedules were selected. CONCLUSIONS: The RFA-RT combined strategy appears to be promising in terms of efficiency and safety with adequate pain control and quality of life improvement. Positive effects on time to local failure and overall survival increase were also observed. Further prospective studies are needed to better delineate RFA-RT treatment benefits. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Paget disease of the breast (PDB) is a rare form of cutaneous breast cancer. Up to date, no randomized studies evaluated the different management strategies. This systematic review investigates the role of radiotherapy and its best technical profile in the treatment of this disease, with great attention to doses and fractionation regimens. MATERIALS AND METHODS: A systematic search was performed on PubMed, Embase and Scopus in order to detect case reports, case series and prospective as well as retrospective clinical studies describing histologically proven PDB and providing information about pertinent radiation treatments. Searching strategy followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. RESULTS: Inclusion criteria were met by six papers, dealing with radiation treatments performed postoperatively and in exclusive settings. No evaluations were performed on preoperative radiotherapy. CONCLUSIONS: Actually, the standard treatment of PDB reflects oncological principles of breast carcinoma therapy, including the role of breast-preserving surgery. The traditional radiotherapic dose is 50 Gy, with daily fractionation of 2 Gy. Adjuvant radiotherapy following breast preserving surgery represents the current standard of care; prospective studies could be of help in defining the role of exclusive radiotherapy, hypofractionated schemes and smaller target volumes. [ABSTRACT FROM AUTHOR]

Idiopathic stabbing headache is a not well known type of pain, and few reports have described the disorder in juvenile age. We report a sample of 30 juvenile patients with clinical features of stabbing headache after having excluded other pain disorders. We observed the presence of psychological features and the lack of association with migraine, unlike in the adult form. Some patients needed pharmacological treatment but the prognosis was good. Further studies are needed to better understand the mechanisms of pain and possible triggering factors. [ABSTRACT FROM AUTHOR]

An increasingly important role for gut microbiota in the initiation and progression of colorectal cancer (CRC) has been described. Even in the early stages of transformation, i.e., colorectal adenomas, changes in gut microbiota composition have been observed, and several bacterial species, such as pks + Escherichia coli and enterotoxigenic Bacteroides fragilis , have been proposed to drive colon tumorigenesis. In recent years, several strategies have been developed to study mucosa-associated microbiota (MAM), which is more closely associated with CRC development than lumen-associated microbiota (LAM) derived from fecal samples. This review summarizes the state of the art about the oncogenic actions of gut bacteria and compares the different sampling strategies to collect intestinal microbiota (feces, biopsies, swabs, brushes, and washing aspirates). In particular, this article recapitulates the current knowledge on MAM in colorectal adenomas and serrated polyps, since studying the intestinal microbiota associated with early-stage tumors can elucidate the molecular mechanisms underpinning CRC carcinogenesis.

Colorectal cancer (CRC) ranks among the most prevalent malignant tumors worldwide, with a multifactorial etiology encompassing genetic, environmental, and life-style factors, as well as the intestinal microbiota and its metabolome. These risk factors often work together in specific groups of patients, influencing how CRC develops and progresses. Importantly, alterations in the gut microbiota act as a critical nexus in this interplay, significantly affecting susceptibility to CRC. This review highlights recent insights into unmodifiable and modifiable risk factors for CRC and how they might interact with the gut microbiota and its metabolome. Understanding the mechanisms of these interactions will help us develop targeted, precision-medicine strategies that can adjust the composition of the gut microbiota to meet individual health needs, preventing or treating CRC more effectively., (© 2024. The Author(s).)

Background: This multicentric, retrospective study investigated the use of stereotactic body radiotherapy (SBRT) in patients (pts) with metastatic renal cell carcinoma (mRCC) who experienced oligoprogression during a combination therapy with an immune checkpoint inhibitor (ICI) and a tyrosine-kinase inhibitor (TKI)., Methods: We retrospectively evaluated 34 pts affected by oligoprogressive RCC treated with an ICI-TKI combination between January 2020 and December 2023. SBRT was delivered to each site of oligoprogressive metastatic disease. After SBRT, pts were given follow-up clinical evaluations. 6-12-18-month local control (LC) rates and median next-line treatment-free survival (NEST-FS) were the primary endpoints. The secondary endpoints were overall response rate (ORR), clinical benefits and safety., Results: After a median follow-up of 24 months, 6-12-18-month LC rates were 100%, 71% and 43%, respectively, and the median NEST-FS was 20 months. ORR was 90%, while clinical benefit was 100%. No > G2 adverse events related to SBRT were recorded., Conclusions: In our study, SBRT for oligoprogressive mRCC turned out to be a safe and useful treatment which was able to preserve current treatment. Further prospective studies are necessary to explore the effects of the ICIs-TKIs combination and SBRT upon oligoprogressive sites in mRCC.

Aims: SCLC is the most aggressive lung cancer histology with a 5-year OS <10%. At the diagnosis, almost two-thirds of the SCLC an Extended Disease presentation. Two randomized studies (CASPIAN and ImPower133) demonstrated an OS improvement, when immunotherapy was prescribed as maintenance therapy after standard chemotherapy. To date, SABR has had a limited indication in managing metastatic SCLC, although recent reports proposed it as a valid treatment option in selected patients. We propose a retrospective multicentric analysis of patients treated with SABR for oligometastatic SCLC., Method: Data of patients affected by oligometastatic-SCLC treated with SABR between 2017 and 2022 in 11 Italian centers were collected. Clinical and therapeutic variables together with OS and time to next treatment were analyzed. Univariate analysis with Kaplan-Meier curve were calculated, and log-rank test were applied. Cox proportional hazard model was used for multivariate analysis., Results: Data from 93 patients and 132 metastatic lesions were analyzed. The median age was 64 years (36-86) and all but 1 had Performance Status 0 or 1. Fifty-two patients presented ED at diagnosis. The first line treatment was radiochemotherapy in 42%, CHT alone in 24% and CHT-IO in 28%, others treatment accounts for 4% and only 2% of patients underwent best supportive care. Of the 132 lesions treated with SBRT 55 were in brain, 27 in lung, 11 in liver, 10 in lymph nodes, 8 in bones and 20 in adrenal gland. Median OS was 14 months, 1 year-OS and 2 years OS were 53% and 27%, respectively. The median TtNT was 14 months for the entire population. Of all the analyzed variables only, the anatomical site of the metastases and their number showed statistical significance in the univariate analysist, confirmed in the subsequent multivariate., Conclusion: SABR seems to play a role in delaying further systemic lines in oligometastatic disease and to extend the use of ongoing treatment in oligoprogressive state. Prospective studies are needed to confirm these findings., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: This monocentric, single-arm, retrospective study investigated the role of stereotactic body radiotherapy in patients with metastatic castration resistant prostate cancer who experienced oligoprogression during androgen receptor targeted agents., Methods: We retrospectively enrolled metastatic castration resistant prostate cancer patients treated with androgen receptor targeted agents between December 2016 and January 2022. All patients experienced an oligoprogression (defined as the appearance and/or the progression of ⩽5 bone or nodal or soft tissue metastases) during treatment with androgen receptor targeted agents and received stereotactic body radiotherapy upon oligoprogressive sites, preserving the androgen receptor targeted agents. Further stereotactic body radiotherapy upon new metastatic sites was permitted. Patients showing visceral metastases or receiving palliative radiotherapy were excluded. Progressive disease at >5 metastatic sites or the appearance of visceral metastases led to a change of the systemic treatment. Primary endpoints were 36-month survival rate and 36-month rate of patients receiving treatment with androgen receptor targeted agents. Secondary endpoints were local disease control, biochemical response and safety., Results: We analyzed data from 30 patients. The 36-month survival rate was 90% (27 patients); 36-month rate of patients who were still on treatment with androgen receptor targeted agents was 50%. 20 of 30 patients had performed imaging control after a single course of stereotactic body radiotherapy: overall response rate was 50%, while clinical benefit was 93%. No ⩾G2 adverse events related to stereotactic body radiotherapy were recorded., Conclusions: Stereotactic body radiotherapy in oligoprogressive metastatic sites during androgen receptor targeted agent treatment resulted in a feasible and effective treatment to delay the start of next-line systemic treatment and prolong overall survival in metastatic castration resistant prostate cancer. Longer follow-up and further prospective studies are necessary to confirm our preliminary results.

According to the driver-passenger model for colorectal cancer (CRC), the tumor-associated microbiota is a dynamic ecosystem of bacterial species where bacteria with carcinogenic features linked to CRC initiation are defined as "drivers", while opportunistic bacteria colonizing more advanced tumor stages are known as "passengers". We reasoned that also gut microbiota-associated metabolites may be differentially enriched according to tumor stage, and be potential determinants of CRC development. Thus, we characterized the mucosa- and lumen-associated microbiota (MAM and LAM, respectively) and mucosa-associated metabolites in low- vs. high-grade dysplastic colon polyps from 78 patients. We show that MAM, obtained with a new biopsy-preserving approach, and LAM differ in composition and α/β-diversity. By stratifying patients for polyp histology, we found that bacteria proposed as passengers by previous studies colonized high-grade dysplastic adenomas, whereas driver taxa were enriched in low-grade polyps. Furthermore, we report altered "mucosa-associated metabolite" levels in low- vs. high-grade groups. Integrated microbiota-metabolome analysis suggests the involvement of the gut microbiota in the production and consumption of these metabolites. Altogether, our findings support the involvement of bacterial species and associated metabolites in CRC mucosal homeostasis in a tumor-stage-specific manner. These distinct signatures may be used to distinguish low-grade from high-grade dysplastic polyps.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 ( BAP1 ) lead to BAP1 tumor predisposition syndrome ( BAP1 -TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1 -TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1 -TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1 -TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1 -TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1 -TPDS patients.

Introduction: Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions., Aim: This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments., Methods: NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair., Results: We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat)., Conclusions: Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Grosso reports outside the submitted work personal fees for advisory role, speaker engagements and travel and accommodation expenses from Merck Sharp & Dohme (MSD), Novocure, Bristol Meyer Squibb, Boehringer Ingelheim, PharmaMar and Novartis. Scagliotti reports outside the submitted work personal fees for lectures, presentations, speaker bureaus, article writing and educational events from Eli Lilly, Roche, Pfizer, AstraZeneca, Novartis, MSD, Takeda and Beigene. Scagliotti reports participation on a data safety monitoring board and advisory board from Beigene, Takeda, MSD, Novartis, AstraZeneca, Pfizer, Roche and Eli Lilly outside the submitted work. Mirabelli received payment to discuss court cases with asbestos-related neoplasms from the public prosecution office at the Verbania Court and Turin Court. Magnani received payment for participation in different trials regarding asbestos-related diseases from the public prosecution office and research funding (BRIC Project) from INAIL outside the submitted work. Dianzani has been appointed by the public prosecution office to discuss court cases with asbestos-related neoplasms. The remaining authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Traditionally, Cornelia de Lange Syndrome (CdLS) is considered a cohesinopathy caused by constitutive mutations in cohesin complex genes. Cohesin is a major regulator of chromatin architecture, including the formation of chromatin loops at the imprinted IGF2 / H19 domain. We used 3C analysis on lymphoblastoid cells from CdLS patients carrying mutations in NIPBL and SMC1A genes to explore 3D chromatin structure of the IGF2 / H19 &nbsp; locus and evaluate the influence of cohesin alterations in chromatin architecture. We also assessed quantitative expression of imprinted loci and WNT pathway genes, together with DMR methylation status of the imprinted genes. A general impairment of chromatin architecture and the emergence of new interactions were found. Moreover, imprinting alterations also involved the expression and methylation levels of imprinted genes, suggesting an association among cohesin genetic defects, chromatin architecture impairment, and imprinting network alteration. The WNT pathway resulted dysregulated: canonical WNT, cell cycle, and WNT signal negative regulation were the most significantly affected subpathways. Among the deregulated pathway nodes, the key node of the frizzled receptors was repressed. Our study provides new evidence that mutations in genes of the cohesin complex have effects on the chromatin architecture and epigenetic stability of genes commonly regulated by high order chromatin structure.

The intestinal microbiota is composed of a large number of different bacteria that produce a variety of metabolites. Colorectal cancer, which typically develops from adenomatous polyps, is highly influenced by microbiota. Since a variety of molecular changes may occur as these polyps transform from benign tumor to malignant carcinoma, the ability to study the microbiota-produced metabolites can lead to new discoveries about the development and progression of this cancer. However, to address the complexity of the microbiota-produced molecules, novel methods are needed. To this aim, in the present work, we developed a high-throughput metabolomics method to capture the metabolic complexity of the microbiota metabolome adherent to adenomatous polyps and adenocarcinoma. For the first time, the method enables the simultaneous quantification of almost 300 metabolites, while preserving the integrity of the original sample. The metabolomics approach was analytically validated and had excellent performances in terms of recovery, linearity, specificity, intra- and inter-day precision, limits of detection, and quantification. Furthermore, the clinical potential of the method was demonstrated in adenoma collected for a colorectal adenoma study., Competing Interests: Declaration of competing interest The authors 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 © 2021 Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = -0.09, 95% CI = -0.12|-0.06, p = 1.2 × 10 -7 ), and (ii) cg06633438 in MLLT1 , statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10 -6 ). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10 -11 ) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10 -8 ) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5 . AUC = 0.89, 2.1 × 10 -7 ; BM + cg06633438 at MLLT1 . AUC = 0.89, 6.3 × 10 -8 . Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma generally arising in the anogenital region. Surgery is still considered the treatment of choice for patients with EMPD, while Radiotherapy is a common alternative for inoperable cases and it's necessary in case of lack of surgical radicality. In this article, we described our experience and a review of the literature, with a particular focus on radiation-induced toxicity and on the feasibility of re-irradiation. A 70-year-old patient with EPMD underwent adjuvant radiotherapy in 2015. After 28 months for recurrence another radiant treatment was performed. No G3 (CTCAE v4) toxicity were recorded. In the last follow-up visit at 18 months, no signs of relapse were reported. A search strategy of the bibliographic database PubMed was performed. The inclusion criteria for the articles were case report, clinical prospective, or retrospective studies with histological confirmation of EMPD of scrotum and penis; studies with patients undergoing RT; studies in the past 30 years. In most of the 14 reported studies, RT was overall well tolerated. The major observed toxicity was G3 skin toxicity in one study. To our knowledge, there are no other cases of EPMD re-irradiation in literature. Our patient showed an excellent response and tolerated very well the high doses of both the radiation treatments. This suggests that the tolerance of skin to re-irradiation following a long period between the two treatments may be comparable to the normal constraints., (© 2020 Wiley Periodicals LLC.)

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are imprinting-related disorders associated with genetic/epigenetic alterations of the 11p15.5 region, which harbours two clusters of imprinted genes (IGs). 11p15.5 IGs are regulated by the methylation status of imprinting control regions ICR1 and ICR2. 3D chromatin structure is thought to play a pivotal role in gene expression control; however, chromatin architecture models are still poorly defined in most cases, particularly for IGs. Our study aimed at elucidating 11p15.5 3D structure, via 3C and 3D FISH analyses of cell lines derived from healthy, BWS or SRS children. We found that, in healthy cells, IGF2/H19 and CDKN1C/KCNQ1OT1 domains fold in complex chromatin conformations, that facilitate the control of IGs mediated by distant enhancers. In patient-derived cell lines, we observed a profound impairment of such a chromatin architecture. Specifically, we identified a cross-talk between IGF2/H19 and CDKN1C/KCNQ1OT1 domains, consisting in in cis, monoallelic interactions, that are present in healthy cells but lost in patient cell lines: an inter-domain association that sees ICR2 move close to IGF2 on one allele, and to H19 on the other. Moreover, an intra-domain association within the CDKN1C/KCNQ1OT1 locus seems to be crucial for maintaining the 3D organization of the region.

Background: Catalase gene (CAT) polymorphisms were analyzed as responsible for the deficiency of catalase enzyme activity and concomitant accumulation of excessive hydrogen peroxide in vitiligo patients. Catalase is a well-known oxidative stress regulator that could play an important role in the pathogenesis of vitiligo. This study was conducted to evaluate three CAT gene polymorphisms (-89A/T, 389C/T, 419C/T) and their association with vitiligo susceptibility in Sicilian population., Methods: Sixty out of 73 Sicilian patients with vitiligo were enrolled and submitted to CAT gene analysis., Results: Contrary to the Northern part of Europe but likewise to the Mediterranean area, the frequency of the CAT genotypes in Sicily is equally distributed. Out of all CAT genotypes, only CAT-89 T/T frequency was found to be significantly higher amongst vitiligo patients than controls., Conclusions: Despite the involvement of the CAT enzyme in the pathogenesis of vitiligo, the biological significance of CAT gene polymorphisms is still controversial. With the only exception for CAT variant -89A/T, the other studied CAT gene polymorphisms (389C/T and 419C/T) might not to be associated with vitiligo in Sicilian population.