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Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism in medulloblastoma/PNET and Hodgkin lymphoma:a prospective cohort study

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Frontiers of Medicine 2021年第1期15卷 101-107页

作者： Maura Massimino Marta Podda Lorenza Gandola Emanuele Pignoli Ettore Seregni Carlo Morosi Filippo Spreafico Andrea Ferrari Emilia Pecori Monica Terenziani Pediatric Oncology unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Pediatric Radiotherapy unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Medical Physics unit Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Department of Nuclear Medicine Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy Department of Radiology Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20146Italy

Primary hypothyroidism commonly occurs after radiotherapy(RT),and coincides with increased circulating thyroid-stimulating hormone(TSH)*** tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma(HL)in a prospective cohort *** 1998 to 2001,a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL,scheduled for craniospinal irradiation and mediastinum/neck radiotherapy,respectively,underwent thyroid ultrasound and free triiodothyronine(FT3),free thyroxine(FT4),and TSH evaluation at the beginning and end of craniospinal *** 14 days before and up to the end of radiotherapy,patients were administered L-thyroxine checking every 3 days TSH to ensure a valuedism was considered an increased TSH level greater than normal ***-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels˂0.3μIU/mL and well matched for other *** years on,hypothyroidism-free survival rates differed significantly,being 60%±15%and 15.6%±8.2%in TSH-suppressed ***-TSH suppressed patients,respectively(P=0.001).These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae,but it should be confirmed in a larger cohort.

关键词： iatrogenic primary hypothyroidism late effects of radiotherapy long-term follow-up medulloblastoma Hodgkin lymphoma

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The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response

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Cancer Communications 2018年第1期38卷 745-758页

作者： Andrea Devecchi Loris De Cecco Matteo Dugo Donata Penso Gianpaolo Dagrada Silvia Brich Silvia Stacchiotti Marialuisa Sensi Silvana Canevari Silvana Pilotti Platform of Integrated Biology Department of Applied Research and Technology DevelopmentFondazione IRCCS Istituto Nazionale dei Tumori di Milano2133 MilanItaly Department of diagnostic Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori di Milano20133 MilanItaly Department of Medical Oncology Fondazione IRCCS Istituto Nazionale dei Tumori di Milano20133 MilanItaly

Background:Desmoplastic small round cell tumor(DSRCT)is a rare,aggressive,and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1(EWSR1)-Wilm’s tumor suppressor(WT1)*** used whole-exome sequencing to interrogate six consecutive pretreated DSRCTs whose gene expression was previously ***:DNA libraries were prepared from formalin-fixed,paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq *** sequence data were aligned to the reference genome with Burrows-Wheeler Aligner *** mutations and copy number alterations(CNAs)were identified using MuTect2 and EXCAVATOR2,*** functions associated with altered genes were investigated through Ingenuity Pathway Analysis(IPA)***:A total of 137 unique somatic mutations were identified:133 mutated genes were case-specific,and 2 were mutated in two cases but in different *** the 135 mutated genes,27%were related to two biological categories:DNA damage-response(DDR)network that was also identified through IPA and mesenchymal-epithelial reverse transition(MErT)/epithelial-mesenchymal transition(EMT)already demonstrated to be relevant in *** mutated genes in the DDR network were involved in various steps of transcription and particularly affected *** of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins,which were recently rec-ognized as a new class of DDR *** in genes/gene families,involved in MErT/EMT and DDR,were recurrent across patients and mostly segregated in the MErT/EMT *** addition,recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were ***:The emerging picture is an extreme inter-tumor heter

关键词： Desmoplastic small round cell tumor Whole-exome sequencing Somatic mutations Copy number alterations Chromosome imbalance DNA damage response Genomic stability Mesenchymal-epithelial reverse transition/epithelial-mesenchymal transition Immune response

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Clear cell adenocarcinoma of the colon is a unique morphological variant of intestinal carcinoma:Case report with molecular analysis

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World Journal of Gastroenterology 2008年第42期14卷 6575-6577页

作者： Marta Barisella Andrea Lampis Federica Perrone Antonino Carbone Anathomic Pathology Department of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milano 20133 Italy Experimental Molecular Pathology Department of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milano 20133 Italy

Here we report a new case of clear cell adenocarcinoma (CCA) of the colon in a 54-year-old Caucasian man. Despite of the previous reported cases, the lesion was located in the right colon and was not associated with the conventional adenoma. We performed immunohistochemical and molecular analyses in order to explore whether the CCA had the molecular features generally associated with conventional colorectal carcinoma. The immunohistochemical and molecular analyses showed that the different morphology of CCA does not reflect a distinct biological entity but only an unusual morphological variant of intestinal carcinoma.

关键词： Clear cell carcinoma Colon carcinoma Beta-catenin KRAS Molecular analysis

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One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches

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World Journal of Gastrointestinal Oncology 2020年第8期12卷 833-849页

作者： Monica Niger Michele Prisciandaro Maria Antista Melissa Anna Teresa Monica Laura Cattaneo Natalie Prinzi Sara Manglaviti Federico Nichetti Marta Brambilla Martina Torchio Francesca Corti Sara Pusceddu Jorgelina Coppa Vincenzo Mazzaferro Filippo de Braud Maria di Bartolomeo Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20133Italy First Pathology division Department of Pathology and Laboratory MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilan 20133Italy Hepato-biliary-pancreatic Surgery and Liver Transplantation Department Fondazione IRCCS Istituto Nazionale dei TumoriMilan 20133Italy Universitàdegli studi di milano Milan 20133Italy

Exocrine pancreatic neoplasms represent up to 95%of pancreatic cancers(PCs)and are widely recognized among the most lethal solid cancers,with a very poor 5-year survival rate of 5%-10%.The remainingdian overall survival of 3.6 *** most common type of PC is pancreatic ductal adenocarcinoma(PDAC),which accounts for roughly 85%of all exocrine *** up to 10%of exocrine PCs have rare histotypes,which are still poorly *** subtypes can be distinguished from PDAC in terms of pathology,imaging,clinical presentation and ***,due to their rarity,any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective ***,treatment strategies are generally deduced from those used for PDAC,even if these patients are often excluded or not clearly represented in clinical trials for *** these reasons,it is essential to collect as much information as possible on the management of PC,as assimilating it with PDAC may lead to the potential mistreatment of these ***,we report the most significant literature regarding the epidemiology,typical presentation,possible treatment strategies,and prognosis of the most relevant histotypes among rare PCs.

关键词： Rare pancreatic cancers Pancreatic acinar cell cancer Pancreatic adenosquamous cancer Undifferentiated pancreatic cancer Pancreatoblastoma Pseudopapillary pancreatic cancer

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Integration of genome scale data for identifying newplayers in colorectal cancer

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World Journal of Gastroenterology 2016年第2期22卷 534-545页

作者： Viktorija Sokolova Elisabetta Crippa Manuela Gariboldi Department of Experimental Oncology and Molecular Medicine Fondazione IRCCS Istituto Nazionale dei Tumori20133 MilanoItaly Molecular Genetics of Cancer Fondazione Istituto FIRC di Oncologia Molecolare20139 MilanoItaly

Colorectal cancers(CRCs) display a wide variety of genomic aberrations that may be either causally linked to their development and progression, or might serve as biomarkers for their presence. Recent advances in rapid high-throughput genetic and genomic analysis have helped to identify a plethora of alterations that can potentially serve as new cancer biomarkers, and thus help to improve CRC diagnosis, prognosis, and treatment. Each distinct data type(copy number variations, gene and micro RNAs expression, Cp G island methylation) provides an investigator with a different, partially independent, and complementary view of the entire genome. However, elucidation of gene function will require more information than can be provided by analyzing a single type of data. The integration of knowledge obtained from different sources is becoming increasingly essential for obtaining an interdisciplinary view of large amounts of information, and also for cross-validating experimental results. The integration of numerous types of genetic and genomic data derived from public sources, and via the use of ad-hoc bioinformatics tools and statistical methods facilitates the discovery and validation of novel, informative biomarkers. This combinatory approach will also enable researchers to more accurately and comprehensively understand the associations between different biologic pathways, mechanisms, and phenomena, and gain new insights into the etiology of CRC.

关键词： Colorectal cancer Copy number variations Gene expression miRNA expression Methylome Dataintegration

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Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

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Chinese Journal of Cancer 2016年第10期35卷 546-559页

作者： Vittoria disciglio Andrea Devecchi Orazio Palumbo Massimo Carella Donata Penso Massimo Milione Giorgio Valle Marco Alessandro Pierotti Marco Vitellaro Lucio Bertario Silvana Canevari Stefano Signoroni Loris De Cecco Department of Experimental Oncology and Molecular Medicine Func-tional Genomics and BioinformaticsFondazione IRCCS Istituto Nazionale dei Tumori20133 MilanItaly. Medical Genetics unit IRCCS Casa Sollievo della Soferenza71013 San Giovanni Rotondo FGItaly. Department of Pathol-ogy and Laboratory Medicine Fondazione IRCCS Istituto Nazionale Tumori20133 MilanItaly. Department of Biology University of Padova35131 PaduaItaly. fondazione irccs istituto nazionale dei tumori 20133 MilanItaly. Hereditary digestive Tract Tumors unit Department of Preventive and Pre-dictive MedicineFondazione IRCCS Istituto Nazionale dei Tumori20133 MilanItaly. Colorectal Surgery unit Department of SurgeryFondazione IRCCS Istituto Nazionale dei Tumori20133 MilanItaly.

Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been *** presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human ***: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.

关键词： Androgen insensitivity syndrome Androgen receptor Colorectal cancer Single nucleotide polymorphism array Testosterone Whole exome sequencing

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CHK2 kinase in the DNA damage response and beyond

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Journal of Molecular Cell Biology 2014年第6期8卷 442-457页

作者： Laura Zannini Domenico Delia Giacomo Buscemi Department of Experimental Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Via Amadeo 42 20133 Milan Italy

The serine/threonine kinase CHK2 is a keycomponent of the DNA damage response. In human cells, following genotoxic stress, CHK2 is activated and phosphorylates 〉20 proteins to induce the appropriate cellular response, which, depending on the extent of damage, the cell type, and other factors, could be cell cycle checkpoint activation, induction of apoptosis or senescence, DNA repair, or tolerance of the damage. Recently, CHK2 has also been found to have cellular functions independent of the presence of nuclear DNA lesions. In par- ticular, CHK2 participates in several molecular processes involved in DNA structure modification and cell cycle progression. In this review, we discuss the activity of CHK2 in response to DNA damage and in the maintenance of the biological functions in unstressed cells. These activities are also considered in relation to a possible role of CHK2 in tumorigenesis and, as a consequence, as a target of cancer therapy.

关键词： DNA damage checkpoints apoptosis genomic stability

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Ovarian cancer:a molecularly insidious disease

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Chinese Journal of Cancer 2015年第1期34卷 1-3页

作者： Delia Mezzanzanica unit of Molecular Therapies Department of Experimental Oncology and Molecular Medicine.Fondazione IRCCS Istituto Nazionale dei Tumori

In this issue of the Chinese Journal of Cancer,European,American,and Chinese experts review the current management and future perspectives of epithelial ovarian cancer(EOC),the leading cause of gynecological cancer *** major advances have been made in understanding the cellular and molecular biology of this highly heterogeneous malignancy,the survival rate of women with EOC has changed little since the introduction of platinum-based treatment as a front-line *** papers describe the progress in deciphering the molecular complexity of this disease and the newly available molecular-driven therapies,which have been applied by shifting trial designs toward restricting eligibility to specific subgroups of patients rather than testing agents in unselected *** new trial designs provide potential opportunities for improved efficacy in targeted *** the molecular complexity of this disease,patient survival may be increased by searching for new molecular prognostic/predictive signatures as well as by translating the recent insight of microRNA involvement in EOC progression into new,targeted *** attention has been given to the issue of fertility sparing for women affected by curable diseases.

关键词：分子生物学卵巢癌疾病靶向治疗试验设计 EOC 微RNA 复杂性

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Concomitant medications and circulating tumor cells:friends or foes?

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Cancer Drug Resistance 2023年第1期6卷 30-34页

作者： Serena di Cosimo Vera Cappelletti Department of Advanced diagnostics Fondazione IRCCS Istituto Nazionale dei TumoriMilano 20133Italy

The use of concomitant medications by patients with cancer is observed almost globally;however,little attention has been paid to this topic in the medical *** clinical studies do not describe the type and duration of drugs used at the time of inclusion and during treatment or how these drugs may affect the experimental and/or standard *** less information has been published on the potential interaction between concomitant medications and tumor ***,we do know that concomitant drugs can complicate cancer clinical trials and biomarker development,thus contributing to their interaction,leading to side effects,and resulting in suboptimal adherence to anticancer *** the basis of these premises and moving from the study by Jurisova et al.,which reported the effect of commonly used drugs on the prognosis of women with breast cancer and the detection of circulating tumor cells(CTCs),we comment on the role of CTCs as an emerging diagnostic and prognostic tool for breast *** also report the known and hypothesized mechanisms of CTC interplay with other tumor and blood components,possibly modulated by widespread drugs,including over-the-counter compounds,and discuss the possible implications of commonly used concomitant medications on CTC detection and *** considering all these points,it is conceivable that concomitant drugs are not necessarily a problem,but on the contrary,their virtuous mechanisms can be exploited to reduce tumor spread and enhance the effect of anticancer therapies.

关键词： Breast cancer concomitant medications circulating tumor cells

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Nanotherapeutics approaches to improve the efficacy of CAR-T cells in solid tumors

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BIOCELL 2021年第5期45卷 1171-1173页

作者： FRANCESCO MAININI Immunotherapy and Innovative Therapeutics unit Department of Medical OncologyFondazione IRCCS Istituto Nazionale dei TumoriMilan20133Italy

Adoptive cell therapy and Immune Checkpoint Blockade Inhibitors have recently revolutionized the field of ***,these types of immunotherapeutic approaches have limited success in treating solid *** particular,chimeric antigen receptor(CAR)-T cells efficacy is hampered by immunosuppressive signals in the tumor microenvironment(TME)and by a limited infiltration of re-infused T cells to the tumor *** field of nanobiotechnology applied to oncology is also rapidly ***-based delivery systems can be employed to modulate the activity of immune cells present in the TME enhancing the efficacy of CAR-T ***,nano-backpacks can be attached to CAR-T cells prior to re-infusion to support their homing to the tumor site and to slowly release immunopotentiators directly in the ***,nanovaccines can also be employed to support the in vivo expansion of CAR-T cells with consequent enhancement of their therapeutic *** this viewpoint,recent advancement in the field of nanobiotechnology to support CAR-T cell therapy will be *** development of novel therapeutic CAR-T cells protocols together with nanotherapies is warranted in order to take full advantage of the high therapeutic potential of CAR-T cell therapy.

关键词： Nanoparticle Immunotherapy Cancer Adoptive cell therapy CAR-T Tumor microenvironme

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