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Valentino Martelli,1,2 Maria Maddalena Latocca,1,2 Tommaso Ruelle,1,2 Marta Perachino,1,2 Luca Arecco,1,2 Kristi Beshiri,1,2 Maria Grazia Razeti,1,2 Marco Tagliamento,1,2 Maurizio Cosso,3 Piero Fregatti,4,5 Matteo Lambertini1,2 1Department of Medical Oncology, U.O.C Clinica Di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 2Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy; 3Department of Radiology, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 4U.O.C. Clinica Di Chirurgia Senologica, Department of Surgery, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 5Department of Integrated Diagnostic Surgical Sciences, School of Medicine, University of Genova, Genova, ItalyCorrespondence: Matteo LambertiniIRCCS Ospedale Policlinico San Martino, University of Genova, Largo Rosanna Benzi 10, Genova, 16132, ItalyTel +39 010 555 4254Fax + 39 010 555 6536Email matteo.lambertini@unige.itAbstract: Over the last several decades, improvements in breast cancer treatment have contributed to increased cure rates for women diagnosed with this malignancy. Consequently, great importance should be paid to the long-term side effects of systemic therapies. For young women (defined as per guideline ≤ 40 years at diagnosis) who undergo chemotherapy, one of the most impactful side effects on their quality of life is premature ovarian insufficiency (POI) leading to fertility-related problems and the side effects of early menopause. Regimens, type, and doses of chemotherapy, as well as the age of patients and their ovarian reserve at the time of treatment are major risk factors for treatment-induced POI. For these reasons, childbearing desire and preservation of ovarian function and/or fertility should be discussed with all premenopausal patients before planning the treatments. This manuscript summarizes the available fertility preservation techniques in breast cancer patients, the risk of treatment-induced POI with different anticancer treatments, and the possible procedures to prevent it. A special focus is paid to the role of oncofertility counseling, as a central part of the visit in this setting, during which the patient should receive all the information about the potential consequences of the disease and of the proposed treatment on her future life.Keywords: breast cancer, fertility, young patient, oncofertility, premature ovarian insufficiency, anti-Mullerian hormone

Abstract Background In our studies of genetically isolated populations in a remote mountain area in the center of Sardinia (Italy), we found that 80–85% of the inhabitants of each village belong to a single huge pedigree with families strictly connected to each other through hundreds of loops. Moreover, intermarriages between villages join pedigrees of different villages through links that make family trees even more complicated. Unfortunately, none of the commonly used pedigree drawing tools are able to draw the complete pedigree, whereas it is commonly accepted that the visual representation of families is very important as it helps researchers in identifying clusters of inherited traits and genotypes. We had a representation issue that compels researchers to work with subsets extracted from the overall genealogy, causing a serious loss of information on familiar relationships. To visually explore such complex pedigrees, we developed PedNavigator, a browser for genealogical databases properly suited for genetic studies. Results The PedNavigator is useful for genealogical research due to its capacity to represent family relations between persons and to make a visual verification of the links during family history reconstruction. As for genetic studies, it is helpful to follow propagation of a specific set of genetic markers (haplotype), or to select people for linkage analysis, showing relations between various branch of a family tree of affected subjects. Availability PedNavigator is an application integrated into a Framework designed to handle data for human genetic studies based on the Oracle platform. To allow the use of PedNavigator also to people not owning the same required informatics infrastructure or systems, we developed PedNavigator Lite with mainly the same features of the integrated one, based on MySQL database server. This version is free for academic users, and it is available for download from our site http://www.shardna.com.

Background: Breast cancer is traditionally classified into three clinical subtypes based on hormone receptor and HER2 status (i.e., luminal-like, HER2-positive, and triple negative). Each subtype has distinct clinical-pathological and molecular characteristics and requires tailored treatments. Recent research efforts have been focusing on a new classification, identifying the so-called "HER2-low" category, including tumors characterized by a low level of HER2 expression (immunohistochemistry score 1+ or 2+ without in situ hybridization amplification). Emerging evidence shows that patients with HER2-low tumors can derive benefit from selected anti-HER2 therapies. This represents a major advancement in the field of breast oncology, where a broader proportion of patients with breast cancer can ultimately benefit from new effective targeted treatment strategies., Summary: The antibody-drug conjugate trastuzumab deruxtecan has proven impressive efficacy in patients with HER2-low breast cancer, and several other drugs are currently under investigation in this subset of patients. Additional investigation is needed to address open issues that exist in this field, including appropriate pathological assessment of HER2-low status, clarification of its prognostic implications, and global access to newly approved drugs., Key Message: Our review aims to summarize the available evidence regarding HER2-low breast cancer, illustrating the current challenges that are being addressed and the future perspectives in this exciting new field., Competing Interests: Dr. Molinelli received honoraria from Novartis and Lilly outside the submitted work. Dr. Jacobs declares no conflicts of interest. Dr. Agostinetto received consultancy fees or honoraria from Eli Lilly and Sandoz and support to attend medical conferences from Roche, Novartis, Eli Lilly, and Genetic, Istituto Gentili (all disclosures are outside the submitted work). Dr. Marchiò received honoraria from Bayer, Roche, AstraZeneca, and Daiichi Sankyo. Dr. De Azambuja received honoraria and/or participated to advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs, and Pierre Fabre; received travel grants from Roche/GNE and GSK/Novartis; and received research grant to his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier. Dr. Schettini received personal fees from Novartis for educational material. Dr. Lambertini played an advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, and Exact Sciences and received speaker honoraria from Roche, Daiichi Sankyo, Lilly, Novartis, Pfizer, Sandoz, Libbs, and Takeda and travel grants from Gilead outside the submitted work., (Copyright © 2022 by S. Karger AG, Basel.)

The diagnosis of breast cancer during pregnancy represents a challenging situation for the patient, her caregivers and physicians. Pregnancy adds complexity to oncological treatment planning, as many therapies can be potentially dangerous to the fetus. Therefore, a multidisciplinary approach is needed to offer a proper care for obtaining the best possible outcomes for the mother and the future child. Breast surgery is feasible throughout the pregnancy while radiotherapy should be postponed after delivery. Administration of chemotherapy is considered safe and can be given during the second and third trimesters, while it is contraindicated in the first trimester due to the high risk of fetal malformations. Endocrine therapy and targeted agents are not recommended during the whole pregnancy period; however, limited data are available on the use of the majority of new anticancer drugs in this context. The aim of the current review is to provide an update on the current state of art about the management of women diagnosed with breast cancer during pregnancy.

The metabolic syndrome (MetS) is a large-scale and expanding public-health and clinical threat worldwide. We investigated the determinants of MetS, assessed its prevalence and components and, estimated their genetic contribution, taking advantage of the special characteristics of Sardinian isolated populations. Inhabitants of 10 villages in Ogliastra region participated in a cross-sectional survey in 2002-2008 (n = 9,647). Blood samples, blood pressure (BP), anthropometry and, data from a standardized interview were collected. Prevalence of MetS was estimated by the direct method of standardization. Variables associated with the MetS were identified using multilevel logistic regression. Heritability was determined using variance component models. MetS Prevalence was 19.6% (95% CI 18.9-20.4%) according to NCEP-ATPIII, 24.8% (95% CI 24.0-25.6%) according to IDF and, 29% (95% CI 28.1-29.8%) according to AHA/NHLBI harmonized criteria, ranging from 9 to 26% among villages. The most prevalent combination was BP + HDL-cholesterol (HDL) + triglycerides (TRIG) (19%), followed by BP + HDL + waist circumference (WAIST) (17%) and, BP + HDL + TRIG + WAIST (13.6%). Heritability of MetS was 48% (p = 1.62 × 10(-25)), as the two most common combinations (BP + HDL + TRIG and BP + HDL + WAIST) showed heritability of 53 and 52%, respectively. The larger genetic components of the two most frequent combinations determining MetS deserve greater investigation in order to understand the underlying mechanisms. Besides, further studies are warranted to confirm these findings both in isolated and outbred populations.

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not "a priori" be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates.

For mitochondrial phylogenetic analysis, the best result comes from complete sequences. We therefore decided to sequence the entire mitochondrial DNA (mtDNA) (coding and D-loop regions) of 63 individuals selected in 3 small Ogliastra villages, an isolated area of eastern Sardinia: Talana, Urzulei, and Perdasdefogu. We studied at least one individual for each of the most frequent maternal genealogical lineages belonging to haplogroups H, V, J, K, T, U, and X. We found in our 63 samples, 172 and 69 sequence changes in the coding and in the D-loop region, respectively. Thirteen out of 172 sequence changes in the coding region are novel. It is our hypothesis that some of them are characteristic of the Ogliastra region and/or Sardinia. We reconstructed the phylogenetic network of the 63 complete mtDNA sequences for the 3 villages. We also drew a network including a large number of European sequences and calculated various indices of genetic diversity in Ogliastra. It appears that these small populations remained extremely isolated and genetically differentiated compared with other European populations. We also identified in our samples a never previously described subhaplogroup, U5b3, which seems peculiar to the Ogliastra region.

Background: In our studies of genetically isolated populations in a remote mountain area in the center of Sardinia (Italy), we found that 80-85% of the inhabitants of each village belong to a single huge pedigree with families strictly connected to each other through hundreds of loops. Moreover, intermarriages between villages join pedigrees of different villages through links that make family trees even more complicated. Unfortunately, none of the commonly used pedigree drawing tools are able to draw the complete pedigree, whereas it is commonly accepted that the visual representation of families is very important as it helps researchers in identifying clusters of inherited traits and genotypes. We had a representation issue that compels researchers to work with subsets extracted from the overall genealogy, causing a serious loss of information on familiar relationships. To visually explore such complex pedigrees, we developed PedNavigator, a browser for genealogical databases properly suited for genetic studies., Results: The PedNavigator is useful for genealogical research due to its capacity to represent family relations between persons and to make a visual verification of the links during family history reconstruction. As for genetic studies, it is helpful to follow propagation of a specific set of genetic markers (haplotype), or to select people for linkage analysis, showing relations between various branch of a family tree of affected subjects., Availability: PedNavigator is an application integrated into a Framework designed to handle data for human genetic studies based on the Oracle platform. To allow the use of PedNavigator also to people not owning the same required informatics infrastructure or systems, we developed PedNavigator Lite with mainly the same features of the integrated one, based on MySQL database server. This version is free for academic users, and it is available for download from our site http://www.shardna.com.