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      Fertility Preservation and Restoration Options for Pre-Pubertal Male Cancer Patients: Current Approaches

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          Abstract

          Fertility preservation for prepubertal male patients undergoing gonadotoxic therapies, potentially depleting spermatogonial cells, is an expanding necessity, yet most of the feasible options are still in the experimental phase. We present our experience and a summary of current and novel possibilities regarding the different strategies to protect or restore fertility in young male patients, before proceeding with chemotherapy or radiotherapy for malignances or other diseases. Adult oncological patients should always be counselled to cryopreserve the semen before starting treatment, however this approach is not suitable for prepubertal boys, who aren’t capable to produce sperm yet. Fortunately, since the survival rate of pediatric cancer patients has skyrocketed in the last decade and it’s over 84%, safeguarding their future fertility is becoming a major concern for reproductive medicine. Surgical and medical approaches to personalize treatment or protect the gonads could be a valid first step to take. Testicular tissue autologous grafting or xenografting, and spermatogonial stem cells (SSCs) transplantation, are the main experimental options available, but spermatogenesis in vitro is becoming an intriguing alternative. All of these methods feature both strong and weak prospects. There is also relevant controversy regarding the type of testicular material to preserve and the cryopreservation methods. Since transplanted cells are bound to survive based on SSCs number, many ways to enrich their population in cultures have been proposed, as well as different sites of injection inside the testis. Testicular tissue graft has been experimented on mice, rabbits, rhesus macaques and porcine, allowing the birth of live offspring after performing intracytoplasmic sperm injection (ICSI), however it has never been performed on human males yet. In vitro spermatogenesis remains a mirage, although many steps in the right direction have been performed. The manufacturing of 3D scaffolds and artificial spermatogenetic niche, providing support to stem cells in cultures, seems like the best way to further advance in this field.

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          Cancer statistics, 2016.

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population.
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            Long-term proliferation in culture and germline transmission of mouse male germline stem cells.

            Spermatogenesis is a complex process that originates in a small population of spermatogonial stem cells. Here we report the in vitro culture of spermatogonial stem cells that proliferate for long periods of time. In the presence of glial cell line-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, and leukemia inhibitory factor, gonocytes isolated from neonatal mouse testis proliferated over a 5-month period (>10(14)-fold) and restored fertility to congenitally infertile recipient mice following transplantation into seminiferous tubules. Long-term spermatogonial stem cell culture will be useful for studying spermatogenesis mechanism and has important implications for developing new technology in transgenesis or medicine.
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              Epidemiology of childhood cancer.

              The present contribution reports childhood cancer incidence and survival rates as well as time trends and geographical variation. The report is based on the databases of population-based cancer registries which joined forces in cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE. According to these data, which refer to the International Classification of Childhood Cancer, leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, represent the largest diagnostic groups among the under 15-year-olds. The most frequent single diagnoses are: acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the mid of the last century. In Europe, the yearly increase averages 1.1% for the 1978-1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas. The probability of survival has risen considerably over the past decades, with the EUROCARE data showing an improvement of the relative risk of death by 8% when comparing the 2000-2002 time span to the 1995-1999 period. Regarding the years 1995-2002, the data show an overall 5-year survival probability of 81% for Europe and similar values for the USA. The data presented here describe the cancer situation with a specific, European focus. They are drawn from population-based cancer registries that ensure excellent data quality, and as a consequence represent the most valid European population-based data existing at present. It is also apparent that not all countries have data available from nationwide childhood cancer registries, a situation which warrants further improvement. 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                16 June 2022
                2022
                : 13
                : 877537
                Affiliations
                [1] 1 Department of Medicine and Surgery, University of Perugia , Perugia, Italy
                [2] 2 Department of Medicine and Medical Specialties, Division of Medical Andrology and Endocrinology of Reproduction, University of Terni , Terni, Italy
                [3] 3 Division of Anatomic Pathology and Histology, Department of Experimental Medicine, University of Perugia , Perugia, Italy
                [4] 4 Unit of Andrology and Reproductive Medicine, Department of Medicine, School of Medicine and Surgery, University of Padua , Padua, Italy
                [5] 5 Section of Pathology (Terni), Department of Medicine and Surgery, University of Perugia , Perugia, Italy
                [6] 6 International Biotechnological Center for Endocrine, Metabolic and Embryo-Reproductive Translational Research (CIRTEMER), Department of Medicine and Surgery, University of Perugia , Perugia, Italy
                Author notes

                Edited by: Antonino Belfiore, University of Catania, Italy

                Reviewed by: Giuseppe Grande, Catholic University of the Sacred Heart, Rome, Italy; Robin Mark Hobbs, Monash University, Australia

                *Correspondence: Elena Eugeni, eugeni.elena@ 123456gmail.com

                †These authors have contributed equally to this work and share first authorship

                ‡These authors have contributed equally to this work and share last authorship

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2022.877537
                9244702
                35784573
                c41edabe-60f0-45f2-82e5-23e96998e887
                Copyright © 2022 Eugeni, Arato, Del Sordo, Sidoni, Garolla, Ferlin, Calafiore, Brancorsini, Mancuso and Luca

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 February 2022
                : 25 April 2022
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 207, Pages: 14, Words: 6082
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                fertility,spermatogonial cell,gonadotoxic cancer treatment,cryopreservation,testicular tissue transplantation,sscs transplantation,de novo morphogenesis, in vitro spermatogenesis

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