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Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18–39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23–1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18–7·20], p=0·020, in participants ≤24 years; 1·61 [1·05–2·48], p=0·029, in those aged 25–29 years; and 1·37 [1·11–1·69], p=0·0035, in those aged 30–40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46–0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America.

Neuroblastoma is the most common extracranial solid tumour occurring in childhood and has a diverse clinical presentation and course depending on the tumour biology. Unique features of these neuroendocrine tumours are the early age of onset, the high frequency of metastatic disease at diagnosis and the tendency for spontaneous regression of tumours in infancy. The most malignant tumours have amplification of the MYCN oncogene (encoding a transcription factor), which is usually associated with poor survival, even in localized disease. Although transgenic mouse models have shown that MYCN overexpression can be a tumour-initiating factor, many other cooperating genes and tumour suppressor genes are still under investigation and might also have a role in tumour development. Segmental chromosome alterations are frequent in neuroblastoma and are associated with worse outcome. The rare familial neuroblastomas are usually associated with germline mutations in ALK , which is mutated in 10–15% of primary tumours, and provides a potential therapeutic target. Risk-stratified therapy has facilitated the reduction of therapy for children with low-risk and intermediate-risk disease. Advances in therapy for patients with high-risk disease include intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy; these have improved 5-year overall survival to 50%. Currently, new approaches targeting the noradrenaline transporter, genetic pathways and the tumour microenvironment hold promise for further improvements in survival and long-term quality of life. Neuroblastoma is a neuroendocrine tumour that arises in the developing sympathetic nervous system and is the most common malignancy diagnosed in the first year of life. This Primer by Matthay et al . reviews the mechanisms, diagnosis and risk-stratified management of neuroblastoma.

Incorporating genetic factors into risk models improves the prediction of severe obesity for survivors of childhood cancer, which could promote early interventions and better long-term care.

Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5–28·4]; median age at diagnosis 6·1 years [3·0–12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7–210·8) and 128·9 per 100 siblings (123·0–134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7–1·9) and in female versus male survivors (1·4; 1·4–1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3–1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4–30·4), endocrine (6·7, 5·2–8·7), cardiovascular (6·6, 5·2–8·3), respiratory (5·3, 3·4–8·2), spine (2·4, 1·8–3·2), breast (2·1, 1·7–2·6), renal or urinary (2·0, 1·5–2·6), musculoskeletal (1·5, 1·4–1·7), gastrointestinal (1·4, 1·3–1·6), and head and neck (1·2, 1·1–1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1–346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5–351·3] per 100 survivors), and osteosarcoma (269·6 [250·1–289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33–46) in the purged group versus 36% (30–42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43–56) in the purged group compared with 51% (44–57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma. National Cancer Institute and Alex's Lemonade Stand Foundation.

Cancer treatments may compromise the fertility of children, adolescents, and young adults, and treatment-related infertility represents an important survivorship issue that should be addressed at diagnosis and in follow-up to ensure optimal decision-making, including consideration of pursuing fertility preservation. Risk of infertility varies substantially with patient and treatment factors. The ability to accurately assess fertility risk for many patients is hampered by limitations of the current literature, including heterogeneity in patient populations, treatments, and outcome measures. In this article, we review and synthesize the available data to estimate fertility risks from modern cancer treatments for both children and adult cancer survivors to enable clinicians to counsel patients about future fertility.

Neuroblastoma: a genetic link to ALK Neuroblastoma is the most common childhood cancer. There is a strong familial association and it was predicted over 30 years ago that there was a genetic element to the disease. Four groups now report the identification of mutations in the tyrosine kinase receptor ALK (anaplastic lymphoma kinase) in neuroblastoma patients. ALK acts as a neuroblastoma predisposition gene, and somatic point mutations occur in sporadic neuroblastoma cases. These mutations promote ALK's kinase activity and can transform cells and display tumorigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferation, so have potential as anticancer drugs. This is one of four papers in this issue that identifies mutations in the tyrosine kinase receptor ALK in neuroblastoma, the most frequent childhood cancer. ALK is found to be a neuroblastoma predisposition gene and somatic points mutations were found in sporadic cases of neuroblastoma. These mutations lead the ALK kinase activation and are able to transform cells and display tumourigenic activity in vivo . ALK inhibitors decrease neuroblastoma cell proliferating and are potential anti-cancer drugs for the treatment of neuroblastoma. Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer 1 . High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal 2 , 3 . Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK , of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4 ). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.

Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network—a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40–0·67) for kidney transplantation, 0·49% (0·36–0·62) for heart, 0·19% (0·10–0·27) for liver, and 0·10% (0·04–0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3–7·7), ifosfamide (24·9, 7·4–83·5), total body irradiation (6·9, 2·3–21·1), and mean kidney radiation of greater than 15 Gy (>15–20 Gy, 3·6 [1·5–8·5]; >20 Gy 4·6 [1·1–19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3–11·3) and methotrexate (3·3, 1·0–10·2); for lung transplantation, carmustine (12·3, 3·1–48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6–92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0–97·9) for kidney transplantation, 80·6% (63·6–90·3) for heart, 27·8% (4·4–59·1) for liver, and 34·3% (4·8–68·6) for lung. Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

Background: Limited data inform the outcomes of patients with high-risk neuroblastoma (HR-NBL) who relapse after high-dose chemotherapy, autologous stem cell transplantation (ASCT), and external beam radiotherapy (EBRT). Methods: This is a multi-institutional retrospective study of 84 patients with HR-NBL diagnosed between 1997–2021 with a first recurrence after definitive upfront treatment, including ≥1 ASCT and EBRT. Site(s) of first relapse were defined with relation to a patient’s primary tumor location. Progression-free survival (PFS) and overall survival (OS) outcomes were analyzed using Kaplan–Meier curves and log-rank tests. Cox proportional hazard models were used for univariate and multivariable analyses. Results: Twenty-four patients had local recurrences with or without distant relapses (LR) and 60 had distant relapses only. The LR cohort had higher rates of MYCN amplification (70% vs. 36%, p = 0.016). At relapse, the LR cohort had lower rates of additional radiotherapy (32% vs. 61%, p = 0.029) and higher rates of additional surgery (29% vs. 5%, p = 0.005), with similar rates of chemotherapy for both cohorts. With a median follow-up after first relapse of 1.53 years (range: 0.03–15.82), there were no significant differences in interval PFS and OS between the cohorts. After controlling for age at diagnosis and pattern of recurrence, time to interval relapse ≥ 2 years was a significant predictor of improved OS (HR: 0.50, 95% CI: 0.29–0.85, p = 0.011). Conclusions: Patients with relapsed HR-NBL have poor outcomes with median OS < 2 years. Time to relapse was a significant predictor of OS.

This article provides guidance for care of adult survivors of childhood acute lymphoblastic leukemia, the most common childhood cancer. Treatments are associated with increased late risks of several other conditions; surveillance and patient education strategies are reviewed. Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations. Stage A 26-year-old woman presents to an internist to establish primary care. Her medical history includes a diagnosis of acute lymphoblastic leukemia (ALL) at 3 years of age. She does not know what therapies she received, but her parents told her that she was treated for 2 years and that her leukemia never recurred. She is a high-school graduate and works as a receptionist. What are the issues to consider in the care of this long-term survivor of childhood leukemia? The Clinical Problem Because of the extraordinary advances in pediatric cancer treatment during the past five decades, more than 325,000 . . .