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The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy. ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1 -positive rhabdomyosarcoma or unresected FOXO1 -negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1 -negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1 -negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete. Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0–11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8–4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5–74·1] in the VAC/VI group vs 66·8% [57·5–76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58–1·26]; log-rank p=0·44). The most common grade 3–4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified. Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population. The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health). [ABSTRACT FROM AUTHOR]

Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was − 8.5 % (range −100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined. • Sorafenib and pazopanib are effective treatments for desmoid tumor patients. • Treatment discontinuation should be discussed in radiologically responding patients. • Optimal treatment duration for patients with stable disease remains unknown. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the bladder is a rare but very aggressive tumor. The main cause is Schistosoma hematobium. Bladder cancer with large calculi is rare. We had a report of a 52-year-old Indian male who presented with the chief complaint of poor flow and a history of painful hematuria. Contrast-enhanced computed tomography showed a polypoidal mass involving the right lateral wall of the urinary bladder. whose microscopic features were suggestive of squamous cell carcinoma. Further confirmation, Immuno Histo Chemistry was done by p63 and CK 7. [ABSTRACT FROM AUTHOR]

In this paper, the effect of pre-buckling boundary conditions and the type of nonlinearity for stress stiffening used in different linear and nonlinear buckling approaches is studied for laminated composite plates. The study is conducted using a C 0 finite element (FE) plate model, employing a unified C 1 higher-order shear deformation theory (HSDT). The set of governing equations is derived using the principle of virtual displacement and solved using the tangent-based arc-length method in conjunction with a simple branch switching technique. The performance of the present C 0 FE model is assessed through a validation exercise and comparison with results obtained via the use of ANSYS and, for linear analysis, Navier solution, as well as solutions available in the literature. The influence of the different in-plane loads, boundary conditions, side-to-thickness ratio, fiber orientation, types of imperfection and penalty stiffness matrix are also examined. The results show that the same boundary conditions must be utilized in both pre-buckling and linear eigenvalue analyses for accurate and realistic predictions of critical buckling loads, as confirmed from the nonlinear buckling analyses. Furthermore, the critical buckling loads obtained using Green–Lagrange nonlinearity are observed to be more conservative than those obtained using von Kármán nonlinearity. The nonlinear buckling approach is a generalized approach while the nonlinear eigenvalue approach has a limited range of application. • Importance of consistent pre-boundary conditions in pre-buckling analysis is highlighted. • Green–Lagrange strain is better than von Kármán strain for geometric stiffness matrix. • The superiority of the nonlinear buckling approach over the nonlinear eigenvalue approach is shown. • The significance of considering the penalty stiffness matrix for C1 HSDT in C0 FEM formulation is demonstrated. [ABSTRACT FROM AUTHOR]

Background: The role of denosumab in patients with resectable giant cell tumour of bone remains unclear. We asked the following research question: for patients (aged ≥ 12 years) with resectable giant cell tumour of bone, what are the benefits and harms of denosumab compared with no denosumab in terms of (1) facilitation of surgery (operative time, blood loss), (2) disease recurrence, (3) pain control, (4) disease stability, and (5) adverse effects (e.g., malignant transformation, osteonecrosis of jaw, atypical femur fracture)? One previous systematic review addressed only one outcome—disease recurrence. Therefore, we undertook this new systematic review to address the above five outcomes. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Database of Systematic Reviews databases were searched on June 30, 2020. Results: This systematic review included one previous systematic review and five comparative studies. Due to poor quality, non-randomized studies fraught with selection bias, it is difficult to determine if a significant difference exists in the outcomes for surgical giant cell tumour of bone with perioperative denosumab. There were no reported cases of adverse effects from denosumab. Conclusion: To date, there is insufficient evidence to understand the value of denosumab in the perioperative setting in patients with giant cell tumour of bone. [ABSTRACT FROM AUTHOR]

An area of concern affecting the quality of life of childhood cancer survivors (CCS) is that of sexual dysfunction (SD), which may be a result of both physical and psychosexual challenges associated with cancer and its treatment. This is especially pertinent as CCS are known to experience diminished quality of life compared to peers. Relevant to SD, cancer and its associated treatment are associated with negative effects on body image and romantic relationships, as well as overall physical and mental health. Although CCS have been shown to have SD at higher rates than the general population, this is often under-recognized and CCS commonly report that it is not addressed by their health care providers. To guide future research and improve clinical screening and treatment practices for SD, we performed a narrative review of this understudied topic to summarize existing knowledge of the incidence, risk factors, pathophysiology, and rates of screening for SD in CCS. We also outline current gaps in knowledge and directions for future research. [ABSTRACT FROM AUTHOR]

The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival. Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan–Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed. 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%–62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26–0.80], p = 0.01). Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS. • 370 patients with localized extremity extraskeletal osteosarcoma (ESOS) treated definitively were evaluated. • There is a significant association between radiotherapy (RT) and decreased local recurrence. • Chemotherapy (CT) did not decrease the risk of systemic recurrence. • Neither CT, nor RT, nor both were associated with improved survival. • Adjuvant therapies in resectable ESOS need careful multidisciplinary discussion. [ABSTRACT FROM AUTHOR]

Cancer therapy can result in infertility in childhood cancer survivors; however, little is known about how young adolescent males make sense of infertility and potential future parenthood. What's more, research shows that many healthcare professionals in Canada do not discuss fertility preservation (FP) with this vulnerable population. This study examines how male adolescent childhood cancer survivors understand infertility as a long-term effect of cancer treatments. We used a narrative analysis to examine 16 interviews with 14–18-year-old males. The findings from this research illustrate that FP discussions may raise meaningful questions for young men about how they see themselves and construct their identities. The findings also demonstrate that young men's beliefs about FP may be informed by family narratives, and it shows that biological parenthood may be important to adolescent males. [ABSTRACT FROM AUTHOR]

In this work, an effective numerical approach based on the isogeometric analysis (IGA) employing first-order shear deformation theory (FSDT) is proposed and implemented for the static and transient analysis of sandwich composite plates. By using Hamilton's principle, the governing equation of motion is derived and then discretized using NURBS-based isogeometric approach. The set of governing equations are solved by the Newmark's time integration scheme. The better performance of the present approach in terms of accuracy and reduced computational cost is ascertained by investigating several numerical examples and comparing the evaluated results with different available results in the literature. [ABSTRACT FROM AUTHOR]

With medical advancements and improvements in medical technology, an increasing number of children with chronic conditions survive into adulthood. There is accordant growing interest toward supporting adolescents throughout the transition from paediatric to adult care. However, there is currently a paucity of research focusing on the role that these patients' parents should play during and after the transition to adult care and if maintained parental involvement is beneficial during this transition within a North American context. Accordingly, this scoping review utilized Arksey and O'Malley's five-step framework to consider parental roles during chronically ill children's transition to adult care. APA PsycInfo, CINAHL, EMBASE, MEDLINE, ProQuest, and Scopus were searched alongside advanced Google searches. Thematic content analysis was conducted on 30 articles meeting the following inclusion criteria: (1) published in English between 2010 and 2022, (2) conducted in Canada or the United States, (3) considered adolescents with chronic conditions transitioning to adult care, (4) family being noted in the title or abstract, and (5) patient populations of study not being defined by delays in cognitive development, nor mental illness. Three themes emerged from the literature: the impacts of maintaining parental involvement during transition to adult care for patients, parents experiencing feeling loss of stability and support surrounding the transition of their child's care, and significant nonmedical life events occurring for youths at the time of transition of care. Parents assuming supportive roles which change alongside their maturing child's needs were reported as being beneficial to young peoples' transition processes, while parents who hover over or micromanage their children during this time were found to hinder successful transitions. Ultimately, the majority of reviewed articles emphasized maintained parental involvement as having a net positive impact on adolescents' transitions to adult care. As such, practice and policies should be structured to engage parents throughout the transition process to best support their chronically ill children during this time of change. [ABSTRACT FROM AUTHOR]

Background: There are limited data on utility of diffusion-weighted imaging (DWI) in the evaluation of pediatric liver lesions.Objective: To determine whether qualitative and quantitative DWI can be used to differentiate benign and malignant pediatric liver lesions.Materials and Methods: We retrospectively reviewed MRIs in children with focal liver lesions to qualitatively evaluate lesions noting diffusion restriction, T2 shine-through, increased diffusion, hypointensity on DWI and apparent diffusion coefficient (ADC) maps, and intermediate signal on both, and to measure ADC values. Pathology confirmation or a combination of clinical, laboratory and imaging features, and follow-up was used to determine final diagnosis.Results: We included 112 focal hepatic lesions in 89 children (median age 11.5 years, 51 female), of which 92 lesions were benign and 20 malignant. Interobserver agreement was almost perfect for both qualitative (kappa 0.8735) and quantitative (intraclass correlation coefficient [ICC] 0.96) diffusion assessment. All malignant lesions showed diffusion restriction. Most benign lesions other than abscesses were not restricted. There was significant association of qualitative restriction with malignancy and non-restriction with benignancy (Fisher exact test P<0.0001). Mean normalized ADC values of malignant lesions (1.23x10-3 mm2/s) were lower than benign lesions (1.62x10-3 mm2/s; Student's t-test, P<0.015). However, there was significant overlap of ADC between benign and malignant lesions, with wide range for each diagnosis. Receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.63 for predicting malignancy using an ADC cut-off value of ≤1.20x10-3 mm2/s, yielding a sensitivity of 78% and a specificity of 54% for differentiating malignant from benign lesions.Conclusion: Qualitative diffusion restriction in pediatric liver lesions is a good predictor of malignancy and can help to differentiate between benign and malignant lesions, in conjunction with conventional MR sequences. Even though malignant lesions demonstrated significantly lower ADC values than benign lesions, the use of quantitative diffusion remains limited in its utility for distinguishing them because of the significant overlap and wide ranges of ADC values. [ABSTRACT FROM AUTHOR]

Background: Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences. Methods: We pursued a multidisciplinary study of CDD (n = 17) and three comparison groups: low-functioning ASD (n = 12), high-functioning ASD (n = 50), and typically developing (n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces. Results: We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP, ZNF236, and KIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces. Conclusions: Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level. [ABSTRACT FROM AUTHOR]

Study Objective Alkylating agents are implicated in premature ovarian insufficiency. To optimize counseling regarding future ovarian function in survivors of adolescent cancer, we describe anti-Müllerian hormone (AMH) levels in female adolescents at diagnosis, during, and shortly after completion of chemotherapy. Design, Setting, Participants, Interventions, and Main Outcome Measures This was a prospective single-institution study. Participants were a mixed population of newly diagnosed postmenarchal female adolescents with malignancy. AMH was performed at diagnosis (T1), 6 months from diagnosis (T2), at end of therapy or 12 months [T3, whichever came first], 1 year after the end of therapy or 24 months from diagnosis [T4, whichever came first], and 18 months from the time of diagnosis (T5). All patients had baseline pelvic ultrasound examinations. Presence of menses and hot flashes were recorded at each time point. Results Sixteen participants with a median age at diagnosis of 14.3 years (range 12-17 years) were followed for 18.2 months (range, 14-24 months). Oncology diagnoses included leukemia, lymphoma, and sarcoma. Ten patients (62.5%) received alkylating agents with a median cumulative dose of 3041 mg/m 2 (range, 2639-6478 mg/m 2 ) of cyclophosphamide. Almost half (n = 7; 44%) experienced amenorrhea during treatment with resumption of menses in 6 of 7 patients (85%). Fifteen of 16 (94%) participants showed a decline in mean AMH levels by 6 months (T2) from diagnosis (15.8 IU/mL at T1 vs 6.5 IU/mL at T2; P = .003) and 12 of 15 (80%) showed at least some recovery of AMH (mean AMH at T4 = 13.2 IU/mL compared with 6.5 IU/mL at T2; P = .02). There was no difference in the mean decline nor recovery of AMH in those who did, vs did not receive cyclophosphamide. Conclusion To our knowledge, this is the largest series to date in adolescents showing that AMH is uniformly suppressed during cancer therapy and short-term recovery occurs in just more than half of the patients by 18-24 months. The contribution of short-term AMH measurements in predicting long-term ovarian function remains to be defined. Long-term follow-up with serial AMH levels is required to help predict those at risk for premature ovarian insufficiency. [ABSTRACT FROM AUTHOR]

Literature regarding the development of adolescent and young adult (AYA) cancer programs has been dominantly informed by pediatric centers and practitioners. However, the majority of young adults are seen and treated at adult cancer centers, in which cancer volumes afford the development of innovative supportive care services. Although the supportive care services in adult cancer centers are helpful to AYAs, some of the most prominent and distinct issues faced by AYAs are not adequately addressed through these services alone. This article describes how the AYA Program at Princess Margaret Cancer Centre has collaborated with existing supportive care services in addition to supplying its own unique services to meet the comprehensive needs of AYAs in the domains of: symptom management (sexuality and fatigue), behavior modification (return to work and exercise), and health services (advanced cancer and survivorship). These collaborations are augmented by patient education interventions and timely referrals. The objective of this article was to assist other centers in expanding existing services to address the needs of AYA patients with cancer. [ABSTRACT FROM AUTHOR]

In the article, the author discusses the issue of fertility preservation (FP) among adolescent and young adult (AYA) members of the lesbian, gay, bisexual, and transgender (LGBT) population who are suffering from cancer, particularly in the U.S.

Mesenchymal breast tumors are a rare and diverse group of tumors that present some of the most challenging cases for multidisciplinary breast cancer teams. As a result of overlapping morphologies and a lack of large-scale studies on these tumors, practices are often heterogeneous and slow to evolve. Herein, we present a non-systematic review that focuses on progress, or lack thereof, in the field of mesenchymal breast tumors. We focus on tumors originating from fibroblastic/myofibroblastic cells and tumors originating from less common cellular origins (smooth muscle, neural tissue, adipose tissue, vascular tissue, etc.). [ABSTRACT FROM AUTHOR]

1. Explain the impact of specialized palliative care on reducing high-intensity end-of-life care in adolescents and young adults with cancer 2. Identify subpopulations among adolescents and young adults with cancer who are at highest risk for reduced access to specialized palliative care A high proportion of adolescents and young adults (AYAs) with cancer (ages 15-39 years) receive high-intensity (HI) medical care at the end of life (EOL). We have previously shown that palliative care (PC) involvement in this population is associated with lower risk of HI-EOL care. Whether this association differs by specialized or general PC (SPC, GPC) is unknown. To evaluate the prevalence and predictors of SPC in AYAs with cancer and to evaluate the impact of SPC versus GPC on the intensity of EOL care for AYAs. A decedent cohort of AYAs with cancer who died between 2000 and 2017 in Ontario, Canada was assembled from registries and linked to population-based healthcare data. Based on prior studies, the primary composite measure HI-EOL care included any of intravenous chemotherapy <14 days from death, >1 ED visit, and >1 hospitalization or ICU admission <30 days from death. SPC and GPC were defined via previously validated algorithms based on physician billing codes (SPC if practice consisted of ≥50% PC-specific billing codes and GPC if PC-specific billing codes were between 10% and 50%). Of 7,122 AYAs, 2,140 (30%) received SPC and 942 (13.2%) received GPC. AYAs with hematologic malignancies, male AYAs, and rural AYAs were least likely to have access to SPC. No PC involvement compared to GPC was associated with higher odds of receiving HI-EOL care (OR 1.5; 95% CI, 1.3-1.8; P <.001). However, SPC was associated with the lowest risk of HI-EOL care (OR vs GPC 0.8; 95% CI, 0.7-0.9; P = 0.007). SPC was also associated with decreased odds of ICU admission compared with GPC (OR 0.7; 95% CI, 0.5-0.9; P = 0.006). SPC is associated with a lower risk of HI-EOL care in AYAs with cancer as compared to GPC. However, access to SPC remains a challenge. Our study supports the widespread provision of SPC to AYAs with cancer. [ABSTRACT FROM AUTHOR]

Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk. [ABSTRACT FROM AUTHOR]

In this paper, a computationally efficient isogeometric plate model, employing nonpolynomial shear deformation theory (NPSDT), for static and dynamic analysis of laminated and sandwich composite plates under hygrothermal environment is presented. Transient and steady-state response using Rayleigh damping model and fast Fourier transformation of transient response have also been obtained for the hygrothermal environment. The non-uniform rational B-splines (NURBS) based formulation has been considered, which attribute only five-degree of freedom and satisfies the stringent continuity requirement of the NPSDT model (C 1 -continuity) without any additional variables. A total Lagrangian approach in conjunction with Hamilton's principle is utilized to formulate the governing equations for thermal bending and subsequent dynamic analysis of multilayered composite plates. To model stress stiffening effect due to hygrothermal load, both von Kármán and Green–Lagrange strain displacement relations are incorporated and obtained solutions are compared. It has been shown that at higher temperature (around one fourth of the critical buckling temperature), the consideration of Green–Lagrange strain relationship for modeling stiffening effect due to hygrothermal load is important for better accuracy. Further, it has been shown that bending strip is essential in case of higher-order shear deformation theory (HSDT) to get more accurate solution. In addition, the obtained transient damped/undamped solutions may be used to get the natural frequency from their FFT solution. [ABSTRACT FROM AUTHOR]

Context: Many adolescents and young adults (AYAs; 15-39 years) with cancer receive high intensity (HI) care at the end of life (EOL). Palliative care (PC) involvement in this population is associated with lower risk of HI-EOL care. Whether this association differs by specialized versus generalist PC (SPC, GPC) is unknown.Objectives: (1) To evaluate whether SPC had an impact on the intensity of EOL care received by AYAs with cancer; (2) to determine which subpopulations are at highest risk for reduced access to SPC.Methods: A decedent cohort of AYAs with cancer who died between 2000-2017 in Ontario, Canada was identified using registry and population-based data. The primary composite measure of HI-EOL care included any of: intravenous chemotherapy <14 days from death; more than one ED visit, more than one hospitalization or any ICU admission <30 days from death. Physician's billing codes were used to define SPC and GPC involvement.Results: Of 7,122 AYA decedents, 2,140 (30%) received SPC and 943 (13%) received GPC. AYAs who died in earlier years, those with hematologic malignancies, males and rural AYAs were least likely to receive SPC. No PC involvement was associated with higher odds of receiving HI-EOL care (odds ratio (OR) 1.5; p<0.0001). However, SPC was associated with the lowest risk of HI-EOL care (OR SPC versus GPC 0.8; p=0.007) and decreased odds of ICU admission (OR 0.7; p=0.006).Conclusion: SPC involvement was associated with the lowest risk of HI-EOL care in AYAs with cancer. However, access to SPC remains a challenge. [ABSTRACT FROM AUTHOR]

Improving access to clinical trials for adolescents with cancer remains an important issue for pediatric health care providers. In this brief report, we highlight barriers to increasing the number of clinical trials as a mechanism for addressing this problem. The challenges discussed include: (1) engaging stakeholders to increase funding; (2) increasing cooperation between clinical trial cooperative groups; and (3) permitting delivery of novel drugs to postpubertal adolescents, in the absence of formal pediatric Phase I evaluation. [ABSTRACT FROM AUTHOR]

Background Whole-exome sequencing studies in autism spectrum disorder (ASD) have identified de novo mutations in novel candidate genes, including the synaptic gene Eighty-five Requiring 3A (EFR3A). EFR3A is a critical component of a protein complex required for the synthesis of the phosphoinositide PtdIns4P, which has a variety of functions at the neural synapse. We hypothesized that deleterious mutations in EFR3A would be significantly associated with ASD. Methods We conducted a large case/control association study by deep resequencing and analysis of whole-exome data for coding and splice site variants in EFR3A. We determined the potential impact of these variants on protein structure and function by a variety of conservation measures and analysis of the Saccharomyces cerevisiae Efr3 crystal structure. We also analyzed the expression pattern of EFR3A in human brain tissue. Results Rare nonsynonymous mutations in EFR3A were more common among cases (16 / 2,196 = 0.73%) than matched controls (12 / 3,389 = 0.35%) and were statistically more common at conserved nucleotides based on an experiment-wide significance threshold (P = 0.0077, permutation test). Crystal structure analysis revealed that mutations likely to be deleterious were also statistically more common in cases than controls (P = 0.017, Fisher exact test). Furthermore, EFR3A is expressed in cortical neurons, including pyramidal neurons, during human fetal brain development in a pattern consistent with ASD-related genes, and it is strongly co-expressed (P < 2.2 × 10-16, Wilcoxon test) with a module of genes significantly associated with ASD. Conclusions Rare deleterious mutations in EFR3A were found to be associated with ASD using an experiment-wide significance threshold. Synaptic phosphoinositide metabolism was strongly implicated in syndromic forms of ASD. These data for EFR3A strengthen the evidence for the involvement of this pathway in idiopathic autism. [ABSTRACT FROM AUTHOR]

An 18-year-old male with a history of Charcot-Marie-Tooth disease (CMT) presented with metastatic Ewing sarcoma to the lungs. He had been followed by several healthcare professionals who ascribed his enlarging 23 cm gluteal mass to his CMT. The patient experienced a significant delay in diagnosis, not uncommon in sarcoma. This case explores the various system and cognitive errors that contributed to this delay. [ABSTRACT FROM AUTHOR]

The current study took a quasi-experimental approach investigating the effect of a holistic after-school intervention, on reading comprehension measured by the Gray Oral Reading Test (GORT)-4 on at-risk students in Grade 2 through Grade 5. Analysis of Variance was used to investigate the relationship between pre- and post-intervention scores. The study showed encouraging results. The 91 student participants showed gains in their GORT-4 total scores after the intervention. Results of after-school tutoring lend support to the use of peer-tutoring in afterschool in the elementary schools. Due to the exploratory nature of the study in a single school, there are constraints on generalizability and utility of findings to other schools across the board. [ABSTRACT FROM PUBLISHER]

Abstract: High performance surface plasmon resonance (SPR) sensor is proposed for relative humidity (RH) monitoring. The structure is based on widely used 2S2G chalcogenide glass and gold as SPR active metal applied with silica-based porous film. The angular interrogation method has been used to study the performance of the sensor in terms of intrinsic sensitivity (S I ) that includes the width and shifts of SPR curve for the entire RH-range between 0% and 100%. The effect of temperature is also studied on the proposed sensor's performance. Any possibility of oxidation problem to the proposed SPR sensor due to constantly being in contact with humid environment may be addressed by using a stable buffer layer. Intrinsic sensitivity of the proposed sensor is significantly high for almost entire range of RH values. The proposed sensor has a good resolution of the order of 10−2% RH. [Copyright &y& Elsevier]

Background: Young adults (YA) with cancer have unique psychosocial and medical needs. The objective of this study was to identify information and service needs important to YA cancer patients. Methods: A supportive care needs survey was administered to ambulatory patients (

Background: Adolescents and young adults (AYA, ages 15–39 years) affected by cancer have unique treatment, survivorship, and palliation concerns. Current oncology training does not focus on the distinctive needs of this demographic. Amid this recognition, the Canadian National AYA Cancer Task Force and Canadian Partnership Against Cancer have advocated the need for clinicians with formalized AYA experience. To address this need and standardize training, a national task force developed criteria for structured academic programs in AYA Oncology in Canada. Methods: Workshops were organized to identify and establish the fundamentals of practice in AYA Oncology through consensus. These workshops followed the pre‐existing rigorous process established by the Royal College of Physicians and Surgeons of Canada (Royal College) for new program development. The process includes: (i) developing the tasks associated with the discipline's practice, (ii) identifying the evidence trainees must provide to demonstrate tasks can be performed independently (the competence portfolio), (iii) developing training requirements and summarizing the knowledge, skills and attitudes required to perform these tasks, and (iv) identifying specific experiences essential to acquiring skills and demonstrating competent performance. Results: AYA Oncology is a recognized an Area of Focused Competence (AFC) by the Royal College. Conclusion: The AFC designation in AYA Oncology provides a standardized curriculum, training experience and accreditation process to attract oncologists, promote expertise and advance AYA oncology care. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients aged >10 years with rhabdomyosarcoma have an inferior outcome compared with patients ages 1 to 9 years, which may be explained by toxicities (adverse events [AEs]) that result in chemotherapy dose reductions. METHODS: AEs observed during 1 of 3 randomized chemotherapy regimens (vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide [VAI]; or vincristine, ifosfamide, and etoposide [VIE]) in the Fourth Intergroup Rhabdomyosarcoma Study were recorded. The incidence of toxicities by age and treatment regimen was determined. The odds of developing AEs in a particular age group (ages 5-9 years, 10-14 years, and 15-20 years) were compared with the odds in the control group of patients ages 1 to 4 years. RESULTS: In total, 657 patients were eligible for analysis. The estimated 5-year event-free survival rates were 78%, 83%, 67%, and 58% for the groups ages 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 20 years, respectively. Patients ages 15 to 20 years experienced less neutropenia (odds ratio [OR], 0.43; P < .0001), thrombocytopenia (OR, 0.41; P < .0001), anemia (OR, 0.34; P < .0001), and infection (OR, 0.41; P < .0001) compared with younger patients, although they received similar amounts of chemotherapy. In contrast, peripheral nervous system toxicity was higher in adolescents aged >10 years (OR, 4.18; P < .0001). Females experienced more neutropenia (OR, 1.28; P = .05) and thrombocytopenia (OR, 1.26; P = .06) compared with males. CONCLUSIONS: Adolescents who received treatment for rhabdomyosarcoma experienced significantly less hematologic toxicity and more peripheral nervous system toxicity compared with younger children despite receiving similar amounts of chemotherapy. Although outcomes were inferior in adolescents, it was unclear whether the differences in toxicity observed in the current study had an impact on outcome. The authors concluded that future studies examining the age-related and sex-related differences in pharmacokinetics of chemotherapy are necessary. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined if differences in therapeutic strategy in pediatric and adult specialty sarcoma centers are associated with clinical outcome. The study reviewed the medical data of patients with Ewing sarcoma (EWS), who were treated between 1990 and 2005 at tertiary care pediatric and adult institutions. It discovered that the doses of alkylating agents and timing of local therapy infleunce clinical outcome in patients with EWS.

We describe two cases of chorioretinal dysplasia and microcephaly and review the current literature regarding this topic. [ABSTRACT FROM AUTHOR]

Abstract: Systemic sclerosis is a chronic multi-system disorder predominantly affecting the skin, musculoskeletal, gastrointestinal, pulmonary, and renal systems. Although the exact etiology is unknown, recent evidence suggests that immune activation play a pivotal role in the pathogenesis. Ocular involvement in systemic sclerosis has been documented; however, due to the rare nature of the disease, most papers have been single case reports or small case series. This review paper aims to consolidate the findings of previous papers with a view to providing a comprehensive review of the ocular manifestations of systemic sclerosis. [Copyright &y& Elsevier]

Autism is a strongly genetic disorder, with an estimated heritability of greater than 90%. Nonetheless, its specific genetic etiology remains largely unknown. Over the past several years, the convergence of rapidly advancing genomic technologies, the completion of the human genome project, and successful collaborative efforts to increase the number of deoxyribonucleic acid samples available for study have led to the first solid clues regarding the genetic origins of autism spectrum disorders. This article addresses the obstacles that have confronted gene discovery efforts and reviews recent linkage, cytogenetic, and candidate gene association studies relevant to autism spectrum disorders. In addition, promising avenues for future research and the potential contribution of emerging genomic technologies are considered. [Copyright &y& Elsevier]

The authors recommend a reading tutoring lesson framework, in a checklist format, to guide volunteer tutors during tutoring sessions for children in elementary grades 1-3. The reading tutor checklist is intended to be used by literacy coaches, reading specialists, and classroom teachers to train literacy volunteers in schools. The checklist consists of 7 main components, with each section listing specific instructional strategies including (a) guided reading, (b) phonological awareness, (c) phonics, (d) word study and vocabulary development, (e) word recognition, (f) fluency and (g) writing. Additionally, the checklist allows for introduction of a new book in each session with review or rereading of a book from the previous session. Specific strategies listed under each component provide tutors a structure for teaching respective skills. The authors discuss the use of the checklist during tutor training, parent workshops, and reflection meetings. The tutor checklist provides a systematic framework for volunteers to assist children with a wide range of reading activities. The checklist also offers instructional guidelines for tutors to help at-risk learners to expand their literacy potential. [ABSTRACT FROM AUTHOR]

This paper presents the measurements of gaseous SO2, NO2, HNO3 and NH3 and particulate NH4+, NO3−and SO42− at Rampur, a rural site of semi-arid region of India and annual mean concentrations are 3.7±2.2, 7.3±3.7, 0.7±0.6 and 6.7±4.2 and 1.0±0.4, 1.1±1.3 and 2.6±1.6 μg m−3, respectively. Seasonal variation with higher concentration in winter is observed for gaseous SO2, NO2, and NH3 and particulate NH4+. The concentration of HNO3 and particulate NO3−and SO42− are higher in summer. Summer to winter ratio of HNO3 and particulate NO3− are 3.8 and 1.8, respectively, showing seasonal variation is more pronounced in case of HNO3 than particulate NO3−. The ratio of gaseous NH3 to particulate NH4+ (NH3/NH4+) is more than 1 probably due to basic nature of aerosol. Examination of equilibrium between gaseous NH3 and HNO3 and particulate NH4NO3 shows observed equilibrium constant is lower than theoretical equilibrium constant in summer and vice versa in winter. [Copyright &y& Elsevier]

Cervical cancer screening by Papanicolaou (Pap) smear lowers the incidence and provides early detection of cervical cancer and is a preventative health care measure that should be available on a regular basis to all women at risk. As the population of ethnic women increases, it is important to assess whether these women are aware of and are utilizing this health service. A self-administered questionnaire was completed by 124 South Asian women, aged 18 to 60 years. Sixty-two South Asian students were selected from a university setting and 62 Tamil women were selected from a community center for South Asian women. This study examined the knowledge and use of Pap smears in South Asian women in Canada, and whether their level of acculturation or formal education influenced whether they know about and receive Pap smears. Low level of knowledge about the Pap test and a low prevalence of Pap testing behaviour was significantly correlated (p < 0.001) with a low level of formal education, education taking place outside of Canada, and a low index of acculturation. South Asian students were significantly more acculturated than Tamil women (p < 0.001). In conclusion, there was a low level of knowledge and prevalence of cervical cancer screening among South Asian women. This study highlights the need for educational interventions in Canada directed to ethnic women especially from South Asia. [ABSTRACT FROM AUTHOR]

Background: Most children with Autism Spectrum Disorder (ASD) have co-occurring language impairments and some of these autism-specific language difficulties are also present in their non-autistic first-degree relatives. One of the possible neural mechanisms associated with variability in language functioning is alterations in cortical gamma-band oscillations, hypothesized to be related to neural excitation and inhibition balance. Methods: We used a high-density 128-channel electroencephalography (EEG) to register brain response to speech stimuli in a large sex-balanced sample of participants: 125 youth with ASD, 121 typically developing (TD) youth, and 40 unaffected siblings (US) of youth with ASD. Language skills were assessed with Clinical Evaluation of Language Fundamentals. Results: First, during speech processing, we identified significantly elevated gamma power in ASD participants compared to TD controls. Second, across all youth, higher gamma power was associated with lower language skills. Finally, the US group demonstrated an intermediate profile in both language and gamma power, with nonverbal IQ mediating the relationship between gamma power and language skills. Limitations: We only focused on one of the possible neural contributors to variability in language functioning. Also, the US group consisted of a smaller number of participants in comparison to the ASD or TD groups. Finally, due to the timing issue in EEG system we have provided only non-phase-locked analysis. Conclusions: Autistic youth showed elevated gamma power, suggesting higher excitation in the brain in response to speech stimuli and elevated gamma power was related to lower language skills. The US group showed an intermediate pattern of gamma activity, suggesting that the broader autism phenotype extends to neural profiles. [ABSTRACT FROM AUTHOR]

Human metapneumovirus (HMPV) is a common virus that can cause respiratory problems ranging from mild upper respiratory tract disease to respiratory failure requiring mechanical support. Here, we report a case of a 32-month-old male with a previous history of asthma, who developed respiratory failure two weeks after onset of cough and rhinorrhea and required extracorporeal membrane oxygenation (ECMO) for 9 days after failing high-frequency oscillatory ventilation (HFOV). To our knowledge, this is the oldest reported pediatric patient with respiratory failure secondary to human metapneumovirus that did not respond to mechanical ventilation. This case highlights three critical points: the potentially fatal causative role of HMPV in respiratory failure in an older pediatric age group of immunocompetent hosts, the importance of early recognition of impending respiratory failure, and the timely utilization of ECMO. [ABSTRACT FROM AUTHOR]

• This review outlines chaperone machinery of HSP70 and HSP90. • Roles of HSP70 and HSP90 and their co-chaperons are summarized in various neurodegenerative diseases. • Pharmacological inhibition of HSP90 as a potential treatment of neurodegenerative disorders is discussed. Molecular chaperones have a role to stabilize proteins or assist them in reaching their native fold. Heat shock proteins (HSPs) are a family of molecular chaperons that protect proteins from cellular stress during the assembly of protein complexes and also prevent the proteins from aggregation and disassembly. The immediate increase of HSPs is crucial for cellular adaptation to environmental changes and protection of other proteins from denaturation, thereby maintaining the cellular homeostasis and increasing the longevity of an organism. HSP70 and HSP90 are the most studied HSPs in this very large HSP family. Notably, HSP90 also stabilizes the disease-related proteins in neurodegenerative disorders. Therefore, small molecules that inhibit the HSP90 but also increase the HSP70 has been tested as potential drugs for neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

An effective numerical approach based on the isogeometric analysis (IGA) employing nonpolynomial shear deformation theory (NPSDT) has been proposed and implemented in the present work for the static and dynamic analysis of laminated and sandwich composite plates. The theory assumes the nonlinear distribution of transverse shear stresses, and also satisfy the zero transverse shear deformation at the top and bottom surfaces of the laminates. Using Hamilton's principle, the governing equation of motion is derived and then discretized based on the IGA technique, which facilitates the use of non-uniform rational B-splines (NURBS) basis functions to easily satisfy the stringent continuity requirement of the NPSDT model (C 1 -continuity) without any additional variables. The set of governing equations are solved to obtain transient response using Newmark's time integration scheme. Fourier transformation is carried out on the transient response to obtain the natural frequency. Various numerical examples covering different features of present modeling for laminated and sandwich plates are investigated. The performance of the model has been observed by comparing the evaluated results with different published results available in the open literature which ascertain its precision and range of applicability at a reduced computational cost. [ABSTRACT FROM AUTHOR]

Adolescents and young adults (AYAs) with cancer, representing those between 15 and 39 years of age, face distinctive challenges balancing their life stage with the physical, emotional, and social impacts of a cancer diagnosis. These challenges include fertility concerns, disruptions to educational and occupational pursuits, issues related to body image and sexual health, and the need for age-appropriate psychosocial support within their communities. The Princess Margaret Cancer Centre (PM), a quaternary care center, established a specialized AYA program in 2014, offering holistic and developmentally tailored psychosocial support and currently, efforts are underway to expand this to other regions in the province to address the need for equitable access. The establishment process involves securing funding, conducting an environmental scan, identifying service gaps, developing clinical pathways, and implementing AYA supportive care. An accessible AYA program should also consider social determinants of health, social location, intersectionality, and an interdisciplinary health approach in understanding health inequities in AYA oncology care. This paper describes the processes implemented and challenges faced in creating a community-based AYA program beyond major resource-rich cities and efforts to address intersectionality. [ABSTRACT FROM AUTHOR]

Present research work is based on the unique properties of isogeometric analysis (IGA) like smarter, faster and cheaper analysis for the thermo-elastic bending of laminated and sandwich composite plates. IGA, based on isoparametric concept, is a breakthrough in the area of structural analysis, which employs non-uniform rational B-spline (NURBS) as a basis function to represent less erroneous geometry. Unlike finite-element method (FEM), increasing the polynomial order in IGA gives higher continuous basis functions naturally and easily with reduced computational cost. A procedure has been developed for thermo-elastic bending analysis of laminated composite plates and sandwich structures using IGA approach. The developed NURBS-based code is validated and computational efficacy of thermo-elastic analysis is investigated. A detailed parametric study has been carried out for the quadratic, cubic and quartic NURBS elements with respect to the variation of temperature. Different types of temperature profiles have been considered. Change of deflections, stresses and moment resultants are analysed with an aim to understand the thermo-elastic behaviour of laminated and sandwich composite plates. Several thermo-elastic numerical examples have been analysed extensively. Obtained numerical results are compared with available literature to show the advantage of current formulation. [ABSTRACT FROM AUTHOR]

Young adults (YAs), defined as individuals between the ages of 18 and 39 years, experience unique challenges when diagnosed with advanced cancer. Using the social constructivist grounded theory approach, we aimed to develop a theoretical understanding of how YAs live day to day with their diagnosis. A sample of 25 YAs (aged 22–39 years) with advanced cancer from across Canada participated in semi-structured interviews. Findings illustrate that the YAs described day-to-day life as an oscillating experience swinging between two opposing disease outcomes: (1) hoping for a cure and (2) facing the possibility of premature death. Oscillating between these potential outcomes was characterized as living in a liminal space wherein participants were unsure how to live from one day to the next. The participants oscillated at various rates, with different factors influencing the rate of oscillation, including inconsistent and poor messaging from their oncologists or treatment team, progression or regression of their cancer, and changes in their physical functioning and mental health. These findings provide a theoretical framework for designing interventions to help YAs adapt to their circumstance. [ABSTRACT FROM AUTHOR]

Purpose: Group mindfulness-based interventions are emerging as a promising, nonstigmatizing, and cost-effective strategy that may improve the well-being of individuals living with cancer. This study is a pilot pre–post mixed-method study to examine the feasibility, acceptability, and effects of an 8-week Mindfulness-based Cognitive Therapy group for Young Adults with Cancer (YA-MBCT). Methods: We approached young adults with cancer, who enrolled in YA-MBCT groups, offered at a large cancer hospital in Toronto, Ontario, Canada. Feasibility and acceptability were assessed through attendance rate and a postintervention satisfaction scale. Psychosocial outcomes were evaluated with a pre–post questionnaire package, with validated self-report measures, assessing depression, anxiety, perceived stress, quality of life, mindfulness, and self-compassion. Qualitative interviews were completed among a subset of participants to gain additional feedback. Results: Participants were 70 young adults with cancer, recruited from five YA-MBCT groups. Sixty participants (85%) attended a minimum of six of eight sessions, and overall satisfaction rates were high. All psychosocial outcomes demonstrated statistically significant changes (p < 0.01), with medium to large effect sizes (Cohen's d > 0.5). Qualitative interviews (n = 14) demonstrated overall positive views about the intervention, and provided insight into unique age-specific benefits, including reducing fear of cancer recurrence, improving body image, and creating a sense of belonging. Conclusion: The YA-MBCT is feasible and acceptable among young adults with cancer, with the potential to improve psychosocial outcomes. Our preliminary results should be replicated with larger studies with an active control group. [ABSTRACT FROM AUTHOR]

Purpose: Fertility is a concern for young women with breast cancer. We explore patient preferences for chemotherapy and whether women will trade-off survival benefits to maintain fertility following standardized information delivery. Methods: During a standardized interview, outcomes associated with adjuvant chemotherapy and 5 years of tamoxifen (CT) or 5 years of tamoxifen alone (NoCT) were described to participants. A threshold task was performed, in which each participant participated in two scenarios: (1) 10% absolute survival benefit from treatment and (2) 25% absolute survival benefit from treatment. The threshold point represented the reduction in fertility post-treatment that a participant would accept before she would trade-off CT benefit. Descriptive statistics were used to characterize participants. Demographic factors (age, marital status, parity at diagnosis, and education) associated with willingness to trade-off survival benefits were evaluated with logistic regression. Results: Analysis comprised 50 women with a median age of 34.5 years (range 25–39 years). Thirty-nine women (78%) completed university education. Thirty-four (68%) and 45 (90%) women in scenarios 1 and 2, respectively, were willing to trade-off all fertility (i.e., reduce fertility to 0% chance of conceiving naturally) to undertake CT and maintain survival benefits. Eight (16%) and three (6%) women in scenarios 1 and 2, respectively, chose to not pursue CT at all to maintain natural fertility. Regression analysis did not identify any variables that were predictive of participants' preferences. Conclusion: Most women with breast cancer are not willing to trade-off survival benefits of adjuvant therapy to maintain fertility. [ABSTRACT FROM AUTHOR]

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries. [ABSTRACT FROM AUTHOR]

Objectives: We conducted a retrospective multi‐centre study to assess the real‐world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra‐skeletal mesenchymal CS (ESMC). Methods: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12–76); median starting dose was 60 mg for CABO (n = 37, range 40–60) and 120 mg for REGO (n = 29, range 40–160). Twenty‐eight (42.4%) patients required dose reduction: hand‐foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7–13.1); 13.4 months (n = 18, 95% CI 3.4–27.2), 8.1 (n = 4, 95% CI 4.1–9.3) and 18.2 (n = 5, 95% CI (10.4–na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8–5), 3.9 (n = 18, 95% CI 2.1–5.9), 5.53 (n = 4. 95% CI 2.13–NA) and 11.4 (n = 5, 95% CI 1.83–14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. Conclusion: Our real‐world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research. Real‐world national CanSaRCC data support the use of regorafenib and cabozantinib in children and adults with relapsed bone sarcoma. [ABSTRACT FROM AUTHOR]