Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.

Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.

Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

Advanced Cancer in Young Adults (YAs): Living in a Liminal Space.

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.

Desmoid Tumors in Familial Adenomatous Polyposis Patients: Favorable Outcomes with Multidisciplinary Management.

OBJECTIVE: In this study, we aimed to describe the clinical features, management, and outcomes of desmoid tumors (DTs) in familial adenomatous polyposis (FAP) patients at a high-volume sarcoma center. METHODS: Consecutive patients with FAP and DTs were identified from our institutional databases (1985-2021). Patient demographics, treatment, and outcomes were described. Categorical data were compared using Fisher's exact test, and Kaplan-Meier curves were used to estimate progression-free survival (PFS). RESULTS: Forty-five patients with 67 DTs were identified: 39 mesenteric or retroperitoneal (58.2%), 17 abdominal wall (25.4%), 4 extremity (6%), 4 breast (6%) and 3 back (4.4%). Severe DT symptoms were present in 12 patients (26.7%). Initial treatments per tumor were observation in 30 (44.8%) DTs, chemotherapy in 15 (22.4%) DTs, surgery in 10 (14.9%) DTs, and other systemic therapies in 10 (14.9%) DTs. The majority of DTs remained stable with observation or a single intervention (77.8%). Median PFS was 23.4 years (95% confidence interval 7.6-39.2). In the 12 severely symptomatic patients, four patients required more than two interventions for DT control. At a median follow-up of 6.0 years (range 0.7-35.8 years), 33 (73.3%) patients were alive with disease, 7 (15.6%) were alive without disease, and 5 (11.1%) died of other causes. No patients died of DT-related complications. CONCLUSIONS: The majority of DTs in FAP patients remained stable with observation or a single intervention. There were no DT-related deaths; however, 12 of 45 patients (26.7%) experienced significant tumor morbidity and required more interventions for disease control. Further studies on quality of life are required.

Common queries in managing rhabdomyosarcoma in low- and middle-income countries: An Indo-North American collaboration.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma among children and adolescents. The management of RMS involves risk stratification of the patients based on various clinicopathological characteristics. The multimodality treatment approach requires chemotherapy, surgery, and/or radiation. The treatment of RMS necessitates the involvement of multiple disciplines, such as pathology, pediatric oncology, surgery, and radiation oncology. The disease heterogeneity, molecular testing, evolving treatment regimens, and limited resources are some of the challenges faced by clinicians while treating a patient with RMS in low- and middle-income countries (LMICs). In this review, we endeavor to bring experts from varying fields to address clinicians' common questions while managing a child or adolescent with RMS in LMICs. This review is most applicable to level 2 centers in LMICs as per the levels of services described by the Adapted Treatment Regimens Working Group of the Pediatric Oncology in Developing Countries committee of the International Society of Pediatric Oncology.

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.

BACKGROUND: Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS. METHODS: The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15 mg/m2 /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12 weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs). RESULTS: Ten patients (seven males and three females; median age = 4.5 years [range: 0.2-14.4 years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1 weeks (range: 11.7-15 weeks). CONCLUSIONS: Weekly temsirolimus at 15 mg/m2 /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.

Primitive Myxoid Mesenchymal Tumor of Infancy With Brain Metastasis Case Report and Literature Review.

Primitive myxoid mesenchymal tumor of infancy (PMMTI), a rare soft tissue tumor with distinct characteristics. PMMTI tends to have an aggressive local course, with multiple relapses and poor response to treatment. Rare cases of distant metastases have been described before. We described the second case of PMMTI with brain metastasis.

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective. METHODS: A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs. RESULTS: Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices. CONCLUSIONS: Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions. LAY SUMMARY: Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

Multidisciplinary Intervention in Radiation-Associated Angiosarcoma of the Breast: Patterns of Recurrence and Response to Treatment.

BACKGROUND: Radiation-associated angiosarcoma (RAAS) of the breast is an aggressive malignancy affecting 1 in 1000 breast cancer patients. This study aimed to determine differences in treatments and outcomes for RAAS initially managed through a sarcoma multi-disciplinary team (SMDT) compared with an outside center (OC) and to describe outcomes after recurrence. METHODS: Patients with a diagnosis of breast RAAS between 2004 and 2019 were identified from our sarcoma database. Clinicopathologic characteristics, recurrence patterns, and factors predictive of survival were assessed. Differences in local recurrence-free survival (LRFS) and disease-specific survival (DSS) were estimated using Kaplan-Meier and compared using the log-rank test. RESULTS: Surgery was performed for 49 women with RAAS, who had a median age of 74 years (range 41-89 years). Primary management was performed by SMDT for 26 patients and by OC for 23 patients. Radical mastectomy and reconstruction were performed for 96% of the SMDT group versus 17% of the OC group (p = 0.00001). The proportion patients who received chemotherapy, radiation, or both was 42.3% in the SMDT group and 0% in the OC group. During a median follow-up period of 26 months, recurrence was experienced by 38% (10/26) of the SMDT cohort and 83% (19/23) of the OC cohort (p = 0.002). The 3-year LRFS was better in the SMDT cohort (59.3% vs 31.8%; p = 0.019). Of the 29 recurrences 16 received chemotherapy and 6 received radiation, surgery, or both. At the last follow-up visit, 20 patients were in first remission, 1 patient was in second remission, 8 patients were alive with disease, and 20 patients had died of disease. CONCLUSION: Initial treatment by SMDT was associated with more extensive surgery, multimodal treatments, and a better 3-year LRFS. Patients with breast RAAS likely benefit from early referral and treatment by an SMDT.

Psychological distress and experiences of Adolescents and Young Adults with cancer during the COVID-19 pandemic: A cross-sectional survey.

BACKGROUND: This study investigated prevalence of psychological distress, factors associated with distress, and experiences of Adolescents and Young Adults (AYAs) with cancer during the COVID-19 pandemic. It also compared distress in this group to previously surveyed Canadian AYAs with cancer in 2018 by the Young Adults with Cancer in their Prime (YACPRIME) study. METHODS: A cross-sectional, online, self-administered survey of AYAs diagnosed with cancer between 15 and 39 years of age was conducted. Psychological distress was measured by the Kessler Psychological Distress Scale (K10). Associations between variables and high psychological distress (K10 ≥ 25), and comparison of prevalence of psychological distress with the YACPRIME study were done using multivariable logistic regression. Summative qualitative content analysis analyzed participant experiences during this pandemic. RESULTS: We included 805 participants. High psychological distress was present in over two-thirds of the group (68.0%; 95% CI, 64.7%-71.2%). Employment impact during pandemic (AOR (adjusted odds ratio), 2.16; 95% CI, 1.41-3.31) and hematologic malignancy (AOR, 1.76; 95% CI 1.08-2.97) were associated with higher psychological distress, while older age [AOR, 0.95; 95% CI, 0.92-0.99] and personal income < $40,000 (AOR, 0.38; 95% CI, 0.24-0.58) were associated with lower distress. Adjusted odds of experiencing psychological distress among AYAs with cancer during pandemic compared to pre-pandemic years was 1.85 (95% CI: 1.36-2.53). Overarching themes of pandemic experiences included: inferior quality of life, impairment of cancer care, COVID-19 related concerns and extreme social isolation. CONCLUSION: AYAs diagnosed with cancer are experiencing high psychological distress during this pandemic. Distress screening and evidence-based interventions to alleviate distress are essential.

Impact of locus of care on outcomes in adolescents and young adults with osteosarcoma and Ewing sarcoma treated at pediatric versus adult cancer centers: An IMPACT cohort study.

BACKGROUND: Location of cancer care (LOC; pediatric vs. adult center) impacts outcomes in adolescents and young adults (AYA) with some cancer types. Data on the impact of LOC on survival in AYA with osteosarcoma (OSS) and Ewing sarcoma (EWS) are limited OBJECTIVES: To compare differences in demographics, disease/treatment characteristics, and survival in a population-based cohort of AYA with OSS or EWS treated at pediatric versus adult centers METHODS: The Initiative to Maximize Progress in Adolescent Cancer Therapy (IMPACT) cohort captured demographic, disease, and treatment data for all AYA (15-21 years old) diagnosed with OSS and EWS in Ontario, Canada between 1992 and 2012. Patients were linked to provincial administrative health care databases. Outcomes were compared between patients treated in pediatric versus adult centers. RESULTS: One hundred thirty-seven AYA were diagnosed with OSS (LOC: 47 pediatric, 90 adult) and 84 with EWS (38 pediatric, 46 adult). AYA treated at pediatric centers were more likely to be enrolled in a clinical trial (OSS 55% vs. 1%, p < .001; EWS 53% vs. 2%, p < .001) and received higher cumulative chemotherapy doses. Five-year event-free survival (EFS ± standard error) in OSS and EWS were 47% ± 4% and 43% ± 5%, respectively. In multivariable analysis, the impact of LOC (pediatric vs. adult center) on EFS in OSS (adjusted hazard ratio [HR] 1.15, 95% confidence interval [CI]: 0.58-2.27, p = .69) and EWS (adjusted HR 1.82, 95% CI: 0.97-3.43, p = .06) was not statistically significant. CONCLUSION: Despite disparities in trial participation and chemotherapy doses, outcomes did not differ by LOC suggesting that AYA with bone tumors can be treated at either pediatric or adult centers.

Diagnostic and treatment intervals are not associated with survival in rhabdomyosarcoma: A Cancer in Young People in Canada study.

BACKGROUND: Delay in diagnosis and treatment initiation can be associated with adverse outcomes in children with cancer. Diagnostic interval (DI) is defined as the time between the date of first health care contact for symptoms related to cancer to the date of cancer diagnosis, and treatment interval (TI) is defined as interval between the definitive cancer diagnosis and cancer treatment initiation. We aimed to determine the predictors of DI and TI in children with rhabdomyosarcoma (RMS) and their association with event-free survival (EFS) and overall survival (OS). METHODS: Using the Cancer in Young People in Canada (CYP-C) national population-based database, we conducted a retrospective cohort study of children (0-14.99 years) newly diagnosed with RMS between 2001 and 2015 in Canada. Quantile regression was used to assess the predictors of DI and TI, and Cox regression was used to determine if these intervals were associated with EFS and OS. RESULTS: Median DI and TI were 16.5 days (interquartile range [IQR] 6.0-38.0) and 5 days (IQR 0-12), respectively. DI and TI were not significantly associated with age at diagnosis, sex, race, tumor site, stage or histology, treatment region, distance from treatment center, income quintile or diagnosis year (all p > .05). DI and TI were not associated with EFS (DI: hazard ratio [HR] 1.00, 95% CI 0.96-1.05, p = .871; TI: HR 1.03, 95% CI 1.00-1.05, p = .053) or OS (DI: HR 0.99, 95% CI 0.94-1.05, p = .797; TI: HR 1.02, 95% CI 0.99-1.05, p = .155). CONCLUSIONS: In the publicly funded Canadian health care system, DI and TI did not affect the survival of children with RMS.

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series.

Neurofibromatosis type 1-associated plexiform neurofibromas can cause debilitating symptoms and be life threatening. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumours following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen-activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumour shrinkage/stabilisation and symptom improvement. We report a national case series of 19 children treated with selumetinib. All patients experienced symptom improvement or stabilisation with an acceptable toxicity profile, including those patients previously treated with trametinib. This real-world experience confirms previous trials showing significant clinical benefit for this patient population.

A neurogenetic analysis of female autism.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

Bone Health in Osteosarcoma at Presentation and Its Impact on Cancer Treatment: A Case Series of 3 Pediatric Patients.

Osteosarcoma is the most common pediatric malignant bone tumor. Concomitant osteoporosis has typically been attributed to oncologic therapy. The present case series is aimed to describe 3 patients who presented with osteoporosis or osteopenia before, or early in, their oncology treatment. In our patients, bone health and its complications had significant impacts including pain, reduced mobility, prolonged admission, and delays in recovery. Our patients experienced improvement with resection of their primary tumor and with bisphosphonate infusion. Future studies are required to determine the prevalence osteoporosis at presentation of osteosarcoma and the role of bisphosphonates.

Is Detection of Relapse by Surveillance Imaging Associated With Longer Survival in Patients With Rhabdomyosarcoma?

BACKGROUND: We investigated whether surveillance imaging had an impact on post-relapse survival in patients with rhabdomyosarcoma (RMS). We hypothesized that relapse detected by imaging (group IM) would be associated with longer survival compared with relapse detected with a clinical sign or symptom (group SS). MATERIALS AND METHODS: We performed an observational multi-institutional study in 127 patients with relapsed RMS comparing overall survival (OS) after relapse using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Relapse was detected in 60 (47%) group IM and 67 (53%) SS patients. Median follow-up in survivors was 4 years (range 1.0 to 16.7 y). Four-year OS rates were similar between group IM (28%, 95% confidence interval [CI]: 14%-40%) and SS (21%, 95% CI: 11%-31%) ( P =0.14). In multivariable analyses accounting for institution, age at diagnosis, time to relapse, risk group at diagnosis, and primary site, not receiving chemotherapy (hazard ratio [HR]: 6.8, 95% CI: 2.8-16.6), radiation (HR: 3, 95% CI: 1.7-5.3), or surgery (HR: 2.8, 95% CI: 1.6-4.8) after relapse were independently associated with poor OS. CONCLUSION: These results on whether surveillance imaging provides survival benefit in patients with relapsed RMS are inconclusive. Larger studies are needed to justify current surveillance recommendations. Chemotherapy, radiotherapy and surgery to treat recurrence prolong OS.

Loneliness among adolescents and young adults with cancer during the COVID-19 pandemic: a cross-sectional survey.

BACKGROUND: Adolescents and young adults (AYAs) diagnosed with cancer are at an increased risk of experiencing social isolation and loneliness secondary to their cancer and its treatment. The physical distancing measures implemented during the COVID-19 pandemic may have further increased loneliness among this group. This study examined the prevalence of loneliness and factors associated with loneliness among AYAs with cancer during this pandemic. METHODS: We conducted a self-administered, online, cross-sectional survey of Canadian AYAs diagnosed with cancer between 15 and 39 between January and February 2021. Loneliness was measured using the 3-item UCLA Loneliness Scale. Factors associated with higher levels of loneliness were identified using multiple logistic regression. RESULTS: The analysis included 805 AYAs. The prevalence of loneliness was 52.2% [N = 419, 95% CI (confidence interval) 48.7 to 55.6%]. Individuals who were 18-25 years old [AOR (adjusted odds ratio)1.60, CI 1.03-2.47, p = 0.035], currently undergoing cancer therapy (AOR 1.46, 95% CI 1.03-2.07, p = 0.035), who self-disclosed the presence of a pre-pandemic mental health condition (AOR 2.09, 95% CI = 1.22-3.58, p = 0.007), or were not in a relationship (AOR 2.22, 95% CI 1.57-3.14, p < 0.001) were more likely to report loneliness than others. Participants that lived in rural or remote locations were less likely to experience loneliness (AOR 0.59, 95%CI 0.40-0.87, p = 0.008). CONCLUSION: One in two AYAs with cancer are feeling lonely during the COVID-19 pandemic. Future studies for developing interventions to target loneliness, particularly for those at greater risk, are necessary to improve the health and quality of life of AYAs with cancer.

Case of epithelioid hemangioendothelioma occurring in the postradiation setting for breast cancer.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor, which is typically characterized by recurrent fusion genes. EHEs most commonly occur in the lung, liver, bone, and internal organs. EHE has rarely been reported to occur in the post-radiotherapeutic setting, the breast site or in association with breast cancer. The differential diagnosis for radiation-associated vascular lesions of the breast is classically limited to atypical vascular lesion and angiosarcoma and does not include EHE. We present the case of a woman with a history of breast cancer and post-surgical radiotherapy who went on to develop an EHE of the chest wall skin within 3 years of the completion of radiotherapy. Microscopically, the lesion was infiltrative and composed of anastomosing nests of epithelioid-to-spindled cells with eosinophilic and vacuolated cytoplasm. By immunohistochemistry, the cells were positive for ERG, D2-40, and CD31. The diagnosis was confirmed by identification of a characteristic WWTR1-CAMTA1 fusion gene using RNA sequencing. This case expands our understanding of radiation-associated tumors.

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).