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BACKGROUND: In the general population, individuals with minoritized sexual orientation and gender identity have a higher burden of chronic health conditions than heterosexual individuals. However, the extent to which sexual orientation is associated with excess burden of chronic conditions in adolescent and young adult cancer survivors (AYACS) is unknown. METHODS: Lesbian, gay, and bisexual (LGB) AYACSs, LGB individuals without a history of cancer, and heterosexual AYACSs were identified by self-reported data from the cross-sectional National Health Interview Survey (2013-2020). Socioeconomic factors and the prevalence of chronic health conditions were compared between groups using χ2 tests. Logistic regression methods were used to determine the odds of chronic conditions by socioeconomic factors within and between survivor and comparison groups. RESULTS: One hundred seventy LGB cancer survivors, 1700 LGB individuals without a history of cancer, and 1700 heterosexual cancer survivors were included. Compared with heterosexual survivors, LGB survivors were less likely to be married (p = .001) and more likely to have never been married (p < .001). LGB survivors were more likely to have incomes between 100% and 200% of the federal poverty level than LGB individuals without a history of cancer (p = .012) and heterosexual survivors (p = .021) and were less likely to report incomes >200% the federal poverty level. LGB survivors had higher odds of chronic health conditions than LGB individuals without a history of cancer (odds ratio, 2.45; p < .001) and heterosexual survivors (odds ratio, 2.16; p = .003). CONCLUSIONS: LGB AYACSs are at increased risk of having chronic health conditions compared with both LGB individuals without a history of cancer and heterosexual AYACSs.
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Neoplasias , Minorias Sexuais e de Gênero , Humanos , Adolescente , Adulto Jovem , Feminino , Masculino , Estudos Transversais , Identidade de Gênero , Bissexualidade , Comportamento Sexual , Sobreviventes , Doença Crônica , Neoplasias/epidemiologiaRESUMO
There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.
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Antraciclinas , Sobreviventes de Câncer , Cardiotoxicidade , Predisposição Genética para Doença , Humanos , Adolescente , Antraciclinas/efeitos adversos , Adulto Jovem , Masculino , Feminino , Cardiotoxicidade/genética , Adulto , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Antibióticos Antineoplásicos/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors. PATIENTS AND METHODS: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores <50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models. RESULTS: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% Hispanic, 10% Black, and 7% other race/ethnicity) were 43.6 and 46.7, respectively. Women with breast cancer reported the most favorable PCS (50.8), and those with cervical cancer reported the lowest MCS (42.8). Age at diagnosis was associated positively with PCS (P<.001) and inversely with MCS (P<.001). Females had higher PCS yet lower MCS than males (both P<.001). Marginalized racial and ethnic populations reported lower PCS than White patients (P<.001). Physical and mental HRQoL were prognostic and associated with increased risk of poor survival (hazard ratio, 1.95; 95% CI, 1.72-2.21 for physical HRQoL, and 1.26; 95% CI, 1.13-1.40 for mental HRQoL). CONCLUSIONS: Physical and mental HRQoL at diagnosis vary across patient characteristics in AYA cancer survivors. Poor HRQoL at diagnosis may be a prognosticator of diminished overall survival among AYA cancer survivors.
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Neoplasias , Qualidade de Vida , Humanos , Adolescente , Feminino , Masculino , Adulto Jovem , Neoplasias/psicologia , Neoplasias/diagnóstico , Neoplasias/mortalidade , Adulto , Sobreviventes de Câncer/psicologia , Sobreviventes de Câncer/estatística & dados numéricos , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , PrognósticoRESUMO
BACKGROUND: Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Classification of bulk tumors by their individual cellular constituents has also created new opportunities to generate single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous promise of this technology, recent evidence studying epithelial tissues and diverse carcinomas suggests the methods used for tissue processing, cell disaggregation, and preservation can significantly bias gene expression and alter the observed cell types. To determine whether sarcomas - tumors of mesenchymal origin - are subject to the same technical artifacts, we profiled patient-derived tumor explants (PDXs) propagated from three aggressive subtypes: osteosarcoma (OS), Ewing sarcoma (ES), desmoplastic small round cell tumor (DSRCT). Given the rarity of these sarcoma subtypes, we explored whether single-nuclei RNA-seq from more widely available archival frozen specimens could accurately be identified by gene expression signatures linked to tissue phenotype or pathognomonic fusion proteins. RESULTS: We systematically assessed dissociation methods across different sarcoma subtypes. We compared gene expression from single-cell and single-nucleus RNA-sequencing of 125,831 whole-cells and nuclei from ES, DSRCT, and OS PDXs. We detected warm dissociation artifacts in single-cell samples and gene length bias in single-nucleus samples. Classic sarcoma gene signatures were observed regardless of the dissociation method. In addition, we showed that dissociation method biases could be computationally corrected. CONCLUSIONS: We highlighted transcriptional biases, including warm dissociation and gene-length biases, introduced by the dissociation method for various sarcoma subtypes. This work is the first to characterize how the dissociation methods used for sc/snRNA-seq may affect the interpretation of the molecular features in sarcoma PDXs.
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Sarcoma de Ewing , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Transcriptoma , Sarcoma/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Análise de Sequência de RNA/métodos , RNA-Seq/métodosRESUMO
PURPOSE: Survivors of adolescent and young adult (AYA) cancer experience psychological distress and insufficient access to mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes in this population. This study compared psychological distress, mental health care use, and inability to afford mental health care between Hispanic/Latino survivors of AYA cancer and Hispanic/Latino controls. METHODS: The National Health Interview Survey data (2010-2018) were analyzed to identify Hispanic/Latino survivors of AYA cancer and Hispanic/Latino age- and sex-matched non-cancer controls. Sociodemographic, chronic health, modifiable factors, and psychological outcomes were compared using chi-square tests. Logistic regression models with survey weights were used to assess the log-odds of psychological distress in relation to covariates, along with the cancer group. Interactions were evaluated between each variable and cancer group. RESULTS: The study included 370 Hispanic/Latino survivors of AYA cancer (mean time since diagnosis = 12.34 years) and 3700 Hispanic/Latino controls. Compared to controls, survivors were more likely to report moderate/severe distress (OR = 2.23, p < 0.001), use of mental health care (OR = 2.11, p < 0.001) and inability to afford mental health care (OR = 3.05, p < 0.001). Forty-one percent of survivors reported moderate/severe distress and only 16% utilized mental health care. Among survivors, having more than two chronic health conditions and public insurance (compared to private insurance) were associated with the presence of moderate/severe distress. Among survivors experiencing moderate/severe distress, lack of insurance was associated with decreased utilization of mental health care. CONCLUSIONS: Having cancer as an AYA may exacerbate disparities in psychological health within the Hispanic/Latino population.
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Sobreviventes de Câncer , Serviços de Saúde Mental , Neoplasias , Aceitação pelo Paciente de Cuidados de Saúde , Angústia Psicológica , Adolescente , Humanos , Adulto Jovem , Hispânico ou Latino/psicologia , Neoplasias/terapia , Neoplasias/psicologia , Sobreviventes de Câncer/psicologiaRESUMO
PURPOSE: Radiation therapy (RT) is a critical component of treatment for adolescents and young adults (AYAs, age 15-39 years old) diagnosed with cancer. Limited prior studies have focused on AYAs receiving RT despite the potentially burdensome effects of RT. We reviewed the literature to assess health-related quality of life (HRQOL) in AYAs with cancer who received RT. METHODS: The MEDLINE, EMBASE, and Web of Science databases were searched in January 2022 to identify studies that analyzed HRQOL measured by patient-reported outcomes in AYAs who received RT. After title (n = 286) and abstract (n = 58) screening and full-text review (n = 19), articles that met eligibility criteria were analyzed. RESULTS: Six studies were analyzed. Two studies included AYAs actively receiving treatment and all included patients in survivorship; time between diagnosis and HRQOL data collection ranged from 3 to > 20 years. Physical and mental health were commonly assessed (6/6 studies) with social health assessed in three studies. AYA-relevant HRQOL needs were rarely assessed: fertility (1/6 studies), financial hardship (1/6), body image (0/6), spirituality (0/6), and sexual health (0/6). No study compared HRQOL between patients actively receiving RT and those post-treatment. None of the studies collected HRQOL data longitudinally. CONCLUSION: HRQOL data in AYAs receiving RT is limited. Future studies examining longitudinal, clinician- vs. patient-reported, and AYA-relevant HRQOL are needed to better understand the unique needs in this population.
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Neoplasias , Qualidade de Vida , Humanos , Adolescente , Adulto Jovem , Adulto , Qualidade de Vida/psicologia , Neoplasias/terapia , Saúde Mental , Sobrevivência , Medidas de Resultados Relatados pelo PacienteRESUMO
PURPOSE: Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients' decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services. METHODS: Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes. RESULTS: The sample comprised 21 AYAs who had genetic counseling and nine who did not. Motivational factors identified included learning genetic counseling is an available service, concern about the impact of a hereditary syndrome on family members and family planning, learning about the need for cancer screening or prevention, affordability of genetic testing, and easing worry about additional cancer risks. For those who did not pursue genetic counseling, barriers included scheduling or other priorities, worry, and cost. However, the majority expressed they would reconsider genetic counseling in the future. CONCLUSION: AYA cancer patients have similar motivational factors to pursue genetic counseling compared to other patients; however, their younger age of diagnosis may alter how these factors affect decision-making. While there are barriers limiting access to genetic services, they did not decrease interest in future genetic counseling for most patients. Genetic counseling and testing should be discussed with patients who previously declined genetic services.
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Aconselhamento Genético , Neoplasias , Adolescente , Aconselhamento , Testes Genéticos , Humanos , Neoplasias/terapia , Sobrevivência , Adulto JovemRESUMO
BACKGROUND: Low-dose UCN-01 mediates G1 arrest in normal proliferating cell lines with an intact G1 to S transition but not tumour cells with a deregulated G1 to S checkpoint. Here we hypothesised that UCN-01 is effective in mediating a selective, reversible G1 arrest of normal proliferating cells, resulting in decreased chemotoxicity, improved tolerance and enhanced chemotherapeutic efficacy in vivo in both non-tumour-bearing mice and in breast cancer cell line xenograft models. METHODS: Murine small bowel epithelium was used to examine the kinetics and mechanism of low-dose UCN-01-mediated arrest of normal proliferating cells and if it can protect tumour-bearing mice (MDA-MB-468 xenografts) against the toxic effects of chemotherapy (5-fluorouricil (5-FU)) allowing for its full therapeutic activity. RESULTS: UCN-01 causes significant, reversible arrest of normal gut epithelial cells at 24 h; this arrest persists for up to 7 days. Normal cellular proliferation returns by 2 weeks. Pre-treatment of both non-tumour-bearing and MDA-MB-468 tumour-bearing mice with UCN-01 prior to bolus 5-FU (450 mg/kg) yielded enhanced therapeutic efficacy with significantly decreased tumour volumes and increased survival. CONCLUSIONS: UCN-01 mediates a specific, reversible G1 arrest of normal cells in vivo and provides a cytoprotective strategy that decreases toxicity of cytotoxic chemotherapy without compromising efficacy.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citostáticos/uso terapêutico , Fase G1/efeitos dos fármacos , Estaurosporina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Citostáticos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Estaurosporina/farmacologia , Estaurosporina/uso terapêuticoRESUMO
Conventional osteosarcoma (OS) is a high-grade intraosseous malignancy with production of osteoid matrix; however, a deeper dive into the underlying genetics reveals genomic complexity and instability that result in significant tumor heterogeneity. While early karyotyping studies demonstrated aneuploidy with chromosomal complexity and structural rearrangements, further investigations have identified few recurrent genetic alterations with the exception of the tumor suppressors TP53 and RB1. More recent studies utilizing next-generation sequencing (NGS; whole-exome sequencing, WES; and whole-genome sequencing, WGS) reveal a genomic landscape predominantly characterized by somatic copy number alterations rather than point/indel mutations. Despite its genomic complexity, OS has shown variable immune infiltrate and limited immunogenicity. In the current chapter, we review the hallmarks of OS genomics across recent NGS studies and the immune profile of OS including a large institutional cohort of OS patients with recurrent and metastatic disease. Understanding the genomic and immune landscape of OS may provide opportunities for translation in both molecularly targeted therapies and novel immuno-oncology approaches.
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Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Genoma Humano/genética , Genômica , Osteossarcoma/genética , Osteossarcoma/imunologia , Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MutaçãoRESUMO
BACKGROUND: There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five-year event-free survival (EFS) of adults on pediatric studies of ES (44%-47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution. MATERIALS AND METHODS: Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician-reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected. RESULTS: Seventy-one patients were identified who received VID as initial therapy. The median age was 25 (range: 16-64). Forty-two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5-year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five-year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5-year OS (42%) to the 33 with primary tumors at other sites (75%). The 5-year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5-year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5-year OS: 53%). CONCLUSION: In adults with primary ES, VID combined with an adjuvant strategy based on post-treatment percent necrosis has favorable outcomes compared with historical adult controls. IMPLICATIONS FOR PRACTICE: Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other adult sarcomas and reviewed the charts of 71 adult patients with ES treated with vincristine, ifosfamide, and doxorubicin (VID). In adults with primary ES, VID combined with an adjuvant strategy based on post-treatment percent necrosis has favorable outcomes compared with historical adult controls.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/uso terapêutico , Ifosfamida/uso terapêutico , Sarcoma de Ewing/tratamento farmacológico , Vincristina/uso terapêutico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Intervalo Livre de Doença , Doxorrubicina/farmacologia , Feminino , Humanos , Ifosfamida/farmacologia , Masculino , Pessoa de Meia-Idade , Vincristina/farmacologia , Adulto JovemRESUMO
PURPOSE: Soft tissue sarcomas (STSs) of the head and neck (H&N) are rare malignancies that are challenging to manage. We sought to describe the outcomes of patients treated with curative intent using combined surgery and radiation therapy (RT) for H&N STS. METHODS AND MATERIALS: We performed a single-institution retrospective review of patients with nonmetastatic STS of the H&N who were treated from 1968 to 2020. The Kaplan-Meier method was used to estimate disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVAs) were conducted using Cox proportional hazards model. RESULTS: One hundred ninety-two patients had a median follow-up of 82 months. Tumors arose in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). Most patients were treated with postoperative RT (n = 134, 70%). Postoperative RT doses were higher (median, 60 Gy; preoperative dose, 50 Gy; P < .001). Treatment sequence was not associated with LC (preoperative RT, 78% [63%-88%]; postoperative RT, 75% [66%-82%]; P = .48). On MVA, positive/uncertain margin was the only variable associated with LC (hazard ratio [HR], 2.54; 95% CI, 1.34-4.82; P = .004). LC was significant on MVA (HR, 4.48; 95% CI, 2.62-7.67; P < .001) for DSS. Patients who received postoperative RT were less likely to experience a major wound complication (7.5% vs 22.4%; HR, 0.28; 95% CI, 0.11-0.68; P = .005). There was no difference in the rate of late toxicities between patients who received preoperative or postoperative RT. CONCLUSIONS: H&N STS continues to have relatively poorer LC than STS of the trunk or extremities. We found LC to be associated with DSS. Timing of RT did not impact oncologic or long-term toxicity outcomes; however, preoperative RT did increase the chance of developing a major wound complication.
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Purpose: While there are known disparities in socioeconomic status (SES) and health outcomes among racially and ethnically minoritized adolescent and young adult (AYA; ages 15-39 years at diagnosis) cancer survivors compared with White survivors, outcomes in the Asian survivor population are understudied. To better understand the association of an AYA cancer diagnosis with SES and health outcomes within a minoritized population, the current study makes comparisons between individuals of the same race or ethnicity with and without a history of AYA cancer. Methods: Non-Hispanic, Asian AYA cancer survivors and non-Hispanic, Asian age- and sex-matched controls were identified from self-reported data in the National Health Interview Survey (2009-2020). Prevalence of chronic health conditions and socioeconomic factors were compared between groups using chi-square tests. Odds of chronic conditions by SES factors were determined within and between survivors and controls using logistic regression methods. Results: One hundred and thirty-one survivors and 1310 controls were included. Survivors were less likely to be married compared with controls; however, there were no differences in other SES factors examined. Survivors had higher odds of at least one chronic condition diagnosis (odds ratio = 4.17, p < 0.001) compared with controls. Of the chronic conditions assessed, survivors had higher odds of arthritis, pulmonary disease, and hypertension compared with controls. Conclusions: Asian AYA cancer survivors are at increased risk of chronic health conditions compared with Asian individuals without a cancer history. Culturally adapted targeted interventions are needed to improve health outcomes for this population.
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Neoplasias , Humanos , Adolescente , Adulto Jovem , Neoplasias/diagnóstico , Sobreviventes , Classe Social , Etnicidade , Doença CrônicaRESUMO
BACKGROUND: Neighborhood socioeconomic deprivation has been linked to adverse health outcomes, yet it is unclear whether neighborhood-level social determinants of health (SDOH) measures affect overall survival in adolescent and young adult patients with cancer. METHODS: This study used a diverse cohort of adolescent and young adult patients with cancer (N = 10â261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI values representing worse SDOH. RESULTS: ADI was statistically significantly worse (P < .050) for Black (61.7) and Hispanic (65.3) patients than for White patients (51.2). Analysis of ADI by cancer type showed statistically significant differences, mainly driven by worse ADI in patients with cervical cancer (62.3) than with other cancers. In multivariable models including sex, age at diagnosis, cancer diagnosis, and race and ethnicity, risk of shorter survival for people residing in neighborhoods with the least favorable ADI quartile was greater than for individuals in the most favorable ADI quartile (hazard ratio = 1.09, 95% confidence interval = 1.00 to 1.19, P = .043). CONCLUSION: Adolescent and young adult patients with cancer and the worst ADI values experienced a nearly 10% increase in risk of dying than patients with more favorable ADI values. This effect was strongest among White adolescent and young adult survivors. Although the magnitude of the effect of ADI on survival was moderate, the presence of a relationship between neighborhood-level SDOH and survival among patients who received care at a tertiary cancer center suggests that ADI is a meaningful predictor of survival. These findings provide intriguing evidence for potential interventions aimed at supporting adolescent and young adult patients with cancer from disadvantaged neighborhoods.
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Hispânico ou Latino , Neoplasias , Determinantes Sociais da Saúde , Humanos , Adolescente , Feminino , Masculino , Adulto Jovem , Neoplasias/mortalidade , Hispânico ou Latino/estatística & dados numéricos , População Branca/estatística & dados numéricos , Características da Vizinhança , Negro ou Afro-Americano/estatística & dados numéricos , Adulto , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/etnologia , Modelos de Riscos Proporcionais , Características de Residência , Fatores SocioeconômicosRESUMO
BACKGROUND: Cancer is a life-threatening, stressful event, particularly for young adults due to delays and disruptions in their developmental transitions. Cancer treatment can also cause adverse long-term effects, chronic conditions, psychological issues, and decreased quality of life (QoL) among young adults. Despite numerous health benefits of health behaviors (eg, physical activity, healthy eating, no smoking, no alcohol use, and quality sleep), young adult cancer survivors report poor health behavior profiles. Determining the associations of stress (either cancer-specific or day-to-day stress), health behaviors, and QoL as young adult survivors transition to survivorship is key to understanding and enhancing these survivors' health. It is also crucial to note that the effects of stress on health behaviors and QoL may manifest on a shorter time scale (eg, daily within-person level). Moreover, given that stress spills over into romantic relationships, it is important to identify the role of spouses or partners (hereafter partners) in these survivors' health behaviors and QoL. OBJECTIVE: This study aims to investigate associations between stress, health behaviors, and QoL at both within- and between-person levels during the transition to survivorship in young adult cancer survivors and their partners, to identify the extent to which young adult survivors' and their partners' stress facilitates or hinders their own and each other's health behaviors and QoL. METHODS: We aim to enroll 150 young adults (aged 25-39 years at the time of cancer diagnosis) who have recently completed cancer treatment, along with their partners. We will conduct a prospective longitudinal study using a measurement burst design. Participants (ie, survivors and their partners) will complete a daily web-based survey for 7 consecutive days (a "burst") 9 times over 2 years, with the bursts spaced 3 months apart. Participants will self-report their stress, health behaviors, and QoL. Additionally, participants will be asked to wear an accelerometer to assess their physical activity and sleep during the burst period. Finally, dietary intake (24-hour diet recalls) will be assessed during each burst via telephone by research staff. RESULTS: Participant enrollment began in January 2022. Recruitment and data collection are expected to conclude by December 2024 and December 2026, respectively. CONCLUSIONS: To the best of our knowledge, this will be the first study that determines the interdependence of health behaviors and QoL of young adult cancer survivors and their partners at both within- and between-person levels. This study is unique in its focus on the transition to cancer survivorship and its use of a measurement burst design. Results will guide the creation of a developmentally appropriate dyadic psychosocial or behavioral intervention that improves both young adult survivors' and their partners' health behaviors and QoL and potentially their physical health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53307.
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Sobreviventes de Câncer , Comportamentos Relacionados com a Saúde , Qualidade de Vida , Estresse Psicológico , Adulto , Feminino , Humanos , Masculino , Sobreviventes de Câncer/psicologia , Qualidade de Vida/psicologia , Cônjuges/psicologia , Estresse Psicológico/psicologia , Inquéritos e Questionários , Sobrevivência , Projetos de PesquisaRESUMO
Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.
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Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.
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Reparo do DNA , Leiomiossarcoma , Ribonuclease H , Humanos , Ribonuclease H/genética , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Leiomiossarcoma/mortalidade , Feminino , Biomarcadores Tumorais/genética , Masculino , Prognóstico , Pessoa de Meia-Idade , Idoso , Dano ao DNARESUMO
Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.
Assuntos
Inibidores de Checkpoint Imunológico , Lipossarcoma , Terapia Neoadjuvante , Neoplasias Retroperitoneais , Humanos , Lipossarcoma/tratamento farmacológico , Lipossarcoma/imunologia , Terapia Neoadjuvante/métodos , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/imunologia , Masculino , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Idoso , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Sarcoma/terapia , Sarcoma/imunologia , Sarcoma/tratamento farmacológico , Nivolumabe/uso terapêutico , Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacosRESUMO
BACKGROUND: Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline-induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status. METHODS: Computed tomography (CT) scans were used to investigate changes in skeletal muscle of 153 AYA sarcoma and Hodgkin lymphoma patients at thoracic vertebra 4 after anthracycline treatment. Images were examined at three time points during the first year of treatment. In parallel, we used translational juvenile mouse models to assess the impact of doxorubicin (DOX) in the soleus and gastrocnemius on muscle wasting. RESULTS: Significant reductions in total skeletal muscle index and density were seen after chemotherapy in AYA cancer patients (p < 0.01 & p = 0.04, respectively). The severity of skeletal muscle loss varied by subgroup (i.e., cancer type, sex, and treatment). Murine models demonstrated a reduction in skeletal muscle fiber cross-sectional area, increased apoptosis and collagen volume for both the soleus and gastrocnemius after DOX treatment (all p < 0.05). After DOX, hindlimb skeletal muscle blood flow was significantly reduced (p < 0.01). CONCLUSION: Significant skeletal muscle loss is experienced early during treatment in AYA cancer patients. Reductions in skeletal muscle blood flow may be a key contributing factor to anthracycline doxorubicin induced skeletal muscle loss.
Assuntos
Doença de Hodgkin , Sarcoma , Humanos , Adolescente , Adulto Jovem , Camundongos , Animais , Antraciclinas/efeitos adversos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina , Doença de Hodgkin/induzido quimicamente , Sarcoma/metabolismoRESUMO
Background: Adolescents and young adult (AYA) patients with sarcoma are at heightened risk of reduced physical capacity and disease-related weakness. Sit-to-stand (STS) performance correlates with lower extremity functionality and activities of daily living; however, little is known regarding the relationship between muscular status and STS performance in patients with sarcoma. This study assessed STS performance in patients with sarcoma and the association between STS performance and the skeletal muscle index (SMI) and skeletal muscle density (SMD). Methods: This study included 30 patients with sarcoma (15-39 years old) treated with high-dose doxorubicin. Patients performed the five-times-STS test before starting treatment and 1 year after the baseline test. STS performance was correlated with SMI and SMD. SMI and SMD were quantified using computed tomography scans taken at the level of the 4th thoracic vertebra (T4). Results: Mean performance on the STS test at baseline and 1 year was 2.2-fold and 1.8-fold slower than the age-matched general population, respectively. A lower SMI was associated with worse performance on the STS test (p = 0.01). Similarly, lower SMD at baseline was also associated with poorer STS performance (p < 0.01). Conclusion: Patients with sarcoma have very poor STS performance at baseline and 1 year, which was accompanied by low SMI and SMD at T4.The inability for AYAs to return to healthy age normative STS standards by 1 year may indicate a need for early interventions to enhance skeletal muscle recovery and promote physical activity during and after treatment.
Assuntos
Atividades Cotidianas , Sarcoma , Humanos , Adolescente , Adulto Jovem , Adulto , Músculo Esquelético/fisiologia , Exercício Físico , Nível de SaúdeRESUMO
PURPOSE: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions. EXPERIMENTAL DESIGN: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples were collected from mice treated with DOX or DOX + exercise. Plasma samples from 13 DOX-treated patients with sarcoma were also evaluated before and 24 hours after therapy. RESULTS: Elevations in plasma miRNA-1, miRNA-499 and IL1α, IL1ß, and IL6 were seen in DOX-treated mice with decreased ejection fraction and fractional shortening 24 hours after DOX therapy. Troponin levels were not elevated until 4 weeks after therapy. In mice treated with exercise during DOX, there was no elevation in these biomarkers and no change in cardiac function. Elevations in these biomarkers were seen in 12 of 13 patients with sarcoma treated with DOX. CONCLUSIONS: These findings define a potential set of biomarkers to identify and predict patients at risk for developing acute and late cardiovascular diseases with the goal of focused monitoring and early intervention. Further studies are needed to confirm the predictive value of these biomarkers in late cardiotoxicity.