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OBJECTIVES: In our study, we aimed to characterise adult childhood cancer survivors (ACCS), assess their health issues, gauge health-related quality of life (HRQOL) and evaluate visit satisfaction. DESIGN: Prospective cohort study using data from clinical visits and questionnaires. SETTING: Interdisciplinary follow-up programme for ACCS based on the long-term follow-up (LTFU) guidelines of the Children's Oncology Group and overseen by internists in two Swiss hospitals. PARTICIPANTS: ACCS attending our LTFU clinics between April 2017 and January 2022 were eligible. INTERVENTIONS: We documented medical history, current health status and assessed HRQOL using Short Form-36 V.2, comparing it with Swiss general population (SGP) norms (T mean=50, SD=10; age stratified). 3 months post visit, a feedback questionnaire was distributed. MAIN RESULTS: Among 102 ACCS (mean age: 32 years (range: 18-62 years), 68% women), 43 had no prior follow-up (36 ACCS>28 years, 7 ACCS≤28 years). A notable 94% had health issues, affecting an average of 6.1 (SD=3.3) organ systems. HRQOL was lower in ACCS>28 years than the SGP>28 years (physical: 44.8 (SD=11.65) vs 49.3 (SD=10.29), p=0.016; mental: 44.4 (SD=13.78) vs 50.53 (SD=9.92), p=0.004). Older ACCS (>28 years) reported inferior physical (44.8 vs 50.1 (SD=9.30), p=0.017) and mental HRQOL (44.4 vs 50.3 (SD=7.20), p=0.009) than younger ACCS. The majority of respondents reported high levels of satisfaction with the consultation, exceeding 90%. CONCLUSION: ACCS attending LTFU clinics face diverse health issues impacting multiple organ systems and exhibit lower HRQOL compared with the SGP. Thus, internist-led LTFU clinics are crucial for optimising follow-up care.
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Sobreviventes de Câncer , Neoplasias , Qualidade de Vida , Humanos , Feminino , Masculino , Sobreviventes de Câncer/psicologia , Estudos Prospectivos , Adulto , Suíça , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Neoplasias/psicologia , Neoplasias/terapia , Inquéritos e Questionários , Satisfação do Paciente , Seguimentos , Nível de SaúdeRESUMO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%-70%) and alveolar RMS (aRMS; 20%-30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion-positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion-negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long-term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.
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In couples dealing with health problems, we-disease appraisals can influence dyadic coping strategies to alleviate distress. This study describes the development and validation of a self-report scale to assess we-disease appraisals of health problems. The newly developed We-Disease Questionnaire (WDQ) was administered in three samples: parents of children with type 1 diabetes (n = 240) or cancer (n = 125) and individuals with visual impairment and their partners (n = 216). Reliability was measured by coefficient omega. To assess construct validity, correlations with other measures of individual and dyadic adjustment were examined. Descriptive statistics across all samples were compared. A 4-item version of the WDQ demonstrated good reliability and validity and showed meaningful associations with established scales. We-disease appraisals were highest among parents of children with cancer and lowest among couples with visual impairment. The WDQ is a reliable and valid measure that can be used across different health problems.
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PURPOSE: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS: Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS: One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION: The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.
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Neuroblastoma , Topotecan , Criança , Humanos , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Temozolomida/uso terapêutico , Irinotecano/uso terapêutico , Topotecan/efeitos adversos , Bevacizumab/efeitos adversos , Dacarbazina/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neuroblastoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations.
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Lipossomos , Rabdomiossarcoma , Criança , Humanos , Lipossomos/metabolismo , Nucleolina , Vincristina/uso terapêutico , Linhagem Celular Tumoral , Peptídeos/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/metabolismoRESUMO
PURPOSE: Reported prevalence of cancer-related fatigue (CRF) among childhood cancer survivors (CCS) varies widely, and evidence on factors associated with CRF among CCS is limited. We aimed to investigate the prevalence of CRF and its associated factors among adult CCS in Switzerland. METHODS: In a prospective cohort study, we invited adult CCS who survived at least 5 years since last cancer diagnosis, and were diagnosed when age 0-20 years and treated at Inselspital Bern between 1976 and 2015 to complete two fatigue-measuring instruments: the Checklist Individual Strength subjective fatigue subscale (CIS8R; increased fatigue 27-34, severe fatigue ≥ 35) and the numerical rating scale (NRS; moderate fatigue 4-6, severe fatigue 7-10). We collected information about previous cancer treatment and medical history, and calculated ß coefficients for the association between CIS8R/NRS fatigue scores and potential determinants using multivariable linear regression. RESULTS: We included 158 CCS (participation rate: 30%) with a median age at study of 33 years (interquartile range 26-38). Based on CIS8R, 19% (N = 30) of CCS reported increased fatigue, yet none reported severe fatigue. CRF was associated with female sex, central nervous system (CNS) tumors, sleep disturbance, and endocrine disorders. Lower CRF levels were observed among CCS age 30-39 years compared to those younger. CONCLUSIONS: A considerable proportion of adult CCS reported increased levels of CRF. IMPLICATIONS FOR CANCER SURVIVORS: CCS who are female and < 30 years old, have a history of CNS tumor, report sleep disturbance, or have an endocrine disorder should be screened for CRF.
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Sobreviventes de Câncer , Neoplasias , Adulto , Humanos , Criança , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Masculino , Neoplasias/complicações , Neoplasias/epidemiologia , Estudos Prospectivos , Prevalência , Suíça/epidemiologia , Fadiga/epidemiologia , Fadiga/etiologiaRESUMO
OBJECTIVE: Childhood cancer survivors are at risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapeutics, radiotherapy, and surgery. Longitudinal data on lung function and its change over time are scarce. We investigated lung function trajectories in survivors over time and the association with lung-toxic treatments. METHODS: This retrospective, multicenter cohort study included Swiss survivors diagnosed between 1990 and 2013 and exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs), including forced expiration volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, total lung capacity, and diffusion capacity of the lung for carbon monoxide, were obtained from hospital charts. We calculated z-scores and percentage predicted, described lung function over time, and determined risk factors for change in FEV1 and FVC using multivariable linear regression. RESULTS: We included 790 PFTs from 183 survivors, with a median age of 12 years at diagnosis and 5.5 years of follow-up. Most common diagnosis was lymphoma (55%). Half (49%) of survivors had at least one abnormal pulmonary function parameter, mainly restrictive (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. Survivors treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (-2.02 to -0.15) and an FVC of -1.42 z-scores (-2.27 to -0.57) compared to those without surgery. CONCLUSION: Reduced pulmonary function was frequent but mainly of mild to moderate severity. Nevertheless, more research and long-term surveillance of this vulnerable population is needed.
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Sobreviventes de Câncer , Neoplasias , Humanos , Criança , Estudos de Coortes , Estudos Retrospectivos , Suíça/epidemiologia , Pulmão , Capacidade Vital , Volume Expiratório ForçadoRESUMO
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 (B7-H3) is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activity in vitro and in vivo. METHODS: Four different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8α or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were tested in vitro. The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluated in vivo in three orthotopic RMS mouse models. RESULTS: CD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3ζ) showed the strongest killing of RMS cells, and the highest release of IFN-γ and Granzyme B in vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3ζ) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumors in vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276low JR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice. CONCLUSIONS: CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276high RMS tumors in vivo. CD276low tumors escaped the therapy highlighting a correlation between antigen density and effectiveness. FGFR4-CAR Ts showed specific killing in vitro but could only delay RMS growth in vivo. Our results demonstrate that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression.
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Antígenos B7 , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos , Rabdomiossarcoma , Linfócitos T , Animais , Camundongos , Antígenos B7/metabolismo , Antígenos CD28/metabolismo , Linhagem Celular Tumoral , Recidiva Local de Neoplasia/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Rabdomiossarcoma/terapia , Rabdomiossarcoma/patologiaRESUMO
BACKGROUND: After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5-year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. METHODS: We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self-reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25-29.9 kg/m2 ) and obesity (≥30 kg/m2 ) using multinomial regression. RESULTS: We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27-32 vs. 24%, 21-29; obesity: 29%, 27-32 vs. 7%, 5-10] and siblings (overweight: 30%, 27-32 vs. 25%, 22-29; obesity: 24%, 22-26 vs. 6%, 4-8). Survivors in North America [odds ratio (OR) = 1.24, 1.01-1.53] and Switzerland (1.27, 0.74-2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7-9.0); male (1.7, 1.3-2.3); attained age (≥45 years: 5.1, 2.4-10.8); Non-Hispanic Black (3.4, 1.6-7.0); low household income (2.3, 1.4-3.5); young age at diagnosis (1.6, 1.1-2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0-1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. CONCLUSIONS: Although treatment-related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.
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Sobrepeso , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Criança , Masculino , Humanos , Pessoa de Meia-Idade , Sobrepeso/epidemiologia , Sobrepeso/complicações , Suíça/epidemiologia , Obesidade/epidemiologia , Obesidade/complicações , Estudos de Coortes , Fatores de Risco , América do Norte/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaçõesRESUMO
BACKGROUND: Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance. METHODS: Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed. RESULTS: Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively. CONCLUSION: Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.
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Policetídeos , Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Criança , Etoposídeo , Carboplatina , Estudos Retrospectivos , Topotecan , Ciclofosfamida , Doença Crônica , Antraciclinas , Recidiva , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
OBJECTIVE: In recent years, genotypic characterization of congenital vascular malformations (CVMs) has gained attention; however, the spectrum of clinical phenotype remains difficult to attribute to a genetic cause and is rarely described in the adult population. The aim of this study is to describe a consecutive series of adolescent and adult patients in a tertiary center, where a multimodal phenotypic approach was used for diagnosis. METHODS: We analyzed clinical findings, imaging, and laboratory results at initial presentation, and set a diagnosis according to the International Society for the Study of Vascular Anomalies (ISSVA) classification for all consecutively registered patients older than 14 years of age who were referred to the Center for Vascular Malformations at the University Hospital of Bern between 2008 and 2021. RESULTS: A total of 457 patients were included for analysis (mean age, 35 years; females, 56%). Simple CVMs were the most common (n = 361; 79%), followed by CVMs associated with other anomalies (n = 70; 15%), and combined CVMs (n = 26; 6%). Venous malformations (n = 238) were the most common CVMs overall (52%), and the most common simple CVMs (66%). Pain was the most frequently reported symptom in all patients (simple, combined, and vascular malformation with other anomalies). Pain intensity was more pronounced in simple venous and arteriovenous malformations. Clinical problems were related to the type of CVM diagnosed, with bleeding and skin ulceration in arteriovenous malformations, localized intravascular coagulopathy in venous malformations, and infectious complications in lymphatic malformations. Limb length difference occurred more often in patients with CVMs associated with other anomalies as compared with simple or combined CVM (22.9 vs 2.3%; P < .001). Soft tissue overgrowth was seen in one-quarter of all patients independent of the ISSVA group. CONCLUSIONS: In our adult and adolescent population with peripheral vascular malformations, simple venous malformations predominated, with pain as the most common clinical symptom. In one-quarter of cases, patients with vascular malformations presented with associated anomalies on tissue growth. The differentiation of clinical presentation with or without accompanying growth abnormalities need to be added to the ISSVA classification. Phenotypic characterization considering vascular and non-vascular features remains the cornerstone of diagnosis in adult as well as pediatric patients.
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Malformações Arteriovenosas , Malformações Vasculares , Feminino , Humanos , Malformações Vasculares/complicações , Malformações Vasculares/diagnóstico por imagem , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/terapia , Veias/anormalidades , Dor , FenótipoRESUMO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis for patients with high-grade and metastatic disease is still very poor, and survivors are burdened with long-lasting side effects. Therefore, more effective and less toxic therapies are needed. Surface proteins are ideal targets for antibody-based therapies, like bispecific antibodies, antibody-drug conjugates, or chimeric antigen receptor (CAR) T-cells. Specific surface targets for RMS are scarce. Here, we performed a surfaceome profiling based on differential centrifugation enrichment of surface/membrane proteins and detection by LC-MS on six fusion-positive (FP) RMS cell lines, five fusion-negative (FN) RMS cell lines, and three RMS patient-derived xenografts (PDXs). A total of 699 proteins were detected in the three RMS groups. Ranking based on expression levels and comparison to expression in normal MRC-5 fibroblasts and myoblasts, followed by statistical analysis, highlighted known RMS targets such as FGFR4, NCAM1, and CD276/B7-H3, and revealed AGRL2, JAM3, MEGF10, GPC4, CADM2, as potential targets for immunotherapies of RMS. L1CAM expression was investigated in RMS tissues, and strong L1CAM expression was observed in more than 80% of alveolar RMS tumors, making it a practicable target for antibody-based therapies of alveolar RMS.
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Molécula L1 de Adesão de Célula Nervosa , Rabdomiossarcoma , Criança , Animais , Humanos , Xenoenxertos , Rabdomiossarcoma/metabolismo , Linhagem Celular , Fatores de Transcrição , Modelos Animais de Doenças , Moléculas de Adesão de Célula Nervosa/uso terapêutico , Linhagem Celular Tumoral , Antígenos B7 , Moléculas de Adesão Celular/uso terapêutico , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Background: Generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), kaposiform lymphangiomatosis (KLA), and central conducting lymphatic anomaly (CCLA) are rare, multisystem lymphatic disorders, referred to as complex lymphatic anomalies (CLAs). Their etiology remains poorly understood; however, somatic activating mutations have recently been discovered, and the results of targeted treatments are promising. This study aimed to elaborate on the phenotypic description of CLA. Methods: Thirty-six consecutive patients were recruited for the "GLA/GSD Registry" of the University Hospital of Freiburg, Germany (2015-2021). Clinical data were prospectively collected provided that a signed informed consent form was obtained. The latest proposed diagnostic guidelines were retrospectively applied. Results: Thirty-two patients (38% males) were included in the study; 15 GLA, 10 GSD, 3 KLA, and 4 CCLA patients were identified. Eighty-four percent already had symptoms by the age of 15 years. Osteolysis and periosseous soft-tissue infiltration were associated with GSD (p < 0.001 and p = 0.011, respectively), ascites and protein-losing enteropathy with CCLA (p = 0.007 and p = 0.004, respectively), and consumption coagulopathy with KLA (p = 0.006). No statistically significant differences were found in organ involvement, distribution of osteolytic lesions, number of affected bones and fractures. Twenty-five patients had complications; one patient with GLA died despite multimodal treatment. Spontaneous regression was seen in one patient with untreated KLA. Conclusions: CLA are rare, and their overlapping clinical presentations make differential diagnosis difficult. The characterization of our case series contributes to the phenotypic description and differentiation of these four clinical entities. A further understanding of their pathogenesis is crucial for evaluating targeted therapies and optimizing medical care.
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Anormalidades Linfáticas , Vasos Linfáticos , Osteólise Essencial , Masculino , Humanos , Adolescente , Feminino , Estudos Retrospectivos , Anormalidades Linfáticas/diagnóstico por imagem , Anormalidades Linfáticas/terapia , Osso e Ossos , Osteólise Essencial/diagnóstico , Osteólise Essencial/tratamento farmacológico , Osteólise Essencial/patologia , Vasos Linfáticos/patologiaRESUMO
BACKGROUND: Vascular anomalies comprise a diverse group of rare diseases with altered blood flow and are often associated with coagulation disorders. The most common example is a localized intravascular coagulopathy in venous malformations leading to elevated D-dimers. In severe cases, this may progress to a disseminated intravascular coagulopathy with subsequent consumption of fibrinogen and thrombocytes predisposing to serious bleeding. A separate coagulopathy is the Kasabach-Merritt phenomenon in kaposiform hemangioendothelioma characterized by platelet trapping leading to thrombocytopenia and eventually consumptive coagulopathy. Our previous work showed impaired von Willebrand factor and platelet aggregometry due to abnormal blood flow, i.e., in ventricular assist devices or extracorporeal membrane oxygenation. With altered blood flow also present in vascular anomalies, we hypothesized that, in particular, the von Willebrand factor parameters and the platelet function may be similarly impacted. METHODS: We prospectively recruited 73 patients with different vascular anomaly entities and analyzed their coagulation parameters. RESULTS: Acquired von Willebrand syndrome was observed in both of our patients with Kasabach-Merritt phenomenon. In six out of nine patients with complex lymphatic anomalies, both the vWF antigen and activity were upregulated. Platelet aggregometry was impaired in both patients with Kasabach-Merritt phenomenon and in seven out of eight patients with an arteriovenous malformation. CONCLUSIONS: The analysis of coagulation parameters in our patients with vascular anomalies advanced our understanding of the underlying pathophysiologies of the observed coagulopathies. This may lead to new treatment options for the, in part, life-threatening bleeding risks in these patients in the future.
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Transtornos da Coagulação Sanguínea , Coagulação Sanguínea , Malformações Vasculares , Humanos , Plaquetas , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/fisiopatologia , Hemangioendotelioma/etiologia , Hemangioendotelioma/fisiopatologia , Síndrome de Kasabach-Merritt/etiologia , Síndrome de Kasabach-Merritt/fisiopatologia , Fator de von Willebrand/metabolismo , Malformações Vasculares/complicações , Malformações Vasculares/fisiopatologia , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/fisiopatologiaRESUMO
Active drug delivery by tumor-targeting peptides is a promising approach to improve existing therapies for rhabdomyosarcoma (RMS), by increasing the therapeutic effect and decreasing the systemic toxicity, e.g., by drug-loaded peptide-targeted nanoparticles. Here, we tested 20 different tumor-targeting peptides for their ability to bind to two RMS cell lines, Rh30 and RD, using quantum dots Streptavidin and biotin-peptides conjugates as a model for nanoparticles. Four peptides revealed a very strong binding to RMS cells: NCAM-1-targeting NTP peptide, nucleolin-targeting F3 peptide, and two Furin-targeting peptides, TmR and shTmR. F3 peptide showed the strongest binding to all RMS cell lines tested, low binding to normal control myoblasts and fibroblasts, and efficient internalization into RMS cells demonstrated by the cytoplasmic delivery of the Saporin toxin. The expression of the nucleophosphoprotein nucleolin, the target of F3, on the surface of RMS cell lines was validated by competition with the natural ligand lactoferrin, by colocalization with the nucleolin-binding aptamer AS1411, and by the marked sensitivity of RMS cell lines to the growth inhibitory nucleolin-binding N6L pseudopeptide. Taken together, our results indicate that nucleolin-targeting by F3 peptide represents a potential therapeutic approach for RMS.
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Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.
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Anormalidades Linfáticas , Escleroterapia , Humanos , Escleroterapia/efeitos adversos , Escleroterapia/métodos , Resultado do Tratamento , Anormalidades Linfáticas/diagnóstico , Anormalidades Linfáticas/terapia , Anormalidades Linfáticas/etiologia , Pescoço , Cabeça , Estudos RetrospectivosRESUMO
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare, but lethal pediatric brain tumor with a median survival of less than 1 year. Existing treatment may prolong life and control symptoms, but may cause toxicity and side effects. In order to improve child- and family-centered care, we aimed to better understand the treatment decision-making experiences of parents, as studies on this topic are currently lacking. PROCEDURE: The data for this study came from 24 semistructured interviews with parents whose children were diagnosed with DIPG in two children's hospitals in Switzerland and died between 2000 and 2016. Analysis of the dataset was done using reflexive thematic analysis. RESULTS: For most parents, the decision for or against treatment was relatively straightforward given the fatality of the tumor and the absence of treatment protocols. Most of them had no regrets about their decision for or against treatment. The most distressing factor for them was observing their child's gradual loss of independence and informing them about the inescapability of death. To counter this powerlessness, many parents opted for complementary or alternative medicine in order to "do something." Many parents reported psychological problems in the aftermath of their child's death and coping strategies between mothers and fathers often differed. CONCLUSION: The challenges of DIPG are unique and explain why parental and shared decision-making is different in DIPG compared to other cancer diagnoses. Considering that treatment decisions shape parents' grief trajectory, clinicians should reassure parents by framing treatment decisions in terms of family's deeply held values and goals.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Neoplasias do Tronco Encefálico/terapia , Humanos , Pais/psicologia , Pesquisa QualitativaRESUMO
BACKGROUND: The cancer diagnosis and its intensive treatment may affect the long-term psycho-social adjustment of childhood cancer survivors. We aimed to describe social, emotional, and behavioral functioning and their determinants in young childhood cancer survivors. PROCEDURE: The nationwide Swiss Childhood Cancer Survivor Study sends questionnaires to parents of survivors aged 5-15 years, who have survived at least 5 years after diagnosis. We assessed social, emotional, and behavioral functioning using the Strengths and Difficulties Questionnaire (SDQ). The SDQ includes four difficulties scales (emotional, conduct, hyperactivity, peer problems), a total difficulties indicator, and one strength scale (prosocial). We compared the proportion of survivors with borderline and abnormal scores to reference values and used multivariable logistic regression to identify determinants. RESULTS: Our study included 756 families (response rate of 72%). Thirteen percent of survivors had abnormal scores for the total difficulties indicator compared to 10% in the general population. The proportion of survivors with abnormal scores was highest for the emotional scale (15% vs. 8% in the general population), followed by the peer problems scale (14% vs. 7%), hyperactivity (8% vs. 10%), and conduct scale (6% vs. 7%). Few survivors (4% vs. 7%) had abnormal scores on the prosocial scale. Children with chronic health conditions had a higher risk of borderline and abnormal scores on all difficulties scales (all p < 0.05). CONCLUSION: Most childhood cancer survivors do well in social, emotional, and behavioral life domains, but children with chronic health conditions experience difficulties. Therefore, healthcare professionals should offer specific psycho-social support to these survivors.
Assuntos
Sobreviventes de Câncer , Transtornos Mentais , Neoplasias , Criança , Emoções , Humanos , Transtornos Mentais/epidemiologia , Neoplasias/terapia , Inquéritos e QuestionáriosRESUMO
The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.
Assuntos
Hemangioma , Neoplasias Cutâneas , Doenças Vasculares , Europa (Continente) , Hemangioma/complicações , Hemangioma/diagnóstico , Hemangioma/terapia , Humanos , Lactente , Neoplasias Cutâneas/complicações , Síndrome , Doenças Vasculares/complicaçõesRESUMO
OBJECTIVE: Arteriovenous malformations of the lower extremities (AVMLE) can present as simple or complex combined or syndromic forms (eg, Parkes Weber Syndrome). We aimed to characterize the differences in clinical presentation and natural history of these potentially life- and limb-threatening congenital vascular malformations. METHODS: We conducted a retrospective analysis of a consecutive series of patients with AVMLE who presented to a tertiary referral center in Switzerland between 2008 and 2018. Clinical baseline characteristics, D-dimer level, and course were summarized and differences between simple, non-syndromic and combined or syndromic AVMLE determined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS: Overall, 506 patients were prospectively enrolled in the Bernese Congenital Vascular Malformation Registry, 31 (6%) with AVMLE. There were 16 women and 15 men, with a mean age of 18 years at first diagnosis (range, 1 month to 72 years). Simple AVMLE was present in 22 (71%) and combined or syndromic AVMLE with limb overgrowth in 9 patients (29%), respectively. Common symptoms and signs were pain (n = 25; 81%), swelling (n = 21; 68%), and soft tissue hypertrophy (n = 13; 42%). Among combined or syndromic patients, three patients died from wound infection with sepsis or disseminated intravascular coagulation with bleeding complications (intracranial hemorrhage and bleeding from extensive leg ulcers). Combined or syndromic patients presented more often with bleeding (67% vs 5%; P < .001), malformation-related infection (44% vs 5%; P = .017) and leg length difference (56% vs 14%; P = .049). D-dimer levels were elevated (mean, 17,256 µg/L; range, 1557-80,000 µg/L) and angiographic appearance showed complex, mixed type of AVMs, including interstitial type IV, in all patients with combined or syndromic AVMLE. CONCLUSIONS: Patients with congenital simple AVMLE most often present with benign clinical features and rarely with complications related to hemodynamic changes. Patients with combined or syndromic AVMLE often face serious outcomes dominated by complications other than direct high-flow-related heart failure.