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Frontiers in Immunology 2023Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for...
INTRODUCTION
Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for novel therapeutic strategies. Applying chimeric antigen receptor (CAR) technology to natural killer (NK) cells may offer safe, effective, and affordable therapies that enhance cancer immune surveillance.
METHODS
Here, we assess the efficacy of clinically usable CAR-engineered NK cell line NK-92/5.28.z against ErbB2-positive RMS and in a metastatic xenograft mouse model.
RESULTS
Our results show that NK-92/5.28.z cells effectively kill RMS cells and significantly prolong survival and inhibit tumor progression in mice. The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors.
DISCUSSION
These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS.
Topics: Humans; Animals; Mice; Rhabdomyosarcoma, Alveolar; Receptors, Chimeric Antigen; Immunotherapy; Rhabdomyosarcoma; Disease Models, Animal; Killer Cells, Natural; Neoplasms, Second Primary
PubMed: 37662907
DOI: 10.3389/fimmu.2023.1228894 -
PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.Nature Communications Nov 2023Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma....
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Topics: Animals; Child; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Forkhead Box Protein O1; Gene Expression Regulation, Neoplastic; Muscle, Skeletal; Oncogene Proteins, Fusion; Paired Box Transcription Factors; PAX3 Transcription Factor; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar
PubMed: 37968277
DOI: 10.1038/s41467-023-43044-1 -
Heart, Lung & Circulation May 2024Cardiac tumours can occur in association with genetic syndromes. Rhabdomyomas have been reported in association with tuberous sclerosis, myxomas with Carney's complex,... (Review)
Review
Cardiac tumours can occur in association with genetic syndromes. Rhabdomyomas have been reported in association with tuberous sclerosis, myxomas with Carney's complex, cardiac fibromas with Gorlin syndrome, and paragangliomas with multiple endocrine neoplasm syndrome. The presentation and prognosis of cardiac tumours associated with genetic syndromes differ compared with sporadic cases. Knowledge about the associated syndromes' genetic features and extracardiac manifestations is essential for the diagnosis, prognosis, and management of cardiac neoplasms. Moreover, identifying genetic mutations in benign and malignant cardiac tumours is needed to personalise management and improve treatment outcomes. Thus, this review discusses the genetic abnormalities associated with cardiac tumours, the current genetic screening recommendations, and the effect of those genetic mutations on the outcomes.
Topics: Humans; Heart Neoplasms; Mutation; Genetic Testing; Rhabdomyoma
PubMed: 38161083
DOI: 10.1016/j.hlc.2023.11.005 -
BMC Women's Health Sep 2023Intravenous leiomyomatosis (IVL) is a rare and specific type of smooth muscle tumor that is histologically benign but has a malignant biological behavior. It is commonly...
BACKGROUND
Intravenous leiomyomatosis (IVL) is a rare and specific type of smooth muscle tumor that is histologically benign but has a malignant biological behavior. It is commonly associated with a history of uterine leiomyomas.
CASE PRESENTATION
A 36-year-old woman, G1P1, presented to the hospital with left lower abdominal pain for 2 months and she has accepted hysteroscopic myomectomy about 1 year ago. Ultrasound venography, echocardiography and computed tomography venography (CTV) of inferior vena cava were performed, which revealed IVL located in left intramural myometrium walls growing along the left ovarian vein reaching the level of the lumbar 5-sacral 1 disc. Laparoscopic bilateral salpingo-oophorectomy and hysterectomyis were scheduled. The IVL in the left ovarian vein and parauterine venous plexus were detected and excised completely during surgery. IVL was diagnosed by postoperative pathology and immunohistochemistry. The patient recovered well after surgery. No surgical-related or anesthesia-related complications occurred.The 3-month follow-up CTV of inferior vena cava and echocardiography examination revealed normal.
CONCLUSIONS
The cause of IVL is unknown, this observation demonstrates that hysteroscopic myomectomy might lead to the occurrence of IVL.
Topics: Female; Humans; Adult; Leiomyomatosis; Abdominal Pain; Echocardiography; Myometrium; Pelvis
PubMed: 37697329
DOI: 10.1186/s12905-023-02618-3 -
European Journal of Radiology Sep 2023Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over... (Review)
Review
Rhabdomyosarcoma is the most common soft-tissue neoplasm in the pediatric population. The survival of children with rhabdomyosarcoma has only marginally improved over the past 25 years and remains poor for those with metastatic disease. A significant challenge to advances in treatment of rhabdomyosarcoma is the relative rarity of this disease, necessitating years to complete clinical trials. Progress can be accelerated by international cooperation and sharing national experiences. This necessitates agreement on a common language to describe patient cohorts and consensus standards to guide diagnosis, treatment, and response assessment. These goals formed the premise for creating the INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) in 2017. Multidisciplinary members of this consortium have since developed international consensus statements on the diagnosis, treatment, and management of pediatric soft-tissue sarcomas. Herein, members of the INSTRuCT Diagnostic Imaging Working Group present international consensus recommendations for imaging of patients with rhabdomyosarcoma at diagnosis, at staging, and during and after completion of therapy. The intent is to promote a standardized imaging approach to pediatric patients with this malignancy to create more-reliable comparisons of results of clinical trials internationally, thereby accelerating progress in managing rhabdomyosarcoma and improving survival.
Topics: Child; Humans; Sarcoma; Rhabdomyosarcoma; Combined Modality Therapy; Soft Tissue Neoplasms; Diagnostic Imaging
PubMed: 37541182
DOI: 10.1016/j.ejrad.2023.111012 -
Fertility and Sterility Jul 2024Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is... (Review)
Review
Fibroids are benign uterine tumors characterized by the proliferation of uterine smooth muscle cells, embedded in an abundant extracellular matrix. Their prevalence is estimated to be >50% in women aged >45 years. Fibroids represent a considerable health burden. It is time to acquire a deeper mechanistic understanding of uterine fibroid-related etiology and pathogenesis, which may help pinpoint new strategies and an individualized approach. There is a need to gather prospective data and conduct studies to compare alternative approaches and assess long-term outcomes with respect to quality of life, recurrence of symptoms (bleeding and bulk symptoms), fertility, and even complications The goal of this review was to evaluate the widely accepted pathogenesis and identify risks factors and future directions for clinical and basic research into fibroids.
Topics: Humans; Female; Leiomyoma; Uterine Neoplasms; Risk Factors; Animals
PubMed: 38453042
DOI: 10.1016/j.fertnstert.2024.02.048 -
American Journal of Obstetrics and... Apr 2024Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear.
OBJECTIVE
We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata.
STUDY DESIGN
With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (n/n=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata.
RESULTS
Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (r, -0.17; P=3.65×10), age at natural menopause (r, 0.23; P=3.26×10), and age at first birth (r, -0.16; P=1.96×10). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10). No causal association in the reverse direction was found.
CONCLUSION
Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.
Topics: Female; Humans; Genome-Wide Association Study; Phenotype; Menopause; Risk Factors; Leiomyoma
PubMed: 38191017
DOI: 10.1016/j.ajog.2023.12.040 -
Pediatric Blood & Cancer Sep 2023The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the...
The Children's Oncology Group (COG) Epidemiology Committee has a primary focus on better understanding the etiologies of childhood cancers. Over the past 10 years, the committee has leveraged the Childhood Cancer Research Network, and now more recently Project:EveryChild (PEC), to conduct epidemiologic assessments of various childhood cancers, including osteosarcoma, neuroblastoma, germ cell tumors, Ewing sarcoma, rhabdomyosarcoma, and Langerhans cell histiocytosis. More recent studies have utilized questionnaire data collected as part of PEC to focus on specific characteristics and/or features, including the presence of congenital disorders and the availability of stored cord blood. Members of the COG Epidemiology Committee have also been involved in other large-scale National Institutes of Health efforts, including the Childhood Cancer Data Initiative and the Gabriella Miller Kids First Pediatric Research Program, which are improving our understanding of the factors associated with childhood cancer risk. Future plans will focus on addressing questions surrounding health disparities, utilizing novel biospecimens in COG epidemiology studies, exploring the role of environmental factors on the etiologies and outcomes of childhood cancer, collaborating with other COG committees to expand the role of epidemiology in childhood cancer research, and building new epidemiologic studies from the Molecular Characterization Initiative-all with the ultimate goal of developing novel prevention and intervention strategies for childhood cancer.
Topics: Child; Humans; Neoplasms; Sarcoma, Ewing; Medical Oncology; Rhabdomyosarcoma; Osteosarcoma; Bone Neoplasms
PubMed: 37449937
DOI: 10.1002/pbc.30566 -
Clinical Cancer Research : An Official... Dec 2023Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS....
PURPOSE
Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity.
EXPERIMENTAL DESIGN
We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models.
RESULTS
Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity.
CONCLUSIONS
Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.
Topics: Animals; Mice; Humans; Leiomyosarcoma; DNA Repair; DNA Damage; Doxorubicin; DNA
PubMed: 37773632
DOI: 10.1158/1078-0432.CCR-23-0998 -
Advances in Clinical and Experimental... Oct 2023Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. About 40% of all... (Review)
Review
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. About 40% of all registered soft tissue tumors are RMSs. This paper describes our current understanding of the RMS subtypes (alveolar (ARMS), embryonic (ERMS), pleomorphic (PRMS), and spindle cell/sclerosing (s/scRMS)), diagnostic methods, molecular bases, and characteristics. We also present the currently used treatment methods and the potential use of natural substances in the treatment of this type of cancer. Natural cytotoxic substances are compounds that have been the subject of numerous studies and discussions in recent years. Since anti-cancer therapies are often limited by a low therapeutic index and cancer resistance to pharmacotherapy, it is very important to search for new, effective compounds. Additionally, compounds of a natural origin are usually readily available and have a reduced cytotoxicity. Thus, the undiscovered potential of natural anti-cancer compounds makes this field of research a very important area. The introduction of model species into research examining the use of natural cytostatic therapies for RMS will allow for further assessment of the effects of these compounds on cancerous and healthy tissues.
Topics: Child; Humans; Cytostatic Agents; Rhabdomyosarcoma; Sarcoma; Soft Tissue Neoplasms
PubMed: 36920267
DOI: 10.17219/acem/161165