Abstract Purpose: The study of cell-free DNA (cfDNA) enables sequential analysis of tumor cell–specific genetic alterations in patients with neuroblastoma. Experimental Design: Eighteen patients with ...relapsing neuroblastoma having received lorlatinib, a third-generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for nine patients and sequentially for five patients (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed by ALK-targeted ddPCR of the hotspot mutations F1174L, R1275Q, and I1170N; variant allele fraction (VAF) detection limit 0.1% and whole-exome sequencing (WES) to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. Results: Overall response rate to lorlatinib was 33% (CI, 13%–59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF < 0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. Conclusions: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in patients with neuroblastoma receiving ALK-targeted therapy.
To study the impact of hematopoietic stem cell transplantation (HSCT) on the uterine volume of childhood acute leukemia (AL) survivor depending on age at HSCT and the type of myeloablative ...conditioning regimen.
Thirteen French University Teaching Hospitals.
Prospective cohort study.
Eighty-eight women who underwent HSCT during childhood or adolescence for AL compared to a control group.
A multicentric prospective national study compared the uterine volume in a cohort of childhood AL survivor adult women treated with HSCT, matched 1:1 to control women. Pelvic magnetic resonance imaging scans included diffusion-weighted imaging sequences. Scans were centralized for a double-blinded reading by 2 radiologists.
Uterine volume, uterine body-to-cervix ratio, and apparent diffusion coefficient.
The mean age at HSCT was 9.1 ± 0.3 years with a mean follow-up duration of 16.4 ± 0.5 years. The cohort of 88 HSCT survivor women was composed of 2 subgroups depending on the myeloablative conditioning regimen received: an alkylating agent–based regimen group (n = 34) and a total body irradiation (TBI)–based regimen group (n = 54). Among the 88 women, 77 were considered as having a “correct hormonal balance” with estrogens supplied by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI) or because of a residual ovarian function. In the control group (n = 88), the mean uterine volume was 79.7 ± 3.3 mL. The uterine volume significantly decreased in all HSCT survivor women. After the alkylating agent–based regimen, the uterine volume was 45.3 ± 5.6 mL, corresponding to a significant volume reduction of 43.1% (28.8–57.4%) compared with that of the control group. After TBI, the uterine volume was 19.6 ± 1.9 mL, corresponding to a significant volume reduction of 75.3% (70.5%–80.2%) compared with that of the control group. After the alkylating agent–based regimen, the uterine volume dramatically decreased in women with POI without HRT compared with that in those with a correct hormonal balance (15.2 ± 2.6 vs. 49.3 ± 6 mL). In contrast, after TBI, the uterine volume was similar in all women, with no positive effect of hormonal impregnation on the uterine volume (16.3 ± 2.6 vs. 20.1 ± 2.2 mL, respectively).
The uterine volume was diminished after HSCT, regardless of the conditioning regimen. The physiopathology needs to be further investigated: specific impact of a high dose of an alkylating agent; impact of hormone deprivation around puberty; poor compliance to HRT; or different myometrial impact of HRT compared with endogenous ovarian estrogens?
ClinicalTrials.gov/NCT 03583294 (enrollment of the first subject, November 11, 2017; enrollment of the last subject, June 25, 2021).
El volumen uterino se ve drásticamente reducido después de un transplante de células madre hematopoyéticas durante la infancia independientemente del régimen de acondicionamiento previo.
Estudiar el impacto del transplante de células madre hematopoyéticas (HSCT) sobre el volumen uterino en las supervivientes de leucemia aguda infantil (AL) según la edad en que se realizó el HSCT y el tipo de régimen de acondicionamiento mieloablativo.
Trece hospitales universitarios franceses.
Estudio prospectivo de cohortes.
Ochenta y ocho mujeres sometidas a HSCT durante su infancia o adolescencia por AL comparadas con un grupo control.
Se comparó el volumen uterino en una cohorte de mujeres adultas supervivientes de AL infantil tratada mediante HSCT en un estudio nacional prospectivo multicéntrico, emparejadas 1:1 con mujeres control. Las imágenes de las resonancias magnéticas pélvicas incluyeron secuencias de imágenes ponderadas por difusión. Las pruebas se centralizaron para una lectura doble-ciego realizada por 2 radiólogos.
Volumen uterino, relación cuerpo-cérvix uterino y coeficiente de difusión aparente.
La edad media en la realización del HSCT fue de 9.1+/- 0.3 años, con una media de duración del seguimiento de 16.4 +/- 0.5 años. La cohorte de 88 mujeres supervivientes de HSCT estaba compuesta por 2 subgrupos dependiendo del régimen de acondicionamiento mieloablativo recibido: un grupo con régimen basado en agentes alquilantes (n=34) y otro con régimen basado en irradiación corporal total (TBI) (n=54). Entre las 88 mujeres, se consideró que 77 tenían un “balance hormonal correcto” con aporte de estrógenos mediante tratamiento hormonal sustitutivo (HRT) por insuficiencia ovárica prematura (POI) o por una función ovárica residual. En el grupo control (n=88), el volumen uterino medio fue de 79.7 +/- 3.3 mL. El volumen uterino estaba significativamente reducido en todas las mujeres supervivientes de HSCT. Tras el régimen basado en agentes alquilantes, el volumen uterino era de 45.3 +/- 5.6 mL, correspondiente a una reducción significativa del volumen del 43.1% (28.8-57.4%) comparada con las del grupo control. Después de TBI, el volumen uterino fue de 19.6 +/- 1.9 mL, correspondiente a una reducción significativa del volumen del 75.3% (70.5%-80.2%) comparadas con las del grupo control. Tras el régimen basado en agentes alquilantes, el volumen uterino disminuyó drásticamente en mujeres con POI sin HRT comparadas con aquellas que tenían un balance hormonal correcto (15.2 +/- 2.6 vs. 49.3 +/- 6 mL). Por el contrario, después de TBI, el volumen uterino fue similar en todas las mujeres, sin efecto positivo de la impregnación hormonal sobre el volumen uterino (16.3 +/- 2.6 vs 20.1 +/-2.2 mL respectivamente).
Después de HSCT se produjo una reducción del volumen uterino independientemente del régimen de acondicionamiento. Son necesarios más estudios para conocer la fisiopatología: impacto específico de altas dosis de agentes alquilantes, impacto de la deprivación hormonal en la pubertad, bajo cumplimiento del HRT o diferente impacto miometrial de la HRT comparada con los estrógenos ováricos endógenos?
Útero, transplante de células madre hematopoyéticas, MRI, quimioterapia, irradiación corporal total.
Background
Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of ...DSD discovery.
Design/methods
All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed.
Results
Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age.
Conclusion
DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.
To evaluate the association between medical and social environmental factors and the risk of repeating a grade in childhood leukemia survivors.
A cross-sectional study of childhood leukemia ...survivors, recruited through the LEA cohort (Leucémie de l'Enfant et de l'Adolescent French Childhood Cancer Survivor Study for Leukemia) in 2014. An adjusted logistic regression model was used to identify variables linked to repeating a grade after the diagnosis among the survivors, and the rates of repeating a grade were compared between the survivors and their siblings using a multilevel logistic regression model.
The mean age at inclusion of the 855 participants was 16.2 ± 7.0 years, and the mean duration of follow-up from diagnosis to evaluation was 10.2 ± 6.2 years. After disease onset, 244 patients (28.5%) repeated a grade, with a median interval of 4 years (IQR, 2-8 years). Independent factors associated with repeating a grade were male sex (OR, 1.78; 95% CI, 1.21-2.60), adolescence (OR, 2.70; 95% CI, 1.63-4.48), educational support during the treatment period (OR, 3.79; 95% CI, 2.45-5.88), low parental education level (OR, 2.493; 95% CI, 1.657-3.750), and household financial difficulties (OR, 2.62; 95% CI, 1.607-4.28). Compared with siblings, survivors were at greater risk of repeating a grade (OR, 1.87; 95% CI, 1.48-2.35).
The most vulnerable patients seemed to be adolescents and those with parents of low socioeconomic status. Improving the schooling career of leukemia survivors will require that the medical community more carefully consider the social status of patients.
The ACTN1 gene has been implicated in inherited macrothrombocytopenia. To decipher the spectrum of variants and phenotype of ACTN1‐related thrombocytopenia, we sequenced the ACTN1 gene in 272 cases ...of unexplained chronic or familial thrombocytopenia. We identified 15 rare, monoallelic, nonsynonymous and likely pathogenic ACTN1 variants in 20 index cases from 20 unrelated families. Thirty‐one family members exhibited thrombocytopenia. Targeted sequencing was carried out on 12 affected relatives, which confirmed presence of the variant. Twenty‐eight of 32 cases with monoallelic ACTN1 variants had mild to no bleeding complications. Eleven cases harbored 11 different unreported ACTN1 variants that were monoallelic and likely pathogenic. Nine variants were located in the α‐actinin‐1 (ACTN1) rod domain and were predicted to hinder dimer formation. These variants displayed a smaller increase in platelet size compared with variants located outside the rod domain. In vitro expression of the new ACTN1 variants induced actin network disorganization and led to increased thickness of actin fibers. These findings expand the repertoire of ACTN1 variants associated with thrombocytopenia and highlight the high frequency of ACTN1‐related thrombocytopenia cases. The rod domain, like other ACTN1 functional domains, may be mutated resulting in actin disorganization in vitro and thrombocytopenia with normal platelet size in most cases.
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