To assess the value of a self-completed questionnaire based on patients’ verbal descriptors of pelvic painful symptoms to identify women with endometriosis.
Prospective 1:2 nonmatched case-control ...study.
Three French endometriosis referral centers.
Endometriosis cases were women aged 18–45 years with endometriosis confirmed by histology. Controls were as follows: asymptomatic women attending a gynecologic consultation for routine examination; women without evidence of endometriosis consulting for pain/infertility; and population-based controls from the same urban locations.
All women completed the 21-item yes/no questionnaire about painful symptoms.
The area under the receiver operating characteristic curve of the full question set model based on binary logistic regression and the diagnostic accuracy of low- and high-risk classification rules based on selected threshold of the prediction model.
We included 105 cases and 197 controls (45 asymptomatic consultation-based controls, 66 women without endometriosis consulting for pain/infertility, and 86 population-based controls). The full question set prediction model, including age, had an area under the receiver operating characteristic curve of 0.92 (95% confidence interval, 0.87–0.95) after internal validation. The high-risk classification rule had a specificity of 98.0% and a positive likelihood ratio of 30.5. The low-risk classification rule had a sensitivity of 98.1% and a negative likelihood ratio of 0.03. For a hypothesized pretest prevalence of 10%, the high- and low-risk prediction rules ascertained endometriosis with posttest probability rates of 77.2% and 0.3%, respectively.
A self-completed patient-centered questionnaire can identify women at low or high risk of endometriosis with a high diagnostic accuracy and, thus, may help early identification of women with endometriosis.
Identificación temprana de mujeres con endometriosis mediante un simple cuestionario completado por el paciente como herramienta de visualización: un estudio diagnóstico.
Evaluar el valor de un cuestionario autocompletado basado en las descripciones verbales de pacientes de síntomas pélvicos dolorosos para identificar mujeres con endometriosis.
Prospectivo 1:2 estudio de casos control no emparejados.
Tres centros franceses referentes de endometriosis.
Casos de endometriosis de mujeres de 18-45 años de edad con endometriosis confirmada por histología. Los controles fueron los siguientes: mujeres asintomáticas realizando una consulta ginecológica para examen de rutina, mujeres sin evidencia de endometriosis consultando por dolor/infertilidad; y controles basados en la población de las mismas localidades urbanas.
Todas las mujeres completaron el cuestionario de 21 ítems por sí/no sobre síntomas dolorosos.
El área bajo la curva característica de funcionamiento del receptor del cuestionario completo del modelo se basó en logística binaria de regresión y la precisión del diagnóstico de bajo y alto riesgo con reglas de clasificación basadas en el umbral seleccionado del modelo de predicción.
Nosotros incluimos 105 casos y 197 controles (45 controles asintomáticos basados en consulta, 66 mujeres sin endometriosis consultando por dolor/infertilidad, y 86 controles basados en la población). El conjunto de preguntas completo del modelo predictivo, incluyendo edad, tuvo un área bajo la curva característica del operador receptor de 0.92 (95% intervalo de confianza, 0.87–0.95) luego de validación interna. La regla de clasificación de alto riesgo tuvo una especificidad de 98.0% y una razón de probabilidad positiva de 30.5. La regla de clasificación de bajo riesgo tuvo una sensibilidad de 98.1% y una razón de probabilidad negativa de 0.03. Para un pretest hipotetizado una prevalencia del 10%, las reglas de predicción de alto y bajo riesgo confirmaron endometriosis por probabilidad de postest de 77.2% y 0.3% respectivamente.
Un cuestionario de autoevaluación y centrada en el paciente puede identificar mujeres con bajo y alto riesgo de endometriosis con una alta precisión diagnóstica y, por lo tanto, puede ayudar a una identificación temprana de mujeres con endometriosis.
Given the very poor prognosis for children with recurrent medulloblastoma, we aimed to identify prognostic factors for survival post-relapse in children with childhood medulloblastoma. We ...retrospectively collected clinico-biological data at diagnosis and main clinical characteristics at relapse of children newly diagnosed with a medulloblastoma between 2007 and 2017 at Gustave Roussy and Necker Hospital. At a median follow-up of 6.6 years (range, 0.4-12.3 years), relapse occurred in 48 out 155 patients (31%). The median time from diagnosis to relapse was 14.3 months (range, 1.2-87.2 months). Relapse was local in 9, metastatic in 22 and combined (local and metastatic) in 17 patients. Second-line treatment consisted of chemotherapy in 31 cases, radiotherapy in 9, SHH-inhibitor in four and no treatment in the remaining four. The 1-year overall survival rate post-relapse was 44.8% (CI 95%, 31.5% to 59.0%). While molecular subgrouping at diagnosis was significantly associated with survival post-relapse, the use of radiotherapy at relapse and time to first relapse (>12 months) might also have a potential impact on post-relapse survival.
Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 (RRM2) was one of the ...key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response.
Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic ...predisposition accounts for 5 to 10% of cancer diagnoses in children
, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma
. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB
)
ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB
. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype
and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U
) position
. Tumours from patients with ELP1-associated MB
were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems
. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the ...(epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.
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•Highly divergent posttranscriptional pathway regulation in MB subgroups•Phosphoproteomic profiles reveal specific kinase activity in MB subgroups•Identification of aberrant ERBB4-SRC signaling as a hallmark of group 4 MBs•Over expression of activated SRC in the developing cerebellum induces MB
Using proteomic analyses, Forget et al. unravel divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas (MB) and identify aberrant ERBB4-SRC signaling in group 4. Expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 MB.
Medulloblastomas (MBs) are the most frequent childhood malignant brain tumor. Four histopathologic variants and 4 genetic subgroups have been defined in the World Health Organization (WHO) 2016 ...Classification and constitute major risk stratification items directly affecting the patient management. Although MB subgroups have been molecularly defined, immunohistochemical surrogates are needed. The aim of our retrospective study was to evaluate the concordance between immunohistochemistry, using 4 antibodies (YAP1, GAB1, OTX2, and β-catenin), and DNA-methylation profiling in MB subgrouping. From a series of 155 MBs, the κ coefficient of concordance was almost perfect (0.90), with only 8/152 discrepant cases (no DNA-methylation analysis was available in 3 cases). Interestingly, the discrepancies mostly concerned (7/8 cases) MBs with divergent differentiations (myogenic, melanotic, and others) with all of those classified into group 3 (n=6) and group 4 (n=1) by DNA-methylation profiling. Another discrepant case concerned a WNT-activated MB (showing only 1% of immunopositive tumor cell nuclei), highlighting the difficulties of determining an appropriate β-catenin immunostaining cutoff. The high concordance of the routine immunohistochemical panel (YAP1, GAB1, OTX2, and β-catenin) and DNA-methylation profiling confirm its utility as a reliable predictive marker of molecular subtype in MBs. We analyzed the accuracy of 10 different IHC combinations for the determination of MB subtype and found that a combination of 2 antibodies (YAP1 and OTX2) allows for the successful characterization of 144 cases of 152 cases. Finally, our series extends the molecular data of the rare morphologic variant of MBs with melanotic/myogenic differentiations.
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