A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

Cancer is not a risk factor for severe COVID-19 in children, except in patients with recent allogeneic hematopoietic stem cell transplantation or comorbidities.

The EPICO (Spanish general registry of COVID-19 in children)-SEHOP (Spanish Society of Pediatric Hematology and Oncology) platform gathers data from children with SARS-CoV-2 in Spain, allowing comparison between children with cancer or allogeneic hematopoietic stem cell transplantation (alloHSCT) and those without. The infection is milder in the cancer/alloHSCT group than in children without comorbidities (7.1% vs. 14.7%), except in children with recent alloHSCT (less than 300 days), of which 35.7% experienced severe COVID-19. These data have been shared with the SEHOP members to support treatment and isolation policies akin to those for children without cancer, except for those with recent alloHSCT or additional comorbidities. This highlights the collaborative registries potential in managing pandemic emergencies.

Neutropenia febril posquimioterapia. Estancia hospitalaria y experiencia en nuestro medio / Post chemoterapy febrile neutropenia. Length of stay and experience in our population

INTRODUCCIÓN: Las infecciones son una causa importante de morbimortalidad en los pacientes con cáncer (mortalidad estimada en 3%). La neutropenia febril conlleva con frecuencia el ingreso hospitalario de los pacientes oncológicos, incrementando el riesgo de infección nosocomial así como los costes sanitarios por ingresos. MÉTODOS: Estudio observacional ambispectivo (01/07/2015 - 31/12/2018) de los episodios de neutropenia febril posquimioterapia en población pediátrica. Se recogieron edad, sexo, percentil de peso (OMS), estancia hospitalaria (días), temperature (oC), aislamiento de germen, foco infeccioso, profilaxis o no antibiótica y antifúngica, cifras de hemoglobina (g/dl), plaquetas (/mm3), neutrófilos (/mm3), linfocitos (/mm3), monocitos (/mm3), proteína C reactiva (PCR) (mg/L) y procalcitonina (PCT) (ng/ml) al ingreso y días con neutropenia < 500/mm3. El análisis estadístico se realizó con el programa SPSSv.23. RESULTADOS: De 69 pacientes, se registraron 101 episodios. La estancia media fue de 7,43 días (mediana 6 días). Se aisló germen en un 44,6% de los episodios, no identificándose foco infeccioso en un 36% de los mismos. Se halló correlación inversa entre hemoglobina, plaquetas y linfocitos al ingreso con la estancia hospitalaria (-0,356 (p 0,001); -0,216 (p 0,042) y -0,216 (p 0,042) respectivamente). La estancia media fue mayor si al ingreso presentaron PCR > 90 mg/L (10,94 vs. 6,66 días p 0,017), si PCT > 1 ng/ml (16,50 vs. 6,77 días p 0,0002), si ≤ 100 neutrófilos (8,27 vs. 5,04 días p 0,039) y si hubo aislamiento microbiológico (9,54 vs. 5,78 días p 0,006). CONCLUSIÓN: La relación entre hemoglobina, plaquetas y linfocitos al ingreso con la estancia media es inversamente proporcional. Además, aquellos pacientes con ≤ 100 neutrófilos al ingreso, PCR > 90 mg/L y PCT > 1 ng/ml presentaron mayor estancia media. Estos factores podrían ser importantes en el manejo de la neutropenia febril en el paciente con cáncer infantil

INTRODUCTION: Infections are significant cause of morbidity and mortality in cancer patients (mortality is estimated at around 3%). Febrile neutropenia often leads to the hospitalisation of cancer patients, increasing the risk of nosocomial infection, as well as health costs due to the hospital admission. METHODS: An ambispective (01 July 2015 - 12 July 2018) observational study was conducted on all episodes of chemotherapy-induced febrile neutropenia in a paediatric population. A record was made of age, gender, weight percentile (WHO), length of hospital stay (days), temperature (oC), microbial isolation, infectious source, antibiotic or antifungal prophylaxis, haemoglobin (g/dl), platelets (/mm3), neutrophils (/mm3), lymphocytes (/mm3), monocytes (/mm3), CRP (mg/L) and procalcitonin (PCT) (ng/ml) on admission, and days with neutropenia < 500/mm3. Statistical analysis was performed using the SPSSv.23 program. RESULTS: The study included 69 patients, and 101 episodes were recorded. The mean stay was 7.43 days (median 6 days). Microbial isolation was found in 44.6% of the episodes, with no infectious source identified in 36% of them. An inverse correlation was found between haemoglobin, platelets, and lymphocytes on admission and the hospital stay (-0.356: P = .001, -0.216: P = .042, and -0.216: P = .042, respectively). The mean stay was greater if there was a CRP > 90 mg/L (10.94 vs. 6.66 days, P=.017), if PCT > 1 ng/ml (16.50 vs. 6.77 days, P = .0002), if ≤ 100 neutrophils (8.27 vs. 5.04 days P=.039) on admission, and if there was microbe isolation (9.54 vs. 5.78 days P = .006). CONCLUSION: The relationship between haemoglobin, platelets, and lymphocytes on admission and the mean stay is inversely proportional. In addition, those patients with ≤ 100 neutrophils, CRP > 90 mg/L, and PCT>1ng/ml on admission had a longer hospital stay