Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Spontaneous remission of angioimmunoblastic T-cell lymphoma in a child with ataxia-telangiectasia: a case report.

BACKGROUND: Angioimmunoblastic T-cell lymphoma is an uncommon subtype of peripheral T-cell lymphoma in children with fewer than 20 cases reported in literature. CASE PRESENTATION: A 3-year-old Omani boy was diagnosed with ataxia-talengectasia presenting with fever and generalized lymphadenopathy. His biopsy revealed atypical lymphocytic infiltrate consistent with the diagnosis of angioimmunoblastic T-cell lymphoma. Within 3 weeks from the initial presentation and without any neoadjuvant therapy, he showed complete recovery of symptoms with absence of fever and regression of all previously affected lymph nodes. He has remained in remission ever since. CONCLUSION: This is the first report of spontaneous improvement of angioimmunoblastic T-cell lymphoma in a patient with ataxia-telangiectasia who was 3 years old at presentation. Owing to the paucity of similar cases, this report adds valuable diagnostic, therapeutic, and monitoring data.

Alarming Antibiotic Resistance in Pediatric Oncology Patients: A Three-Year Prospective Cohort Study from Oman.

Background: Bloodstream infections (BSI) are severe and challenging oncological complications, with a consequent high morbidity and mortality in the immunocompromised. We reviewed the profile and susceptibility of bacteria associated with infections in children under 13 years of age receiving chemotherapy. Methods: Prospective cohort study of pediatric oncology patients was conducted between January 2015 and October 2017 at the Royal Hospital in Oman. Patient demographics, clinical data, laboratory parameters, microbial etiology and susceptibility, and outcomes were retrieved and analyzed. Results: A total of 74 episodes of positive bacterial blood cultures were detected in 38 oncology patients (positive blood culture rate of 51%). Fifty-seven percent were positive for gram-negative organisms with Klebsiella (21%) being the most common gram-negative organism cultured, and the most common gram-positive organism was Staphylococcus (coagulase negative Staphylococcus (CONs) and S. Aureus) (30%). The majority of patients had gastrointestinal complaints (74%), and almost half (51%) had prolonged periods of neutropenia (>7 days). One third of gram-negative organisms were resistant to four or more antibiotics with a major resistance of 31% to piperacillin-tazobactam. Of the gram-positive organisms, 38% were resistant to at least four antibiotics and 30% were pan-resistant (except for vancomycin). Conclusion: The gram-negative organisms were dominant in BSIs with Klebsiella being the most common culprit. Bacteremia was prevalent, however, high resistance to first-line antibiotics was documented amongst gram-negative isolates, demanding strategies to ensure our patients' safety.

Neuroblastoma Among Omani Children: Clinical characteristics and survival outcome from a dedicated centre.

OBJECTIVES: A limited number of publications from the Middle East have focused on neuroblastoma, a common childhood malignancy. This study describes the clinical characteristics and survival outcome of Omani children with neuroblastoma treated at the National Oncology Centre, Oman, between 2010 and 2017. METHODS: From January 2010 to December 2017, data on Omani children aged less than 13 years with neuroblastoma were retrospectively collected. Survival data were statistically correlated with known prognostic factors, including age, stage of disease, MYCN profile and presence of metastasis. RESULTS: A total of 56 Omani children were included. in this study. The male to female ratio was 1:1. The mean age at presentation was one year and 10 months. The two most common presenting complaints were body masses (48.2%) and constitutional symptoms (33.9%). Approximately, 54.5% were high risk, 35.7% were intermediate risk and 9.8% were low risk. High-risk neuroblastoma was mainly found in children older than one year (76.6%), with low risk mainly observed in children less than one year of age (80%). The overall survival of all groups combined was 74% (P <0.05); the event-free survival (EFS) was 67% (P <0.05). The overall survival rates over five years for the high-risk, intermediate-risk and low risk groups were 60%, 88% and 100%, respectively, and the EFS was 51%, 79% and 100%, respectively. CONCLUSION: Omani children with neuroblastoma mainly presented with masses or constitutional symptoms and had an advanced disease at presentation which was associated with inferior survival. The survival outcomes were reasonably similar to published international data.

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

A Cerebellar High-Grade Neuroepithelial Tumour with BCOR Alteration in a five-year-old Child: A case report.

New groups of high-grade neuroepithelial tumours (HGNET) have emerged from the reclassification of central nervous system (CNS) embryonal tumours that have recognised CNS HGNET with BCOR alteration (CNS HGNET-BCOR). We report a two-year, nine-month-old Omani boy who presented to the Royal Hospital, Muscat, Oman, in 2015 with subacute head tilting and neck pain. A well-defined cerebellar lesion was found and he was treated with standard chemoradiotherapy. After a relapse at the age of five years, molecular testing revealed a BCOR alteration. He was treated with further surgery and high-dose chemotherapy; unfortunately, he relapsed and died three years after he was diagnosed.

The patterns and causes of neonatal mortality at a tertiary hospital in oman.

OBJECTIVE: To report the patterns and causes of neonatal death from a tertiary care neonatal intensive care unit over a period of four years. METHODS: This is a retrospective cohort study where four years data (January 2006 - December 2009) of all inborn neonatal admissions and deaths were collected from the neonatal intensive care unit at Sultan Qaboos University hospital on predesigned forms. All out born admissions and deaths were excluded. The causes of neonatal death were classified using Wigglesworth's classification. RESULTS: The number of inborn live births during the study period was 10064 and the total number of inborn neonatal admissions was 1475. The total deaths (neonatal and post neonatal) at the neonatal intensive care unit was 73 (63 inborn and 10 out born). Among the inborn, five deaths were post neonatal deaths and hence, excluded from analysis. Among the remaining inborn neonatal deaths (n=58), 34 (59%) were males and 24 (41%) were females. The number of neonatal admissions increased over the years during the study period from 248 to 356, while the number of deaths also increased from 10 deaths in 2006, to 20 deaths in 2009. The primary causes of neonatal deaths were prematurity and its complications 52% (n=30). Lethal congenital malformations lead to 17 (29%) newborn deaths, specific diagnosis in 7 newborns (12%), and birth asphyxia in four (7%) of cases. CONCLUSION: There was an increasing trend of neonatal admissions and deaths among inborn babies. Prematurity, with sepsis as its major complication and congenital malformations were the leading cause of neonatal mortality.