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.

Retrospective Cohort Analysis of the Impact of Puberty on Plexiform Neurofibroma Growth in Patients with Neurofibromatosis Type 1.

OBJECTIVE: To assess the hypothesis that plexiform neurofibroma (PN) growth rates increase during puberty. STUDY DESIGN: PN growth rates before and during puberty were compared in a retrospective cohort of children with neurofibromatosis type 1 with puberty defined by Tanner staging. Of 33 potentially eligible patients, 25 had adequate quality magnetic resonance imaging for volumetric analysis and were included in ≥1 anchor cohort. Volumetric analysis was performed for all available imaging studies within the 4 years before and after puberty, and before and after 9- and 11-year-old anchor scans. Linear regression was performed to estimate the slope of change (PN growth rate); growth rates were compared with paired t test or Wilcoxon matched-pairs signed rank test. RESULTS: There were no significant difference in rates of PN growth in milliliters per month or milliliters per kilogram per month in the prepubertal vs pubertal periods (mean, 1.33 ± 1.67 vs 1.15 ± 1.38 [P = .139] and -0.003 ± 0.015 vs -0.002 ± 0.02 [P = .568]). Percent increases of PN volumes from baseline per month were significantly higher prepubertally (1.8% vs 0.84%; P = .041) and seemed to be related inversely to advancing age. CONCLUSIONS: Puberty and its associated hormonal changes do not seem to influence PN growth rate. These findings support those previously reported, but from a typical population of children with neurofibromatosis type 1 with puberty confirmed by Tanner staging.

Selumetinib in Children with Inoperable Plexiform Neurofibromas.

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1.

OBJECTIVE: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed. RESULTS: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. CONCLUSIONS: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Carboplatin Rechallenge After Hypersensitivity Reactions in Pediatric Patients With Low-Grade Glioma.

BACKGROUND: The high prevalence of carboplatin hypersensitivity reactions (HSR) significantly affects the treatment of pediatric patients with low-grade glioma (LGG). Rechallenging patients is an option that must balance the risks of repeat allergic reaction to the benefits of retaining an effective anti-tumor regimen. PROCEDURE: We performed a retrospective review of children with LGG treated with carboplatin and vincristine between October 2000 and April 2013, who had a documented HSR to carboplatin. Patients were re-exposed to carboplatin using either precautionary measures (prolonged infusion time and premedication with H1 antagonists, H2 antagonists, and corticosteroids), a desensitization protocol, or both. RESULTS: We report the results of our institutional experience of carboplatin re-exposure using both premedication with a prolonged infusion time and a desensitization protocol. Overall, 40 of 55 (73%) patients were successfully rechallenged with carboplatin, including 19 of 25 (76%) patients who underwent desensitization. CONCLUSION: Our results demonstrate re-exposure to be a safe alternative to abandoning carboplatin for patients with a hypersensitivity reaction. We propose a clinical algorithm for treatment.

Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients.

We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy.

Spontaneous and Engineered Compensatory HSV Mutants that Counteract the Host Antiviral PKR Response.

A virulent recombinant HSV lacking the diploid γ(1)34.5 gene (Δγ(1)34.5) have been investigated over the last two decades both for anti-tumor therapy and as vaccine vectors. The first generation vectors, while safe, are incapable of sustained replication in the majority of treated patients. An interferon inducible host antiviral kinase, protein kinase R (PKR), limits late viral protein synthesis and replication of Δγ(1)34.5 viruses. This review describes the development of new Δγ(1)34.5 vectors, through serial passage selection and direct viral genome engineering, which demonstrate selective PKR evasion in targeted cells and improved viral replication without restoring neurovirulence.

Serial passage through human glioma xenografts selects for a Deltagamma134.5 herpes simplex virus type 1 mutant that exhibits decreased neurotoxicity and prolongs survival of mice with experimental brain tumors.

Previous studies have described in vitro serial passage of a Deltagamma(1)34.5 herpes simplex virus type 1 (HSV-1) strain in SK-N-SH neuroblastoma cells and selection of mutants that have acquired the ability to infect and replicate in this previously nonpermissive cell line. Here we describe the selection of a mutant HSV-1 strain by in vivo serial passage, which prolongs survival in two separate experimental murine brain tumor models. Two conditionally replication-competent Deltagamma(1)34.5 viruses, M002, which expresses murine interleukin-12, and its parent virus, R3659, were serially passaged within human malignant glioma D54-MG cell lines in vitro or flank tumor xenografts in vivo. The major findings are (i) viruses passaged in vivo demonstrate decreased neurovirulence, whereas those passaged in vitro demonstrate a partial recovery of the neurovirulence associated with HSV-1; and (ii) vvD54-M002, the virus selected after in vivo serial passage of M002 in D54-MG tumors, improves survival in two independent murine brain tumor models compared to the parent (unpassaged) M002. Additionally, in vitro-passaged, but not in vivo-passaged, M002 displayed changes in the protein synthesis profile in previously nonpermissive cell lines, as well as early U(S)11 transcription. Thus, a mutant HSV-1 strain expressing a foreign gene can be selected for enhanced antitumor efficacy via in vivo serial passage within flank D54-MG tumor xenografts. The enhanced antitumor efficacy of vvD54-M002 is not due to restoration of protein synthesis or early U(S)11 expression. This finding emphasizes the contribution of the in vivo tumor environment for selecting novel oncolytic HSV specifically adapted for tumor cell destruction in vivo.

Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas.

Gene therapy using viral vectors for the treatment of primary brain tumors has proven to be a promising novel treatment modality. Much effort in the past has been placed in utilizing replication-defective viruses to this end but they have shown many disadvantages. Much recent attention has been focused on the potential of replication-competent viruses to discriminatingly target, replicate within, and destroy tumor cells via oncolysis, leaving adjacent post-mitotic neurons unharmed. The engineered tumor-selective herpes simplex-1 virus (HSV-1) mutants G207 and HSV1716 have completed Phase I investigations in the treatment of recurrent high-grade glioma. The results of these clinical trials are reviewed here. This review also aims to examine the manipulation and development of other viruses for the treatment of malignant glioma, including Newcastle disease virus, reovirus, poliovirus, vaccinia virus, and adenoviruses, in particular the adenovirus mutant ONYX-015.