Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors ...including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis‐1 is well known, with most patients presenting with café‐au‐lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis‐1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to “ash‐leaf like” hypomelanotic macules (five patients), we detected intracranial tuber‐like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients). All our patients also had Neurofibromatosis‐1 like features, mainly café‐au‐lait macules. This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre‐emptive cancer surveillance.
CMMRD is a rare cancer predisposition syndrome
Phenotypic overlap with NF‐1 is well known and described in the literature
This study presents phenotypic overlap with Tuberous sclerosis as well
Patients had intracranial tubers‐like lesions (A), renal angiomyolipomas (B) and cysts and hypopigmented macules (arrow, C). Also shown are café‐au‐lait macules typical of Neurofibromatosis 1 (arrowhead, C)
Background/Aim: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome ...precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. Patients and Methods: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome – one having PTCH1 mutation and one with SUFU mutation – followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. Results: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). Conclusion: Our results help towards finding new treatable molecular targets for these types of medulloblastomas.
Retinoblastoma in Asia Kaliki, Swathi; Vempuluru, Vijitha S.; Mohamed, Ashik ...
Ophthalmology (Rochester, Minn.),
April 2024, Letnik:
131, Številka:
4
Journal Article
Recenzirano
Odprti dostop
To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia.
Multinational, prospective study including treatment-naïve ...patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter.
A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries.
Chemotherapy, radiotherapy, enucleation, and orbital exenteration.
Enucleation and death.
Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1–261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 16%), cT2 (n = 951 34%), cT3 (n = 1136 41%), cT4 (n = 267 10%), N1 (n = 48 2%), and M1 (n = 129 6%) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively.
At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of ...tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 & Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.
Abstract Pediatric low-grade gliomas (PLGG) have excellent outcomes overall but are a major clinical challenge when disseminated. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a recognised ...entity both clinically and pathologically, however many disseminated LGG (DLGG) fall outside this diagnosis. To better understand the clinical and molecular features of DLGG as well as risk factors for dissemination, we assembled an international consortium of 30 sites, contributing over 200 patients with clinical annotation, along with genomic and methylation profiling. DLGG have worse progression-free (PFS) and overall survival (OS) than PLGG overall (p<0.0001). Seventy (35%) presented with a localized mass and secondary dissemination, including some with initial gross-total resection. The most common growth pattern observed (n=77, 40%) is a dominant suprasellar/optic pathway tumor with leptomeningeal drop-metastases involving the brainstem and spinal cord. Only 27 (14%) patients had diffuse tumors (without an identifiable dominant mass), and these had significantly worse OS (p=0.03). The most common pathologic diagnosis was pilocytic/pilomyxoid astrocytoma (n=92; 53%). DLGNT comprised a minority of cases (n=23, 14%), with a trend (p=0.056) towards worse survival compared to other diagnoses. The most frequent molecular alteration was BRAF fusion (78/151 with molecular testing; 52%), followed by FGFR mutations or fusions (18/151; 12%). BRAF V600E was underrepresented (14/151; 9%). 1p deletion was rare (17 patients) but highly associated with DLGNT. Methylation classification (n=70) was highly concordant with histologic diagnoses rather than clinical behavior. Importantly, patients who received upfront targeted therapies (TT; BRAF and/or MEK inhibition, n=9) had better PFS compared to those receiving chemotherapy (n=146, p=0.05). Furthermore, patients who were treated sequentially with chemo then TT had longer PFS on TT (p=0.011). This study presents the largest cohort of DLGG to date, expanding our understanding of the clinical, pathologic, and molecular features of this disease and supports the use of upfront targeted therapy.
Background: Children with hemato-oncological diseases or following stem cell transplantation (SCT) are at high risk for life-threatening infections; sepsis in this population constitutes a ...substantial proportion of pediatric intensive care unit (PICU) admissions. The current pediatric prognostic scoring tools to evaluate illness severity and mortality risk are designed for the general pediatric population and may not be adequate for this vulnerable subpopulation. Methods: Retrospective analysis was performed on all PICU admissions for sepsis in children with hemato-oncological diseases or post-SCT, in a single tertiary pediatric hospital between 2008 and 2021 (n = 233). We collected and analyzed demographic, clinical, and laboratory data and outcomes for all patients, and evaluated the accuracy of two major prognostic scoring tools, the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) and the Pediatric Risk of Mortality III (PRISM III). Furthermore, we created a new risk-assessment model that contains additional parameters uniquely relevant to this population. Results: The survival rate for the cohort was 83%. The predictive accuracies of PELOD-2 and PRISM III, as determined by the area under the curve (AUC), were 83% and 78%, respectively. Nine new parameters were identified as clinically significant: age, SCT, viral infection, fungal infection, central venous line removal, vasoactive inotropic score, bilirubin level, C-reactive protein level, and prolonged neutropenia. Unique scoring systems were established by the integration of these new parameters into the algorithm; the new systems significantly improved their predictive accuracy to 91% (p = 0.01) and 89% (p < 0.001), respectively. Conclusions: The predictive accuracies (AUC) of the PELOD-2 and PRISM III scores are limited in children with hemato-oncological diseases admitted to PICU with sepsis. These results highlight the need to develop a risk-assessment tool adjusted to this special population. Such new scoring should represent their unique characteristics including their degree of immunosuppression and be validated in a large multi-center prospective study.
Background
The MAPK pathway is an emerging target across a number of adult and pediatric tumors. Targeting the downstream effector of MAPK, MEK1, is a proposed strategy to control the growth of ...MAPK-dependent tumors.
Objective
iMATRIX-cobi assessed the safety, pharmacokinetics, and anti-tumor activity of cobimetinib, a highly selective MEK inhibitor, in children and young adults with relapsed/refractory solid tumors.
Patients and Methods
This multicenter Phase I/II study enrolled patients aged 6 months to < 30 years with solid tumors with known/expected MAPK pathway involvement. Patients received cobimetinib tablet or suspension formulation on Days 1–21 of a 28-day cycle. Dose escalation followed a rolling 6 design. The primary endpoint was safety; secondary endpoints were pharmacokinetics and anti-tumor activity.
Results
Of 56 enrolled patients (median age 9 years range 3–29), 18 received cobimetinib tablets and 38 cobimetinib suspension. Most common diagnoses were low-grade glioma (LGG;
n
= 32, including
n
= 12 in the expansion cohort) and plexiform neurofibroma within neurofibromatosis type 1 (
n
= 12). Six patients (11 %) experienced dose-limiting toxicities (including five ocular toxicity events), which established a pediatric recommended Phase II dose (RP2D) of 0.8 mg/kg tablet and 1.0 mg/kg suspension. Most frequently reported treatment-related adverse events were gastrointestinal and skin disorders. Steady state mean exposure (C
max
, AUC
0–24
) of cobimetinib at the RP2D (1.0 mg/kg suspension) was ~ 50 % lower than in adults receiving the approved 60 mg/day dose. Overall response rate was 5.4 % (3/56; all partial responses in patients with LGG).
Conclusions
The safety profile of cobimetinib in pediatrics was similar to that reported in adults. Clinical activity was observed in LGG patients with known/suspected MAPK pathway activation. Cobimetinib combination regimens may be required to improve response rates in this pediatric population.
Clinical Trial Registration
ClinicalTrials.gov NCT02639546, registered December 24, 2015.
PURPOSE: To evaluate the role of the ophthalmologist at presentation and during follow-up of children with arterial stroke.METHODS: This retrospective case series comprised 26 children with arterial ...stroke who were followed for at least 12 months in our tertiary pediatric medical center in 2005-2015. Demographic data and findings on radiological neuroimaging, ophthalmological and neurological examination were retrieved from the patient medical files.RESULTS: Of the 26 children identified with stroke, 5 (20%) had a metabolic syndrome, 3 (11%) cardiac anomaly, 3 (11%) recent major surgery for repair of cardiac anomaly, 3 (11%) vascular anomaly, 3 (11%), head trauma with traumatic dissection, 1 (4%) had hypercoagulability and in 8 patients (31%), no apparent cause was found (idiopathic). Only 9 (35%) had an eye exam during the follow-up. Eleven patients had a nonophthalmological neurological deficit as a result of the stroke. Positive ophthalmological manifestations included hemianopic visual field defect in 2 patients (8%), complete blindness and visual acuity deficit in one patient each (4%). At the last visit, no change in visual function was detected in those with ophthalmological deficit and 5 (20%) of the patients with other neurologic manifestations still had residual neurological deficit. CONCLUSION: Arterial stroke in children is a rare event and only a few are referred for an eye examination. In view of the significant ophthalmological manifestations revealed in the current study, children with arterial stroke should be referred for early ophthalmological evaluation.
Purpose
We report the unexpected absence of early relapse (before 30 months) in 24 consecutive patients with isolated limb primary Ewing sarcoma treated with an intensified pilot protocol, SCMCIE94.
...Methods
Clinical data for the study were collected retrospectively from the patient files. The protocol included 6 courses of chemotherapy, split radiation, and limb salvage surgery. This SCMCIE94 protocol had been used in almost all the patients described in an earlier report, in whom those with non-pelvic isolated tumors and low/absent CD56 expression in Ewing sarcoma tumor cells were all long-term survivors.
Results
The 5-year (10-year) event-free survival rate for the patients with isolated limb primary Ewing sarcoma was 78.95 ± 8.3% (68.6 ± 10.0%) and the overall survival rate was 90.7 ± 6.2% (71.1 ± 11.2%). There were no relapses before 30 months in any of these patients.
Conclusion
The intensified SCMCIE94 pilot protocol has been shown previously to cure patients with localized CD56-negative non-pelvic Ewing sarcoma. The present study shows that among all patients with localized extremity disease who were treated with this protocol, there were no cases of early relapse. Although our cohort was small, the difference in results from studies using other protocols is so striking, that it would seem reasonable to assume it is attributable to the changes made in the protocol itself rather than risk factors. Late relapses of isolated limb CD56-positive Ewing sarcoma suggest minimal residual disease warranting additional therapeutic approaches such as autologous stem cell rescue after Busulfan Melfelan.
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