Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.

INTRODUCTION: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Upfront treatment with mTOR inhibitor everolimus in pediatric low-grade gliomas: A single-center experience.

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumor in children. Adjuvant treatment, consisting in chemotherapy and radiotherapy, is often necessary if a complete surgical resection cannot be obtained. Traditional treatment approaches result in a significant long-term morbidity, with a detrimental impact on quality of life. Dysregulation of the mitogen-activated protein kinase (MAPK) pathway is the molecular hallmark of pLGGs and hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway is frequently observed. We report clinical and radiological results of front-line treatment with everolimus in 10 consecutive patients diagnosed with m-TOR positive pLGGs at the Bambino Gesù Children's Hospital in Rome, Italy. Median duration of treatment was 19 months (range from 13-60). Brain magnetic resonance imaging showed stable disease in 7 patients, partial response in 1 and disease progression in 2. Therapy-related adverse events were always reversible after dose reduction or temporary treatment interruption. To the best of our knowledge, this is the first report of everolimus treatment for chemo- and radiotherapy-naïve children with pLGG. Our results provide preliminary support, despite low sample size, for the use of everolimus as target therapy in pLGG showing lack of progression with a manageable toxicity profile.

Long-term renal function in unilateral non-syndromic renal tumor survivors treated according to International Society of Pediatric Oncology protocols.

BACKGROUND: The risk of renal impairment among survivors of childhood unilateral non-syndromic renal tumors (RTs) is not well defined. We evaluated the prevalence of and possible risk factors for renal impairment by estimating Glomerular Filtration Rate (eGFR) categories and chronic kidney disease (CKD) according to Kidney Disease: Improving Global Outcomes guidelines. PROCEDURE: Since 1978, 82 patients were treated for RT, according to the International Society of Pediatric Oncology protocols in a single oncology unit. Of the 67 survivors, those who underwent nephron sparing surgery, those with short-term follow-up or those who had bilateral and/or syndromic disease or a second malignancy were excluded. Thirty-five adult survivors (14 M/21F; mean age 25 years; mean follow-up 20 years) were studied by chemistry, kidney ultrasound, blood pressure measurement, urinanalysis. Correlations were investigated between the prevalence of eGFR categories and CKD and gender, age at diagnosis, radiotherapy, chemotherapy, body mass index, time of follow-up, and age at study. RESULTS: Eight (22.9%) survivors presented a mildly decreased eGFR (G2 category), the mean value was 80 ± 9.78 ml/min/1.73m(2) (median 84.5, range 63-89). Three (8.6%) survivors had CKD and a fourth (2.9%) hypertension. No significant correlations between G2 category and clinical variables were found. CONCLUSIONS: A small percentage of survivors had CKD or hypertension after two decades. It is not yet clear whether a mildly decreased eGFR that does not constitute CKD in the absence of other markers (albuminuria and/or kidney ultrasound abnormalities) is likely to progress to CKD. Health promotion programs to avoid comorbidities are required.

Case Report: Remarkable breakthrough: successful treatment of a rare intracranial mesenchymal, FET::CREB fusion-positive tumor treated with patient-tailored multimodal therapy.

Background: Intracranial mesenchymal tumors are a rare type of neoplasm (0.3% of all soft tissue tumors) characterized by a fusion of a FET family gene (usually EWSR1, rarely FUS) to CREB family genes (CREB1, ATF1, and CREM) with a slow-growing and favorable prognosis. Mesenchymal tumors are most frequently localized in the subcutaneous tissue (typically in the limbs and hands) of young adults and have rarely been diagnosed in the central nervous system. Surgery is the gold standard treatment; adjuvant radiation therapy and chemotherapy with sarcoma-based regimens have been used in rare cases when complete surgical excision was not recommended. In terms of prognosis, these tumors show a tendency for local relapse. The longest patient outcomes reported in the literature are five years. Case description: This case describes a 27-year-old woman with unconventional extracranial metastatic sites of myxoid intracranial mesenchymal tumor FET::CREB fusion-positive and high expression of PD-1 (40%) and PD-L1 (30%). Based on clinical, molecular, and histological characteristics, she underwent various local and systemic therapies, including surgery, proton beam therapy, the use of immune checkpoint inhibitors, and chemotherapy. These treatments led to a complete remission of the disease after eight years from tumor diagnosis. Conclusions: Our case sheds light on the importance of precision medicine and tailored therapy to explore new treatment opportunities for rare or unknown tumor entities.

SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Background: Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. Materials and methods: We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Results: Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Conclusions: Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle.

Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood-brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.

Long-term response to crizotinib in a 17-year-old boy with treatment-naïve ALK-positive non-small-cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death. NSCLC accounts for 80-90% of cases. In young patients, adenocarcinoma is the most frequent histotype and 3-7% expresses the rearrangement of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by the FDA. CASE: We present a case of a 17-year-old male with metastatic treatment-naïve ALK-positive adenocarcinoma. He was treated with crizotinib and obtained a prolonged response with PFS of 33 months. CONCLUSION: Crizotinib can be extremely effective in adolescents with treatment-naïve ALK-positive NSCLC but fail to prevent a central nervous system relapse. Resistance mechanisms need to be investigated.

Acute Hematological Toxicity during Cranio-Spinal Proton Therapy in Pediatric Brain Embryonal Tumors.

BACKGROUND: Embryonal tumors represent a heterogeneous entity of brain tumors that need a multidisciplinary treatment including cranio-spinal irradiation (CSI), with a known impact on the acute toxicity. Proton therapy (PT) boasts a reduction in acute hematological toxicity. METHODS: We retrospectively examined 20 pediatric patients affected by high-risk medulloblastoma and other rare embryonal brain tumors subjected to CSI with PT from September 2016 to April 2020. Before CSI, all patients received induction chemotherapy, and three patients additionally received two high-dose courses with thiotepa, followed by an autologous haemopoietic stem cell transplantation. We recorded the total white blood cell count, absolute neutrophil count, platelets, and hemoglobin levels for all patients during PT. RESULTS: Leucocytes and neutrophils decreased directly after the beginning of treatment, reaching a complete recovery at the end of treatment. Hemoglobin values remained constant over the treatment course. The median platelet value decreased until reaching a plateau around halfway through therapy, followed by a slow increase. No cases of febrile neutropenia or severe infections were reported. No treatment discontinuation due to hematological toxicity was necessary. CONCLUSIONS: CSI with PT was proven to be safe in this setting of pediatric patients. Our study showed that despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with PT, and, therefore, no treatment was discontinued or delayed.

Synchronous and Metachronous Metastatic Breast Cancer, with Different Histology and Opposite Immunophenotype, Treated with Combination of Chemotherapy, Anti-Her2, and Endocrine Therapy: A Case Report.

In the case of our patient, the synergic action of endocrine therapy and chemotherapy plus dual anti-HER2 combination allowed a complete disease control. Therapy should be scheduled by considering the two cancers as individual entities. The approach to breast cancer is changing from being considered a singular disease to a multiform one, according to current research focused on biological markers such as HER2, ERs, and PRs, with important implications in clinical, prognostic, and therapeutic features.

Circulating vascular endothelial growth factor in childhood solid tumors: plasma and serum measurements.

BACKGROUND: Serum and plasma vascular endothelial growth factor (VEGF) were measured in children with a solid tumor to investigate which provides better prognostic information. PATIENTS AND METHODS: Seventeen patients under treatment were divided into two groups: without (n 8) and with (n 9) detectable disease at radiological assessment (groups I and II). The control group consisted of 26 healthy children. VEGF was tested by enzyme-linked ELISA kit. RESULTS: Serum VEGF concentrations in group II were statistically higher than those in group I (p<0.05) and those in controls (p=0.001), whereas the difference between group I and controls was not statistically significant (p=0.067). Plasma VEGF concentrations in group II were also statistically higher than those in group I (p<0.01) and those in controls (p=0.0001); the difference between group I and controls was also statistically significant (p=0.004). CONCLUSION: Plasma would be the more useful specimen for measurement of circulating VEGF in cancer childhood.