Molecular profiling of pediatric and young adult colorectal cancer reveals a distinct genomic landscapes and potential therapeutic avenues.

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

The European Society of Paediatric Oncology Ependymoma-II program Core-Plus model: Development and initial implementation of a cognitive test protocol for an international brain tumour trial.

It is increasingly accepted that survival alone is an inadequate measure of the success of childhood brain tumour treatments. Consequently, there is growing emphasis on capturing quality of survival. Ependymomas are the third most frequently occurring brain tumours in childhood and present significant clinical challenges. European Society of Paediatric Oncology Ependymoma II is a comprehensive international program aiming to evaluate outcomes under different treatment regimens and improve diagnostic accuracy. Importantly, there has been agreement to lower the age at which children with posterior fossa ependymoma undergo focal irradiation from three years to either eighteen months or one year of age. Hitherto radiotherapy in Europe had been reserved for children over three years due to concerns over adverse cognitive outcomes following irradiation of the developing brain. There is therefore a duty of care to include longitudinal cognitive follow-up and this has been agreed as an essential trial outcome. Discussions between representatives of 18 participating European countries over 10 years have yielded European consensus for an internationally accepted test battery for follow-up of childhood ependymoma survivors. The 'Core-Plus' model incorporates a two-tier approach to assessment by specifying core tests to establish a minimum dataset where resources are limited, whilst maintaining scope for comprehensive assessment where feasible. The challenges leading to the development of the Core-Plus model are presented alongside learning from the initial stages of the trial. We propose that this model could provide a solution for future international trials addressing both childhood brain tumours and other conditions associated with cognitive morbidity.

Nimotuzumab and radiotherapy for treatment of newly diagnosed diffuse intrinsic pontine glioma (DIPG): a phase III clinical study.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. METHODS: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). RESULTS: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. CONCLUSIONS: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Cervical Lymph Node Metastases of Papillary Thyroid Carcinoma, in the Central and Lateral Compartments, in Children and Adolescents: Predictive Factors.

PROBLEM STATEMENT: The aim of our study was to identify predictive factors for lymph node metastases (LNM) in children and adolescents with papillary thyroid carcinoma (PTC) and their impact on survival. METHODS: The authors conducted an Italian multicentric retrospective analysis on 132 pediatric patients (0-18 years old) affected by PTC between 2000 and 2014. The investigated variables were demographic characteristics of the patients, clinicopathological features of PTCs, and persistence/recurrence of disease. The female/male ratio was 3.1:1. The median age was 14.3 ± 3.5 years (range 4-18 years). Total thyroidectomy was performed in all the patients, followed by lymph node dissection in 87 patients (65.9%). Metastatic lymph node involvement was confirmed in 73 patients (55.3%): lateral compartment (LC) in 25 patients (34.2%), central compartment (CC) in 17 patients (23.3%), and both compartments in 31 patients (42.5%). RESULTS: Multifocality (P < .00), vascular invasion (P = .04), infiltration of the thyroid capsule (P < .00), minimal extrathyroidal extension (P < .00), diffuse sclerosing variant of PTC (P = .02), and presence of LNM in the LC (P < .00) were significantly associated with LNM in CC. Infiltration of the thyroid capsule (P < .00), massive extrathyroidal extension (P = .03), distant metastases (P = .02), PTC, not otherwise specified (P < .00), and presence of LNM in the CC (P < .00) were significantly associated with LNM in LC. Age, sex and size of PTC were not correlated with the presence of cervical LNM. Moreover, presence of LNM in CC increases the risk of persistence (P < .01) and recurrence (P < .02) of PTC in children and adolescents. CONCLUSIONS: Most predictors, unfortunately, are only identified post-operatively by histopathologic examination: Just a small part of them can be pre-operatively detected with a low-sensitivity neck ultrasonography. In PTC patients with pre-operative predictors, we suggest an accurate pre- and intra-operative evaluation of CC and/or LC to find suspicious lymph nodes. The presence of LNM in CC has an impact on disease/progression/relapse-free survival. We suggest performing RAI therapy and an accurate follow-up for pediatric patients with only post-operative predictors.

Quality of life in long-term survivors treated for metastatic medulloblastoma with a hyperfractionated accelerated radiotherapy (HART) strategy.

PURPOSE: An intensive therapeutic strategy for metastatic medulloblastoma was launched in 1998 in our Institution. The aim of this study was to examine the long-term quality of life (QoL) in survivor patients at least 3 years after the end of the treatment. METHODS: Patients were asked to complete self-administered QoL questionnaires. An index of physical impairment (IPI) was scored (range 0-100; the lower the score the better) based on clinical objective observations. Patients were divided into two groups (lower IPI group, and higher IPI group) and descriptively compared accordingly. RESULTS: The study was completed by 25/33 eligible patients. Despite patients with a higher IPI reported worse perceived health condition, they had better emotional and psychological scores than those with a lower IPI in all QoL questionnaires. CONCLUSION: In our sample, patients with more severe objective and perceived physical impairments reported a better psychosocial QoL, possibly because the greater attention paid to them by society and family contributes to a better adjustment in long-term survivors. On this base, it should be recommended that all survivors receive a strong support as the most impaired patients.

Never too late to be anxious: validation of the Geriatric Anxiety Inventory, Italian version.

AIM: The aim of this work was to validate the Italian version of GAI (GAI-It) and its short form (GAI-It SF) in an over 65-population. METHODS: In 3 recruitment areas across Italy, two raters reciprocally blind to results assessed eligible subjects; a semi-structured diagnostic clinical interview was performed by a psychiatrist. RESULTS: Among the 76 enrolled subjects (mean age 72.7±6.8 years), anxiety symptoms were very common: 69.7% (moderate/ severe HADS-Anxiety), 76.3% (moderate/severe STAI-state), 71.0% (moderate/severe STAI-trait), 61.8% (GAI), 55.3% (GAI-SF). Sensitivity, specificity and positive predictive value of GAI confirmed a good reliability of the Italian version, with Cronbach's Alpha equal to 0.93 for GAI-It and to 0.77 for GAI-It SF, indicating a very good and good construct validity, respectively, of the scales. The Pearson correlation index demonstrated a moderately positive correlation among GAI, GAI-SF and STAI. CONCLUSIONS: Our data confirm the validity of GAI-It as a valuable instrument to assess anxiety in an elderly population, for clinical and research purposes.

Surgical management of papillary thyroid carcinoma in childhood and adolescence: an Italian multicenter study on 250 patients.

PURPOSE: The extent of surgery for pediatric papillary thyroid carcinoma is debatable. The aim of this study was to evaluate the feasibility of offering pediatric patients a tailored surgical approach based on certain clinical features. METHODS: A national multicenter retrospective review of 250 pediatric patients treated for papillary thyroid carcinoma in a 14-year period was performed. Outcomes of interest included tumor-related features, type of surgery, surgical morbidity, disease-free and overall survival rates. Recurrence was thoroughly analyzed with particular focus on how it correlated with certain patient- and tumor-related features. RESULTS: The majority of patients (58.8 %) had tumors >2 cm in size. Nodal involvement occurred in 115/250 (46 %) patients and distant metastasis in 4 % (10/250). Total thyroidectomy and lobectomy were performed in 90.4 % (226/250) and 9.6 % (24/250) of patients, respectively. The overall rate of surgical complications was 20.8 % (52/250). These included transient and permanent hypoparathyroidism (13.6 and 4.4 %, respectively), and vocal fold palsy (2.8 %). All surgical complications occurred exclusively in the total thyroidectomy group. The rate of recurrent disease was 12 % (30/250) with the vast majority of recurrences (96.6 %) occurring in the total thyroidectomy group. The risk of recurrence correlated significantly with certain tumor-related features (size > 2 cm, multifocality, extrathyroidal invasion, nodal positivity, and distant metastasis). However, it did not correlate with the patient's age or sex. Overall survival was 100 %. CONCLUSION: Pediatric patients are likely to benefit from a tailored surgical strategy. Uniformly offering patients total thyroidectomy seems to be an overly radical approach.

Management of breast cancer after Hodgkin's lymphoma and paediatric cancer.

RATIONALE: The risk of women developing a breast cancer (BC) after receiving chest radiotherapy for paediatric cancers and Hodgkin lymphomas is well established. The aim of this study was to assess these patients' clinical characteristics and clinical outcomes. METHODS: The study concerns women with a history of primary neoplasms treated with chest irradiation ± chemotherapy and subsequently diagnosed with BC. RESULTS: We identified 78 women who developed BC (invasive in 68 cases, 87%). They were a median 18 and 38 years of age when their first neoplasm and BC were diagnosed, respectively. Breast-conserving surgery was performed in 39 patients, and 32 underwent breast irradiation. Twenty of the 41 patients (49%) treated with chemotherapy received an anthracycline-containing regimen. The 5- and 11-year event free survival (EFS) and overall survival (OS) rates were 69% and 42%, respectively. Nine patients (12%) developed a third cancer and 18 (23%) a cardiovascular event. Of the 68 women with invasive BC, the first event involved contralateral BC in 55% of cases: time to progression (TTP) rates were 70% and 47% at 5 and 11 years. The 5- and 11-year BC-specific survival rates (BCSS) were 84% and 68%, respectively. CONCLUSIONS: Judging from our experience, survival rates after BC developing in women previously given chest radiotherapy are not dissimilar to those observed in other women with primary BC. Given the far from negligible risk of subsequent cancers and cardiovascular events, it is mandatory to discuss the best choice of treatment for such patients in terms of their chances of cure and quality of life, and also the risks of late sequelae.

[Differences in sports participation for children and adolescents with solitary kidney due to renal tumors across Europe. Time for harmonization]. / Partecipazione in attività sportive per bambini e adolescent con un solo rene. È tempo di armonizzare in comportamenti in Europa per I ragazzi guariti da un tumore renale.

As a result of advances in treatment, almost 90% of children diagnosed with Wilms tumor became long-term survivors, and have a sustainable quality of life. These patients' involvement in sports during their childhood is hopefully increasing too. The cornerstone of renal tumor cure remains radical nephrectomy, however, so survivors live with a solitary kidney. In most European countries and the USA, the involvement in sports of children with a solitary kidney depends on a responsible physician saying a "qualified yes", pending individual assessment. Unlike the case in the rest of Europe, in Italy having only one kidney automatically disqualifies an individual wishing to participate in any organized "competitive" sports carrying some risk of renal trauma, including basketball, soccer and sometime volleyball. This absolute restriction is based on ad hoc Ministerial rulings concerning "Health protection in sport activities". But available data do not seem to support such an absolute limitation on participation in sports based exclusively on the fact of having a single kidney. The sport-specific incidence of kidney injuries has been estimated at 2.3 injuries per million male athlete/exposures for basketball (2.5 for females), and 2.6 for soccer (6.0 for girls). Kidney injuries are significantly more rare than head or spine injuries. This article aims to provide Italian sport medicine specialists and policy-makers with the necessary background so that the current, over-protective "unquestionably no" response can be reconsidered, and converted into a still well-founded, more permissive attitude to the sports activities suitable for any children with a solitary normal kidney.

High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

[Psycho-organic diseases in children and adolescents affected by pediatric neoplasms]. / Disturbi psico-organici in bambini e adolescenti affetti da neoplasie pediatriche.

At Pediatric Oncology Centers, psychological intervention and psychotherapy are generally offered to children and adolescents for supporting their adjustment to disease and treatment. The clinical practice, however, point out that cognitive and emotional symptoms, such as psychic distortions, fatigue, anxiety, irritability and depression, are sustained by biological mechanisms connected with disease and treatment and not respondent to psychological consultation and to other psychosocial resources. These manifestations could interfere with treatment or with the long-term adjustment and call for psychopharmacological treatments. Biological factors able to cause these alterations are not yet studied in depth in clinical tradition and scientific literature on the integration of psychological and psychopharmacological intervention in pediatric oncology is still poor. In this paper organic components of psychic and behavioral alterations in the course of disease are illustrated, considering the symptoms, causes and possible remedies in the light of the most recent interdisciplinary views. The main mechanism connected with oncologic treatments - chemotherapy, surgery, radiotherapy - and responsible for psycho-organic alterations in children and adolescent with cancer are also described.

Thyroid iatrogenic sequelae after the treatment of pediatric cancer.

Incidental/therapeutic thyroid irradiation causes hypothyroidism and nodular disease. As increasing numbers of children, adolescents and young adults are being cured of cancer after being treated with radiation therapy that has included the thyroid bed, it is important to understand whether early diagnosis and treatment of any radiation-related thyroid changes has an impact on their evolution and outcome. In this review the authors discuss main epidemiologic data, morbidity events, radiation cancerogenic effects and also original data about patients surveillance and evolution control of iatrogenic effects, together with some experiences of prospectively reducing the occurrence of post-radiation hypothyroidism.

Transitory, spontaneously recovering, peripheral facial nerve palsy after vinorelbine administration.

Childhood intrinsic brain-stem gliomas have a dismal prognosis. Different treatment strategies have been adopted over the years without changing the final outcome of this ominous disease. Due to this grim prognosis, experimental therapeutic designs are worthwhile. Vinorelbine is a semi-synthetic vinca alkaloid that has demonstrated a broad spectrum of activity both in in vitro and in vivo experimental systems. By adopting vinorelbine during and after focal radiotherapy in the last two years, we have tried to evocate its known synergistic effect in brain-stem tumour control. Vinorelbine was administered intravenously before, during and after radiotherapy on tumour bed for a total duration of 10 months. All the consecutive patients whose clinical and radiological features corresponded to the diagnosis of an intrinsic brain-stem tumour, i.e., diffuse pontine glioma, have been accrued to this treatment protocol since July 2002. A histological assessment was not required. All patients were treated during hospital stay or in the outpatient clinic at the Istituto Nazionale Tumori of Milan (n=12) and at the Pediatric Clinic of Policlinico in Catania (n=1). Two of the thirteen patients so far treated have developed multiple subsequent, and transitory, episodes of monolateral peripheral facial nerve palsy during vinorelbine administration. The palsy always completely and spontaneously resolved at a short interval-around 30 min-after the end of the drug infusion. Obvious tumour progression was excluded by means of MRI; therefore the drug was administered as scheduled until the end of the treatment. We describe possible neurological and oncological implications of this unusual side effect, until now not reported in any other series dealing with vinorelbine as adjuvant treatment.

A case of relapsing glioblastoma multiforme responding to vinorelbine.

Childhood malignant gliomas are rare and their clinical behavior is almost as aggressive as in adults: they resist treatment, progress rapidly and often spread. Therapeutic strategies at relapse deserve an experimental approach, since none of the conventional-dose treatments have demonstrated a clear superiority over the others and no randomized trials have proved that high-dose chemotherapy is better than conventional treatment. Vinorelbine is a semi-synthetic vinca alkaloid with an in vitro and in vivo experimentally proven broad spectrum of activity, including against malignant brain glioma. We report our experience with a 19-year-old girl with glioblastoma multiforme (GBM) of the deep temporal region recurring 6 months after completing an intensive treatment that included preradiation chemotherapy (chemotherapy as a preradiation "sandwich" phase) with a myeloablative course of thiotepa, tumor bed radiotherapy and postradiation maintenance chemotherapy. The GBM proved fully responsive to intravenous vinorelbine, with a subsequent progression-free interval lasting more than 24 months. This case report suggests that vinorelbine is effective against high-grade pediatric glioma and, since this evidence has only one precedent in the literature (and given the generally poor prognosis for this tumor), even this single success seems worth reporting.

Phase II trial of temozolomide in children with recurrent high-grade glioma.

PURPOSE: The objective of the study was to evaluate the efficacy and toxicity of Temozolomide (TMZ) administered for 5 consecutive days in three daily dosing in children with recurrent or refractory high-grade glioma. PATIENTS AND METHODS: Twenty-four patients with a median age of 10.5 years were enrolled onto this open-label, multicenter, phase II study. The patients were previously treated with surgical resection (17 of 24), radiotherapy (19 of 24) and chemotherapy (18 of 24). Therapy was administered orally three times a day for 5 consecutive days at the dose of 200 mg/m(2)/dx5 for chemotherapy naive patients. In patients heavily pretreated with chemotherapy the starting dose was of 150 mg/m(2)/dx5. RESULTS: A total of 95 cycles were administered. The median progression free-survival (PFS) was 3 months for the entire group while disease stabilization was obtained in 7 patients (29.1%), all with supratentorial tumors. No CR or PR was observed. TMZ treatment showed a limited toxicity. Thrombocytopenia was the most common hematological adverse effect. Our data suggest a marginal activity of TMZ in children with recurrent high-grade glioma.

Psychological and adjustment problems due to acquired brain lesions in childhood: a comparison between post-traumatic patients and brain tumour survivors.

OBJECTIVE: To define and differentiate psychological and adjustment problems due to brain injury or brain tumour in children and adolescents. METHODS: Two groups of patients with acquired brain lesions (24 post-traumatic patients and 22 brain tumour survivors), ranging in age between 8-15 years, received a psychological evaluation, including the Child Behaviour Checklist for Ages 4-18 (CBCL) and the Vineland Behaviour Adaptive Scales (VABS). RESULTS: Both groups showed psychological and social adjustment problems. Post-traumatic patients were more impaired than brain tumour survivors. Social adjustment problems were associated to externalizing problems in post-traumatic patients and internalizing problems in brain tumour surviving patients. CONCLUSIONS: These differences in psychological and behavioural disorders between the two groups must necessarily be considered when developing psychological treatment, rehabilitation plan and social re-entry.

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment.

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988-June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994-1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted.