TOXIC EFFECTS OF ANTICANCER THERAPY

The generally accepted practice of medical technology is to record the first time sick, the results of dynamic observations of patients (follow-up). The first research groups for the study of malignant neoplasms (MNO) in children appeared in the United States in 1955. The article describes the importance of early rehabilitation of patients who have undergone cancer on the example of a clinical case. Advances in the treatment of cancer patients have resulted in a higher percentage of people cured. But very early after the start of the use of anticancer therapy (POT), doctors began to observe manifestations of an iatrogenic nature due to the use of toxic drugs and radiation. At the moment, the influence of genetic factors on the development of complications of chemotherapy and radiation therapy is being actively studied. The molecular mechanisms of the development of abnormally pronounced toxic effects in most cases are associated with disorders in the DNA repair system. To minimize the risk of severe toxic effects, these factors should be taken into account when choosing a treatment strategy. On the example of patient N., 18 years old, the condition after the end of treatment for rhabdomyosarcoma of the temporal region, the duration of remission is 12 years, one can see how the treatment can iatrogenically affect the patient's life in adulthood, having undergone treatment in childhood. With an early start of rehabilitation and timely identification of the long-term consequences of anticancer therapy, it is possible to improve the patient's quality of life. With the accumulation of observation data on the domestic cohort of children and adolescents who completed therapy 15-20 years ago, it will become possible to assess the burden of national health care in the structure of morbidity, disability, and the development of second tumors.

Long term follow-up care in childhood cancer survivors. Initial experience in H. Inf. Univer. del niño Jesus

Currently, in developed countries, cancer is the most frequent cause of mortality in pediatrics in patients older than one year. Thanks to advances in diagnosis, oncological treatment and support, survival in pediatric oncology has increased to around 80% at 5 years. This has increased the detection of long-term side effects and second tumors in long survivors, recently increasing concern and developing specific follow-up models for these patients in the USA. In this descriptive, cross-sectional and prospective study we analyze the data obtained from the first specific unit in Spain for long-term follow-up in pediatric oncology developed at the Hospital Infantil Universitario del Niño Jesús in 2017. The results reproduce what has been described in other recent series, except for later effects such as cardiological alterations underestimated in our sample due to the younger age of our survivors.

Second tumors in children with hematological malignancies

Background. Hemoblastoses treatment success in children made it possible to cure the vast majority of patients. The follow-up period exceeds tens of years, during which the problem of second tumors (ST) becomes urgent. The objective of the study was to characterize ST in patients who underwent a malignant tumor of hematopoietic and lymphoid tissues at the age of 0 to 18 years.Materials and methods. The study included 64 patients with ST development in the period from 1 to 38 years.Results. Most frequently ST developed after treatment of Hodgkin's lymphoma (45.3 %) and acute lymphoblastic leukemia (35.9 %), supported by high cumulative doses of alkylating agents and radiation therapy. Among STs, in 35.9 % of cases, thyroid cancer was diagnosed, in 10.9 % - acute leukemia, in 9.4 % - tumors of the central nervous system. The results of ST treatment are significantly worse than those of primary tumors. Thus, of 64 patients with ST, 46 (71.9 %) are alive, death from ST progression was noted in 18 (28.1 %) cases.Conclusion. Improvement of modern treatment protocols aimed at reducing the indications for radiation therapy and cumulative doses of alkylating agents, along with the development of effective follow-up programs for children cured of hematological malignancies, will probably help reduce the ST incidence.

RONC-22. SECOND TUMORS IN PEDIATRIC PATIENTS TREATED WITH PROTON THERAPY TO THE CENTRAL NERVOUS SYSTEM

BACKGROUND Previous institutional data suggests the 10-year cumulative incidence of second tumors is 3% in children treated with photon radiation for central nervous system (CNS) malignancy, with 90% of these tumors occurring in areas receiving ≤36 Gy. Comparative figures for children treated with proton therapy (PT) does not exist. METHODS 1056 consecutive pediatric patients with a median follow-up of 5.0 years were treated between 2006–2019 with double-scattered PT to a site within the craniospinal axis. 230 patients were ≤3 years old and 14 had neurofibromatosis. A second tumor was defined as any solid neoplasm with histologic features different from the original tumor that had arisen within the irradiated volume. RESULTS Five patients developed second tumors resulting in a 5- and 10-year cumulative incidence of 0.2% (95% CI: 0–1.2%) and 1.6% (95% CI: 0.6%-3.9%), respectively. Of those who developed second tumors, median age at radiation was 4.3 years old (range, 2.1 to 5.1 years old) and diagnoses consisted of medulloblastoma (n=2), ependymoma (n=2), and craniopharyngioma (n=1). The second tumors included high grade gliomas (n=3) and high grade sarcoma (n=1) that occurred in regions receiving at least 54 Gy. One patient with neurofibromatosis developed both a low-grade glioma and choroidal melanoma in craniospinal irradiation regions receiving 36 Gy. Four of five patients with second tumors are alive. CONCLUSION The reduction in moderate-to-low dose radiation exposure from proton therapy may be associated with a decreased incidence of second tumors in children treated for CNS neoplasms. More follow-up is needed to confirm these findings.

The mechanistic GEMMs of oncogenic histones

The last decade’s progress unraveling the mutational landscape of all age groups of cancer has uncovered mutations in histones as vital contributors of tumorigenesis. Here we review three new aspects of oncogenic histones: first, the identification of additional histone mutations potentially contributing to cancer formation; second, tumors expressing histone mutations to study the crosstalk of post-translational modifications, and; third, development of sophisticated biological model systems to reproduce tumorigenesis. At the outset, we recapitulate the firstly discovered histone mutations in pediatric and adolescent tumors of the brain and bone, which still remain the most pronounced histone alterations in cancer. We branch out to discuss the ramifications of histone mutations, including novel ones, that stem from altered protein-protein interactions of cognate histone modifiers as well as the stability of the nucleosome. We close by discussing animal models of oncogenic histones that reproduce tumor formation molecularly and morphologically and the prospect of utilizing them for drug testing, leading to efficient treatment and cure of deadly cancers with histone mutations.

Retinoblastoma: a patient’s story

Relevance. Development and application of novel treatment methods for patients with retinoblastoma (Rb) is a great task since it may provide higher rates of eye salvage and reduce adverse effects of current therapy.Aim of the study was to represent the history of Rb eye-sparing treatment in Russia and worldwide through the one clinical case.Materials and methods. A child was treated by systemic chemotherapy, plaque brachytherapy using non-described techniques, cryotherapy and external beam radiotherapy. Intravitreal chemotherapy was approached for treatment of vitreous seeding. Vitreoretinal surgery with melphalan irrigation was successfully performed after failure of vitreous hemorrhage conservative treatment and parents’ refusal to indicated enucleation. The child died from CNS disseminated esthesioneuroblastoma.Results. The use of various treatment modalities helped to save the single eye.Conclusions. Intravitreal chemotherapy was introduced in Russia for the first time. Performed vitreoretinal surgery with melphalan irrigation was proved to be a safe and effective technique in case of vitreous hemorrhage in the eye with Rb. External beam therapy is associated with fatal second tumors development.

Immune Modulation in Prostate Cancer Patients Treated with Androgen Receptor (AR)-Targeted Therapy

Androgen deprivation therapy (ADT) is a cornerstone of treatment for prostate cancer and, in recent years, androgen receptor (AR)-targeted therapies (abiraterone and enzalutamide) have both been used for the treatment of castration-resistant prostate cancer (CRPC). In our study, we sought to investigate the association between ADT and immune disorders, considering a potential role of androgens in the immune modulation. We retrospectively evaluated CRPC patients treated with abiraterone/enzalutamide between July 2011 and December 2018. We assessed the risk of developing immune alterations and their impact on outcome. We included 844 CRPC patients receiving AR-directed therapies, of whom 36 (4.3%) had autoimmune diseases and 47 (5.6%) second tumors as comorbidities. Median age was 70 years [interquartile range (IQR) = 63–75)]. We showed higher significant incidence of autoimmune diseases during their hormone sensitive status (p = 0.021) and the presence of autoimmune comorbidities before starting treatment with abiraterone/enzalutamide was significantly associated with worse overall survival (OS) (10.1 vs. 13.7 months, HR = 1.59, 95% CI 1.03–2.27, p = 0.038). In a multivariate analysis, the presence of autoimmune disorders was an independent predictor of OS (HR = 1.65, 95% CI 1.05–2.60, p = 0.031). In conclusion, CRPC patients with autoimmune alterations before starting AR-directed therapies may have worse prognosis. Further prospective studies are warranted to assess the role of immune modulation in the management of prostate cancer patients.

Update of NGS analysis of Italian survey of second tumors in patients with diagnosis of GIST (gastrointestinal stromal tumor).

e23518 Background: In patients with GIST, literature reports a risk of second primary tumors between 4.5% and 33% with different distribution in the worldwide. The network of 7 italian EURACAN centers has collected clinical and molecular features of GIST patients with second primary tumors. Methods: We reviewed the clinical characteristics of 201 patients with GIST and second primary tumors in order to evaluate association between risk of dead and each possible factor, using Kaplan meier curve, log-rank test and Cox model for Hazard Ratio and it’s interval Confidence 95% estimation. Furthermore, NGS analysis ( 56 gene onco panel) in 72 patients with GIST was performed. Results: On the basis of the significant correlation previously observed between the Miettinen risk criteria of GIST (low/very low) and the incidence of second primary tumors (gastrointestinal tumors),P < 0.001 (Abstr 11032 ASCO 2019), we observed in these patients a median age of diagnosis of GIST of 68, with prevalent gastric site localization ( KIT exon 11 mutation), NF1 and Lynch (kit/pdgfra WT) syndromes in the low risk subgroup. The more frequent site of second epithelial tumor in gastrointestinal tract was the colon followed by gastric, pancreatic and biliary tract. In patients with GIST with low-very low risk according Miettinen classification, after a median follow-up period of 25 years, we have observed that the gastroenteric site of second tumors occurrence is significantly related to the survival (p < .0003). In the NGS analysis of the GIST we observed the pathogenetic somatic mutations in the following genes: BRCA 2 (p.Thr2125fs), but germline test negative, TP53 (p.Arg192*,p.Gly244Ser,p.His168Leu), RET (p.Lys120Asn, p.His168Leu, p.Thr930Met ), NRAS (p.Gly134Asp), CTNNB1 (p.Ser45Phe), MSH6 (P.Ala164Val), SMARCB1 (p.Arg192), VHL (p.Gly93Val), PTEN(p.Val158Ile, p.Asn323fs), STK1I (p.Arg40Cys), SMO (p.Glu194Lys), EGFR (p.Gly721Asp), ATM (p.Asp2708Asn), ERBB4 (p.Asn181Ile). Conclusions: In our analysis patients with GIST (low-very low classes according to Miettinen) have significant risk to death because of second primary tumors in gastrointestinal tract. Specific attention to gastrointestinal screening during the follow-up of GIST (low and very low risk) is required.