THE IMPACT OF PESTICIDES ON CANCER INCIDENCE AMONG CHILDREN IN UZBEKISTAN: A SURVEY STUDY

Second malignant neoplasms (SMN) in children who have survived their initial encounter with a malignancy have emerged as one of the most troublesome complications in pediatric oncology. Some estimates indicate that as many as 8% to 12% of patients will develop a SMN during a 20-year period. The majority of SMN are osteosarcomas, spindle cell and pleomorphic sarcomas of soft tissues, and hematolymphoid malignancies. We present the clinical and pathologic findings for two children with treated acute leukemias in whom well-differentiated mucoepidermoid carcinomas of the parotid gland developed 6 and 9 years after multidrug chemotherapy and cranial irradiation. Although mucoepidermoid carcinoma has been reported as a complication in adults who received low-dose irradiation as children, these two cases are unique as SMN in the pediatric age population.

Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkin's disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. Two hundred five children with high-risk (HR) ALL were randomly assigned to receive doxorubicin alone (n = 100) or doxorubicin with dexrazoxane (n = 105) during the induction and intensification phases of multiagent chemotherapy. We compared incidence of SMNs in these two groups. With a median follow-up of 6.2 years, no differences in the incidence of SMNs were noted between the group that received dexrazoxane and the group that did not (P = .66). One SMN (a melanoma located outside of the cranial radiation field) occurred in a patient who was randomly assigned to doxorubicin alone. No SMNs were observed in patients randomly assigned to receive dexrazoxane. Dexrazoxane was not associated with an increased risk of SMNs in children treated for HR ALL. Given the potential importance of dexrazoxane as a cardioprotectant, we recommend that dexrazoxane continue to be used and studied in doxorubicin-containing pediatric regimens.

Both intensity-modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity-modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II). From 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard-risk disease (63.5%). The median follow-up was 12.8 years for group I and 8.7 years for group II. The 5-year and 10-year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard-risk patients and 63.1% and 57.3%, respectively, for high-risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5-year and 10-year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia. This analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT. One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity-modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52). The majority of children had standard-risk disease (63.5%). The 5-year and 10-year overall survival rates were 88.8% and 85.1% for standard-risk patients, respectively, and 63.1% and 57.3% for high-risk patients, respectively, with no difference in overall survival by RT group (P = .81). The 5-year and 10-year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).

1 – A Geographic Information System for Evaluating Residential Pesticide Exposure and Prostate Cancer Incidence Agricultural pesticide exposure is hypothesized to be a risk factor for prostate cancer, and such exposures are of particular concern for men living in farming communities where large-scale pesticide applications occur. Prostate cancer incidence data were obtained from the State Health Registry of Iowa for the years 1996 through 2006, and county and census tract level age-adjusted incidence rates were calculated. Historical crop-specific land use records and pesticide sales data for the state of Iowa during 1990 were integrated into a geographic information system (GIS), where estimates of predicted exposure to the four most commonly used pesticides in Iowa (atrazine, metolachlor, cyanazine, alachlor) were produced. Ecological correlation between pesticide exposure and prostate cancer incidence was evaluated using Spearman’s (rank) correlation coefficient and linear regression analysis. Statistically significant associations between prostate cancer incidence and percent of acres of corn and soybean crops were found at both the county (r=0.22, p=.031 and r=0.33, p=.001, respectively) and census tract (r=0.10, p=.007 and r=0.13, p<.001, respectively) level. The associations between percent of land exposed to the specific pesticides and prostate cancer were not statistically significant. Our findings suggest that residential proximity to corn and soybean fields, and by association the pesticides used on those crops, is correlated with increased prostate cancer risk, but that the increase in risk is not correlated with exposure to the four most commonly used pesticides in Iowa in 1990. Findings from this study underscore the need for continued investigation of the association between agricultural exposures and prostate cancer incidence. Abstract 2 – Spatial Analysis of Prostate Cancer Incidence and Residential Pesticide Exposure in Iowa A statistically significant positive association between prostate cancer incidence and residential proximity to corn and soybean fields in Iowa exists. Research suggests that exposure to pesticides used on these crops increases prostate cancer risk. The objective of this study was to investigate clustering of prostate cancer risk in the presence of potential exposure to pesticides in Iowa. Prostate cancer incidence data (1996-2006) were obtained from the State Health Registry of Iowa. Using SaTScan software, clusters of high and low prostate cancer risk were identified. Ecological correlation between exposure to the four most commonly used pesticides (atrazine, metolachlor, cyanazine, alachlor) in Iowa during 1990 and residence in a cluster of relatively high or low prostate cancer incidence was evaluated using Pearson’s chi-square test statistic and logistic regression analysis. Clusters of increased prostate cancer risk were associated with a greater percentage of land used for all crops of interest (i.e., corn and soybean farming (p <0.001), corn farming (p <0.001), soybean farming (p <0.001)) and low exposure to alachlor (p =0.032) than did clusters with decreased risk of prostate cancer. After adjustment for percent of land used for each crop type, no association between pesticide exposure and prostate cancer risk was observed. Residence in or near agricultural communities increases prostate cancer risk. Our findings suggest that residential proximity to exposures specific to corn and soybean farming increases prostate cancer risk. Evaluation of exposure to less commonly used pesticides and those used in lower quantities is needed. Abstract 3 – Multilevel Analysis of Residential Pesticide Exposure and Prostate Cancer Incidence An association between residential exposure to factors specific to corn and soybean farms in Iowa exists. The objectives of this study were to statistically assess spatial autocorrelation in prostate cancer incidence in Iowa and to evaluate the effect of residential exposure to the most commonly used pesticides for corn and soybean farms in Iowa in 1990 on prostate cancer incidence. Prostate cancer incidence data were obtained from the State Health Registry of Iowa for the years 1996 through 2006. Spatial patterning of age-adjusted incidence rates was assessed via Moran’s I global index of spatial autocorrelation. A hierarchical regression modeling approach with an assumed Poisson distribution was used to characterize the relationship between census tract level prostate cancer incidence and exposure to pesticides. Statistically significant spatial patterning of prostate cancer incidence, corn and soybean fields and pesticide use (p<.001 for all variables) was observed. After adjustment for individual and area level characteristics, prostate cancer risk increased by approximately 25% for each percentage point increase in percent of land used for corn and soybean crops. Prostate cancer risk was approximately 25% higher for Black men exposed to corn and soybean fields compared to white men exposed to corn and soybean fields. Results from this study support the need for further evaluation of residential exposure to environmental hazards specific to corn and soybean farming.

Objective: To analyze the incidence of malignant tumors in children and adolescents (aged 0-19 years) in China in 2022. Methods: Data were sourced from GLOBOCAN 2022 and Cancer Incidence in Five Continents (CI5) Volume Ⅻ. Incidence data by sex and age group for childhood and adolescent cancers from Chinese registries in CI5 Volume XII were extracted to calculate the proportion of each subtype. These proportions were then applied to the overall cancer incidence in children and adolescents in China from GLOBOCAN 2022 to estimate the number of incident cases for different tumor types. World standardized incidence rates (WSR) were calculated using Segi's world standard population. Results: In 2022, there were 32 792 new cases of malignant tumors in children and adolescents (aged 0-19 years) in China, with a WSR of 105.93 per million. Among them, 23 121 new cases occurred in children aged 0-14 years, accounting for 70.51% of all cases in children and adolescents, with a WSR of 100.30 per million. The most common diagnostic types of malignant tumors in Chinese children and adolescents in 2022 were leukemia (11 983 cases, 36.54%), followed by central nervous system tumors (4 485 cases, 13.68%) and lymphoma (2 764 cases, 8.43%), with WSR of 39.78 per million, 14.15 per million and 8.35 per million, respectively. Among different age groups, the highest WSR was observed in the 15-19 years (125.28 per million), followed by the 0-4 years (120.67 per million). Except for the 15-19 years group, the age-specific incidence rate was higher in males than in females. The top three cancer types by incidence in both sexes in 0-14 years group were consistent with those in the 0-19 years group, namely leukemia, central nervous system tumors, and lymphoma. In the 15-19 years group, the top three cancers in males were leukemia, bone tumors, and lymphoma, while in females they were malignant melanomas and other malignant epithelial tumors, leukemia, and malignant gonadal germ cell tumors. Conclusions: The incidence rates and cancer type distribution in children and adolescents vary considerably by sex and age group in China. Targeted prevention and control strategies for childhood and adolescent cancer malignant tumors should be developed accordingly.

BACKGROUND: New strategies in epidemiological and toxicological research are needed for environmental and occupational health studies. One major concern about pesticides exposure is associated to the risk of cancer development. Several studies have shown consistent positive associations between pesticides exposures and non-Hodgkin lymphoma, leukemia, solid tumors, brain and prostate cancer. AIMS: The basis of our purpose in this study was the investigation of databases from international organizations such as FAO and IARC to retrieve information concerning pesticides use and cancer incidence and mortality all over the world and search for associations between pesticides exposure and cancer. METHODS: Information concerning pesticides use and consumption for all countries was retrieved at FAO and IARC files databases. For pesticides use we have established a timeline range of analysis from 1995 through 1998 and cancer incidence and mortality data were obtained at GLOBOCAN 2008. A total number of 102 countries were included in the study. Correlation analyses were performed for both total pesticides use or stratified by pesticides classes. Cancer incidence and mortality were outcome variables included in the correlation study. We have also planned linear regression modeling and risk ratios for interquartile comparisons. RESULTS: Overall, we have observed strong positive association (significant at the 0,01 level) between cancer incidence and total pesticide use (r2=0,870), or stratified by classes: insecticides (r2=0,888), fungicides (r2=0,505), herbicides (r2=0,816) and plant growth regulators (r2=0,467). Mortality correlation data followed the same profile. CONCLUSIONS: This is one of the first studies of its kind to analyze global impact of pesticides exposure and cancer incidence and mortality. Results confirm that pesticides use must be considered as one of the major concerns for environmental and occupational health studies.

Malignant solid tumors represent about 50% of all malignant neoplasm in children aged less than 15 years ,They make more than 80% of all malignancies in infants. To focus on clinical and biological characteristics of patients with various types of malignant solid tumors who have been admitted to the Oncology center at Basra Maternity and Children Hospital during the period from the 1st of January 2004 till the end of December 2009. A retrospective study was carried out at Basra Maternity and Children Hospital during the period from the 1st of January 2004 till the end of December 2009.Total cases of cancer admitted to the Center during that period were 704 cases, malignant Solid tumors represented 27.5% of total cases(194 cases). One hundred sixty five patients were included in the study, their age ranged from one month to 14 years, 85 males and 80 females. Sympathetic nervous system tumors represented the highest percentage (35.8%) followed by renal tumors (26.1%), soft tissue sarcomas (18.2%), germ cell tumors (10.3%), retinoblastoma (6.7%) and the least percentage was for hepatic tumors (3%) . The highest frequency of malignant solid tumors was found in the age group of (1-4years), that included 79 patient (47.9%), most of them had neuroblastoma ;32 patients (40%). Most cases with malignant solid tumors were from the center and northern areas of Basra (28.5%,14.6% respectively) and to a lesser extent in western (10.3%), southern (6%), and eastern areas( 1.2%). Other governorates like ThiQar and Maysan account for high rates (21.8%,16.4% respectively) of admissions in Basra pediatric oncology center. The overall mortality was 27.3% (45 cases), it ranged from 11.8%-40%, and most common cause of death was advanced metastatic disease. Non compliance or discontinuation of treatment is an important dilemma for all types of cancer. This study revealed that sympathetic nervous system tumors, the commonest of them was neuroblastoma , most cases presented in stage III or stage IV of the disease. So Improving the diagnostic facilities in Basra Oncology Center by introducing specific type of investigation for evaluation of patient with malignant solid tumors like metaiodobenzylguanidine (MIBG) scan, positron emission tomography (PET), genetic study, and other important biochemical investigations could assign the patient risk group, and not depending only on simple criteria for the classification of the disease .

Malignant orofacial neoplasms in children and adolescents: A clinicopathologic review of cases in a Nigerian tertiary hospital

An increase in neoplasms in Mexican children has been reported. In 1991, the incidence in children from Mexico City (MC) was 70 (x 10(6) child/year), although this rate might be underestimated. The aim of the present study was to estimate the incidence of malignant neoplasms in children resident in MC attending Social Security (SS) hospitals. This study was a retrospective hospital survey. All records of childhood malignant neoplasms diagnosed between 1992 and 1993 in the two SS hospitals which attend childhood neoplasms in MC were reviewed. Histopathological diagnoses were reevaluated and incidence rates (x 10(6) child/ year) in terms of age, sex, and place of residence were estimated. A total of 667 cases were found for the period of study, of which 199 corresponded to residents of MC. The neoplasms with highest prevalence were leukemias (39.2%), lymphomas (17.6%), and central nervous system tumors (12.6%). A general incidence of 94.3 was found, which was highest in children under 5 years of age. Leukemias had an incidence of 36.4, lymphomas of 15.2, and central nervous system tumors of 12.0. Prevalence was higher in boys (male/female ratio of 1.6). As for the place of residence, the highest incidence corresponded to children living in the southern areas of MC. Eighty percent of the leukemias were acute lymphoblastic, while 54% of solid neoplasms were classified as stages III and IV. In conclusion, the incidence of malignant neoplasms in children resident in MC treated at SS hospitals is consistent with that found worldwide, and also with the Latin American pattern.

The development of comprehensive organizational technologies aimed at improving the provision of medical care to children with cancer remains a priority for the public health and healthcare system. Purpose of the study is to develop a comprehensive organizational technology for the early detection of malignant neoplasms in children and a new routing mechanism. Materials and methods. Specialists in pediatric oncology and hematology, anesthesiology and critical care medicine, and healthcare organization participated in the study. The sample of 12 experts was selected based on the following criteria: at least five years of experience in their primary specialty; practical experience providing medical care to patients with specific malignant neoplasms; and employment at a national medical research center specializing in oncology or pediatric oncology. The data collection process included four expert group meetings, during which four questionnaires were collected from each participant. A tiered model for the treatment of children with malignant neoplasms was also developed and tested in several regions of the Russian Federation. Results. The comprehensive organizational technology developed in the course of this study includes two main components: a new mechanism for the timely detection of malignant neoplasms in children (checklist); a new mechanism for routing children with malignant neoplasms (based on a tiered model). The auxiliary components of this organizational technology include: educational activities aimed at improving the knowledge of pediatricians in the field of early detection of malignant neoplasms in children in the constituent entities of the Russian Federation; and the organization of telemedicine consultations with federal medical organizations (NMIC). For the quantitative interpretation of the data obtained using the checklist, the working group determined threshold values based on a consensus assessment of experts: 1–3 points – discuss the need for hospitalization in a federal medical organization; 3–4 points – planned hospitalization in a federal medical organization; 4–6 points – urgent hospitalization in a federal medical organization; 6 and more – emergency hospitalization in a federal medical organization. Findings. It is necessary to conduct an organizational experiment on the implementation of the developed complex organizational technology with a subsequent assessment of the medical effectiveness of this technology in terms of the detection rates of oncological diseases in children in the constituent entities of the Russian Federation and hospital mortality rates in children with oncological diseases in the constituent entities of the Russian Federation.

Pesticides are commonly used worldwide both in agricultural and domestic settings. The benefits to society and agriculture are well documented. There are, however, dangers associated with the use of pesticides. Some pesticides, such as organophosphates (the most commonly used pesticide worldwide), kill pests through a biological pathway that may also cause harm to humans. Acute exposure to pesticides has been associated with negative health effects such as cancer, respiratory disease, Parkinson’s disease and death.1–4 People in low- and middle-income countries (LMICs), such as Sri Lanka, often experience acute exposure alongside chronic exposure due to the widespread and largely unregulated use of pesticides.5 The level of chronic pesticide exposure in LMICs is likely to be higher than in high-income countries, as a large proportion of rural families in Sri Lanka live close to agricultural fields and are not only exposed to pesticides when the fields are being sprayed (Figures 1 and ​and2)2) but also have sustained exposure through their food and drink and through air particles. In addition, villagers in rural Sri Lanka often use the irrigation canals, rivers and lakes as a free source of bathing water (Figure 3). This water source is likely to be heavily contaminated with pesticides, not only due to run-off but also as a direct consequence of the practices of pesticide sprayers (Figure 4).6 Figure 1. Pesticide spraying of banana crop using a power sprayer. No personal protection worn. Figure 2. Manual pesticide spraying of a paddy crop. No personal protection worn. Figure 3. Villagers bathing and washing clothes in the local river. Figure 4. Farmer cleaning and preparing pesticide spraying equipment using the irrigation canal. Equipment is rinsed and water taken from the canal. The success of a crop is imperative for a farmer’s livelihood in rural Sri Lanka. This need, coupled with heavy marketing of pesticides (Figure 5) has led to a nearly ubiquitous use of pesticides on crops.7 It is not clear whether this heavy use, resulting in high levels of both acute and chronic exposure, has any long-term detrimental health effects. The difficulty in assessing this arises because of challenges in the measurement of long-term pesticide exposure. Traditional biological samples, like blood and urine, are difficult to collect and only capture short-term pesticide exposure.8 Figure 5. Example of a pesticide advertisment (approximate size 1 x 2.5 m). In July 2015 a feasibility study was launched to determine whether it would be possible to measure chronic (long-term) exposure to pesticides using hair samples in rural Sri Lanka, as an alternative to blood/urine samples which are logistically difficult to manage in community settings in rural Asia. The additional benefit of hair samples is that pesticide metabolites deposit over time, and it would therefore be possible to ascertain a timeline of exposure over longer periods.9 Following a village introduction (Figure 6), fieldworkers visited households and recruited individuals to take part in the study. A hair sample (head/chest/forearm) was taken alongside self-reported information on pesticide use and exposure (Figures 7 and ​and8).8). The samples will be analysed for organophosphate metabolites using gas chromatography-mass spectrometry (Figure 9). Given that the knowledge of the long-term effects of the levels of pesticide exposure experienced in these countries is limited, there needs to be more research in this area to help inform legislation and effective community programmes for the safer use of pesticides. Figure 6. Village meeting to introduce the research project prior to home visits. Figure 7. Field staff collecting head hair sample. Figure 8. Alternative hair sample collected from men with limited or no head hair. Figure 9. An example of the analysis output (pictured on the right) from organophosphate metabolite hair analysis using a gas chromatography-mass spectrometry (pictured on the left).

Neurofibromatosis type I (NF1) is the monogenic inherited syndrome with established variability of clinical manifestations and the predisposition to the development of malignant tumors. Studying NF1 association with different types of cancers in children is necessary to understand the risk of their occurrence and the prognosis of the disease as well as subsequent studies of this predisposition.&#x0D; Aim. Analysis the clinical data of patients with NF1 and malignant and benign tumors arisen in them.&#x0D; Methods. A retrospective analysis of clinical data of 19 patients from 0 to 18 years old with a malignant tumor, carried out in N.N. Blokhin NMRCO from 1997 to 2018.&#x0D; Results. The clinical signs of NF1 showed an age-dependent timing of their onset. Embryonal tumors were the most common and occurred in 11 out of 19 patients (57.9%), embryonal rhabdomyosarcoma predominated (42.1%), more often affecting the urogenital tract. Familial NF1 was found in 31.6% of patients. NF1 disease of the parents of these children (in four mothers and two fathers) was limited to pigmented skin lesions and multiple neurofibromas. Genetic testing of NF1 gene in three families of children with embryonal tumors revealed 2 de novo mutations — p.V2635FS &amp; p.W1314X and one inherited from father to son (p.2363_2365del). Malignant peripheral nerve sheath tumors developed in 15.8% of patients by puberty. Soft tissue sarcomas and hematopoietic tumors occurred in 10.5% of patients, respectively. Melanoma was found in one patient (5.3%).&#x0D; Conclusion. The data obtained make it possible to supplement the diapason of types of malignant tumors in children associated with NF1 and the possibility of their use in clinical practice for a more rational and targeted observation for patients. Further study of the molecular genetics and clinical aspects of NF1 is necessary for the development of promising therapies for NF1.

The study explores factors that contribute to the development of malignant neoplasms in children 0–14 years old. Uneven geographic distribution of childhood cancer in Russia and across the globe is commonly attributed to exogenous factors. Based on cartographic, comparative, and historical methods, as well as correlation analysis in the current research, we have endeavored to determine the significance of the key environmental and economic factors that lead to the formation of malignant neoplasms in children, such as the degree of urbanization, regional economic development, extent of anthropogenic impact on the environment, parental occupation, etc. The results thus obtained have allowed us to cluster Russian regions with respect to the degree of stress of the oncologic situation in terms of childhood incidence of cancer. The present conclusions can be taken into account when designing cancer prevention programs based on territorial features and when evaluating their efficiency.

Somatic translocations involving the NTRK genes occur in 0.34–2.2% of all malignant neoplasms in children. TRK inhibitors whose efficacy has been demonstrated in prospective clinical studies expand treatment options for patients with solid tumors harboring NTRK gene rearrangements. The aim of our study was to summarize the first Russian experience with the use of the TRK inhibitor entrectinib in patients with extracranial NTRK fusion-positive solid tumors included in the compassionate use program. This study was approved by the Independent Ethics Committee and the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The study included 8 patients who had been treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology and the N.N. Blokhin National Medical Research Center of Oncology. The main criteria for inclusion in the compassionate use program were a confirmed rearrangement of either NTRK1/2/3 genes in a solid tumor in patients with unresectable disease for whom no effective standard systemic therapy was available, progressive or recurrent disease during therapy prescribed according to the established diagnosis, risk group and risk stratification criteria, and the infeasibility of non-mutilating radical surgery. The median age at diagnosis was 4.3 months (range 1.2–83.6). The male to female ratio was 1:1. The primary site distribution was as follows: head and neck (n = 6; 75%), chest wall (n = 1; 12.5%), pelvis (n = 1; 12.5%). None of the patients had regional lymph node involvement or distant metastases at diagnosis. The distribution by histology (according to histopathology reports) was as follows: infantile fibrosarcoma (n = 4; 50%), undifferentiated round cell sarcoma, low-grade (n = 1; 12.5%), undifferentiated spindle cell sarcoma, high-grade (n = 1; 12.5%), NTRK-rearranged spindle cell sarcoma, low-grade (n = 1; 12.5%), spindle cell tumor associated with an NTRK rearrangement (n = 1; 12.5%). Immunohistochemistry (IHC) with a pan-Trk monoclonal antibody was performed in 7/8 (87.5%) patients. Pan-Trk IHC was positive in 4/7 (57%) patients. Rearrangements in the NTRK1 and NTRK3 genes were confirmed in all the patients. The final methods used for the detection of fusion transcripts were as follows: reverse transcription polymerase chain reaction (n = 4; 50%) and RNA-based next-generation sequencing (n = 4; 50%). NTRK1 and NTRK3 gene translocations were detected in 3/8 (37.5%) and 5/8 (62.5%) patients, respectively. The following fusion transcripts were identified: ETV6::NTRK3 (n = 4), DIP2C::NTRK3 (n = 1), TPR::NTRK1 (n = 1), TPM3::NTRK1 (n = 1), MYH10::NTRK1 (n = 1). One (12.5%) patient received entrectinib as first-line therapy, other patients (7/8, 87.5%) received entrectinib as secondor subsequent-line therapy. Three (37.5%) patients had undergone surgery before treatment with entrectinib: 2 had R2 resection, 1 had R0/R1 resection (resection margins were not evaluated). None of the patients received radiation therapy. The median duration of entrectinib therapy at the time of analysis was 11.8 months (range 2.3–20.1). Delayed surgery was performed in 2/8 patients; according to the histopathology reports, they achieved grade IV pathomorphosis. Three patients experienced adverse events during treatment with entrectinib. The median time to adverse events was 0.23 months (range 0.2–7.96). Three patients required temporary interruption in treatment to relieve symptoms, a subsequent dose reduction by one dose level was necessary when resuming therapy in two patients. The median follow-up since diagnosis was 19.5 months (range 14.9–75.0). All the patients included in our analysis were alive, three of them had no radiologic evidence of disease. Fifty percent of the patients completed targeted therapy, another 50% of the patients continued treatment with entrectinib. Complete and very good partial response was achieved in 3/8 and 2/8 patients, respectively. Partial response, minor partial response and stable disease were observed in one patient each. These results indicate high efficacy and safety of entrectinib in pediatric patients with extracranial NTRK fusion-positive solid tumors. Further studies are needed to determine the therapeutic potential of TRK inhibitors in the treatment of different solid malignant neoplasms in children and to assess long-term treatment results.

Laryngeal malignant neoplasms in children and adolescents