Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.

Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors.

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

Primary lung carcinoma in children and adolescents: An analysis of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT).

BACKGROUND: Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1-0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill. PATIENTS AND METHODS: We performed a retrospective case series of children (aged 0-18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome. RESULTS: Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0-17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%. CONCLUSIONS: Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment.

Late effects of childhood cancer recorded at a single outpatient clinic over the course of one year: implications for the follow-up care.

The paper provides a descriptive analysis of medical data and selected patient-reported outcomes from a group of 133 survivors of childhood cancer recruited at St. Anne's University Hospital in Brno, Czech Republic, over the course of one year. The participants were 18-53 years old (mean age 27.9 years) and had been diagnosed with childhood cancer in the period 1979-2016. Treatment data and data on relevant health outcomes were extracted from the medical records and categorized. Patient-reported outcomes were measured using the clinic's questionnaires completed by survivors prior to the medical examination. The most frequent adverse health outcomes in the study were dyslipidemia (50%) and overweight, obesity, and even morbid obesity (45%, 15%, and 1.5%, respectively). Endocrinopathies were observed in more than one-third (35.3%) of the survivors, followed by nephropathy (33.8%). Cardiovascular abnormalities were found in 9.7% of the survivors and fertility impairment in 9%. 38% of the survivors reported chronic fatigue and one-half (51%) reported pain. 20% of the cohort face mobility impairment. A remarkably high percentage of the survivors (70%) communicated some level of mental health issues. Moderate to severe anxiety and/or depression was reported by 25% of the survivors. 40% of the survivors experienced strong fears of disease recurrence, another 40% reported mild or moderate fears. Fear of late effects was communicated by 83% of the survivors, with 38% experiencing high levels of concerns. Only 8% of the survivors had no adverse health outcome. The rate of somatic and mental health outcomes identified in our sample is high. Some of the most frequent outcomes are mutually interconnected and modifiable, which highlights the need for patient education on a healthy lifestyle. There is also a clear need for improved psychological support for childhood cancer survivors to mitigate unnecessary anxieties resulting from unsubstantiated health concerns. Dissemination of personalized and positive messages should be part of routine follow-up care.

Assessment of late cardiotoxic effects in patients treated for cancer in childhood.

Graphical AbstractThe aim was to assess the late cardiotoxic effects in young adults treated for various cancer types in childhood using echocardiography and 24-h ECG Holter monitoring.

Childhood cancer epidemiology in the Czech Republic (1994-2016).

BACKGROUND: The knowledge of cancer burden in the population, its time trends and the possibility of international comparison is an important starting point for cancer control programmes. Our study aimed to evaluate trends in childhood cancer epidemiology of patients aged 0-14 years in the period 1994-2016 in the Czech Republic. METHODS: Data on childhood cancers have been obtained from the Czech National Cancer Registry. These data were validated using the clinical database of childhood cancer patients and combined with data from death certificates. Incidence and mortality trends were assessed by the joinpoint regression method. The life tables method was used to calculate the overall age-standardised five-year survival. RESULTS: The incidence trend was stable; the age-standardised (world) cancer incidence - ASR (W) - was 173.7 per 1 million children in the period 1994-2016. However, there was apparent significant decrease in mortality: ASR (W) dropped from 58.1 per 1 million children in 1994 to 21.4 per 1 million children in 2016. The overall five-year survival increased over time by 10 %. Statistically significant improvements in survival were observed in patients with lymphoid leukaemia, astrocytomas, neuroblastomas, osteosarcomas and rhabdomyosarcomas. CONCLUSION: Such a relevant increase in survival rates, and therefore also a decrease in mortality rates in the Czech Republic, is most likely due to improvements in diagnostic and treatment methods since the 1990s, which were facilitated by the concentration of childhood cancer patients in children's cancer centres.

Mesothelioma in children and adolescents: the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) contribution.

INTRODUCTION: Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon. MATERIAL AND METHODS: The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018. RESULTS: Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin-pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0-20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8-99.9) and 45.1% (95% CI, 28.4-71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient). CONCLUSIONS: Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin-pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.

BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.

DICER1 Syndrome.

DICER1 syndrome is an inherited disorder that increases the risk of different types of malignant and benign tumors. The syndrome is caused by mutations in the DICER1 gene, which is located on the long arm of chromosome 14, region q32.13. Patients with DICER1 syndrome commonly develop pleuropulmonary blastoma (PPB), multinodular goiter, ovarian Sertoli-Leydig cell tumors, and/or other types of tumors. In approximately 35% of families with children manifesting PPB, further (and rather rare) malignancies may be observed, including cystic nephroma, nodular dysplasia of the thyroid gland, medulloepithelioma of the iris, embryonal rhabdomyosarcoma botryoid type, nasal epithelial hamartoma, pituitary blastoma, and/or pineoblastoma. Large studies report a high variability of tumors associated with DICER1. DICER1 syndrome, which is associated with an inherited predisposition to tumors, is inherited in an autosomal dominant pattern. Symptoms of DICER1 syndrome may vary, even within families. Preventive screening of carriers with causative mutations is complicated. Follow-up is undertaken as recommended by the 2016 International PPB Register. This work was supported by grant of Ministry of Health of the Czech Republic AZV 16-3329A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2019 Accepted: 6. 6. 2019.

Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial.

BACKGROUND: Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS: This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS: Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS: The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

Bone marrow metastasis of malignant melanoma in childhood arising within a congenital melanocytic nevus.

BACKGROUND: Malignant melanoma in childhood is infrequent and can arise within congenital melanocytic nevi. Spread of malignant melanoma to the bone marrow, especially in children, is extremely rare. METHODS AND RESULTS: Reported is a case of a 5-year-old boy with a congenital large melanocytic nevus of the head and neck who presented with a short history of low back and leg pain, fever and cervical lymphadenopathy. Despite regular follow-up by a dermatologist and plastic surgeon and repeatedly negative histology of previous partial excisions, diffuse bone marrow infiltration with malignant melanoma was diagnosed. The primary site was identified in the post-excision area. The disease progressed rapidly on ipilimumab immunotherapy and led to death at four months from the diagnosis. CONCLUSION: Surveillance is indispensable in children with a predisposition to melanoma and nonspecific symptoms such as bone pain, gait impairment or cytopenia, should always be taken into account.

Second complete remission of relapsed medulloblastoma induced by metronomic chemotherapy.

Prognosis for children with relapsed medulloblastoma remains poor. Metronomic chemotherapy may offer some benefit to patients treated initially with intensive regimens. However, dosing and duration of such palliative treatment have not been systematically studied. Here we describe a child with medulloblastoma relapsing after initial high-dose chemotherapy and standard radiotherapy. The patient was then treated with metronomic chemotherapy and achieved second complete remission after 21 months of treatment. Three months off therapy he relapsed again and died from progressive disease. This case illustrates the potential benefit of metronomic chemotherapy but also shows the uncertainty of when to stop metronomic chemotherapy while balancing toxicity.

Cytogenetic and array comparative genomic hybridization analysis of a series of hepatoblastomas.

Hepatoblastoma is the most common primary hepatic tumor in children, and only a limited number of detailed karyotypic analyses have been reported to date. In the present study, cytogenetic abnormalities were identified in nine cases of hepatoblastoma from a single institution. Among characteristic chromosomal changes detected were simple numerical aberrations, structural alterations of chromosomes 1, 2, and 8, and the recurrent unbalanced rearrangements der(4)t(1;4)(q25.2;q35.1) and der(6)t(1;6)(q21;q26). Array comparative genomic hybridization was applied in four of the cases. The combined cytogenetic, molecular cytogenetic, and histopathologic analyses are presented here, together with clinical data. The results substantially confirm previous findings of aberrations involving chromosomal loci on 1q, 2 or 2q, 4q, 6q, 8 or 8q, and 20 as significant in the development and clinical course of this disease.

Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study.

BACKGROUND: To outline an outpatient-based treatment for children with relapsed solid tumors, who already have been extensively pretreated, we defined a 4-drug protocol named COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy). Using this protocol, we performed a pilot study to determine its feasibility in children with relapsed and/or high-risk pediatric solid tumors. PATIENTS AND METHODS: 22 children received the COMBAT protocol. Treatment consisted of daily celecoxib administration along with daily 13-cisretinoic acid (2 weeks on / 2 weeks off) and cycles of metronomic temozolomide (90 mg/m2 for 42 days) and low-dose etoposide (21 days). The treatment was scheduled for a period of 1 year. RESULTS: 9 of the 14 patients assessable for response demonstrated evidence of treatment benefit manifested as prolonged disease stabilization or response. The protocol medication was well tolerated with very good compliance. Only minimal side effects where observed which responded to dose modification or local therapy. CONCLUSIONS: The COMBAT regimen is well tolerated by patients with intensive prior therapy including myeloablative regimens. Favorable responses observed in this cohort of patients support the further exploration of this and/or similar strategies in the treatment of pediatric solid tumors.

Severe encephalopathy induced by the first but not the second course of high-dose methotrexate mirrored by plasma homocysteine elevations and preceded by extreme differences in pretreatment plasma folate.

Plasma homocysteine has recently been associated with the occurrence of methotrexate-related neurotoxicity. We observed extreme elevations of homocysteine in a 9-year-old boy presenting with leukemia treated with the ALL-BFM 95 protocol. Coma occurred at about the 71st hour from the first methotrexate administration, and lasted for 30 h but MRI and CT studies showed no intracranial pathology. The second course of high-dose methotrexate was administered with no complications. Homocysteine areas under the curve (AUC) were calculated as the sum of areas of rectangles during the 6-hour intervals from T(0) to T(72) hours (AUC(0--72)) and methotrexate AUCs were evaluated using MW/PHARM 3.3 software. The AUC of homocysteine during the first, toxic course was 5.2 times higher than AUC during the second administration, whereas AUC of methotrexate also differed by a factor of 5. Plasma concentrations of folate prior to the first and the second courses, respectively, were 4.4 versus 45 micromol/l making this difference the most striking discriminator between the two courses. Mutation analysis showed that the patient was heterozygous for the C 677 T mutation in the MTHFR gene. We suggest that plasma homocysteine, pretreatment plasma folate and possibly the presence of MTHFR mutations may be biomarkers of methotrexate toxicity and possibly its antifolate effect targeted towards the tumor as well.

The use of gallium-67 scintigraphy to monitor tumor response rates and predict long-term clinical outcome in patients with lymphoma.

The aim of this study was to determine whether gallium (Ga)-67 scintigraphy can monitor the treatment response rates and predict the long-term clinical outcome in patients with lymphoma. Gallium-67 scintigraphy was performed upon admission (baseline Ga) in 33 consecutive, newly diagnosed patients. Twenty-eight patients (Hodgkin's disease, n = 18; non-Hodgkin's lymphoma, n = 13) with Ga avid tumors were included in the study. All the patients were treated with induction chemotherapy. Gallium-67 scintigraphy was performed in all patients after the first cycle of chemotherapy (post-cycle 1 Ga) and repeated after the fourth cycle (post-cycle 4 Ga) or after completion of treatment (end-of-chemotherapy Ga). Nineteen patients had a fast response (68%, negative in post-cycle 1 and end-of-chemotherapy Ga), 4 intermediate response (14%, partial positive post-cycle 1 Ga that progressed to negative post-cycle 4 Ga), 3 slow response (11%, partial positive in both post-cycle 1 and post-cycle 4 Ga) and 2 no response (7%, positive in both post-cycle 1 and end-of-chemotherapy Ga). In patients who had either fast or intermediate response, 22 (96%) were free of disease at a median follow-up period of 30 months (range, 11-45 months). All 5 patients (100%) who had slow or no response had progressive disease or residual disease. In conclusion, the findings indicate that Ga could effectively be used to monitor the treatment response rates and predict the long-term clinical outcome in patients with lymphoma and should be used in treatment modifications aimed at reducing toxicity of effective therapy in patients with fast response and replacing treatments early in patients with slow or no response.

High survival rate in childhood non-Hodgkin lymphoma without CNS involvement: results of BFM 95 study in Kuwait.

Non-Hodgkin lymphomas (NHL) in children are the second most common malignant tumors in Kuwait. Until 1995 the patients (pts) received institutional protocols. From October 1995 to September 2000 21 children with NHL were treated. Five children were treated by NHL BFM 90 protocol, 7 pts received NHL BFM 95 scheme, and 9 children underwent therapy abroad or according to different types of protocols. The results of a retrospective analysis of NHL BFM 95 protocol in Kuwait are reported. Seven patients diagnosed with NHL--group B: 3 children with Burkitt lymphoma (B-cell NHL) and group A: 4 children with lymphoblastic lymphoma (T-cell NHL)--were treated from October 1995 to September 2000 in the Kuwait Cancer Control Centre according to NHL BFM 95 protocol. Group B consisted of 2 girls and 1 boy; median age at diagnosis was 4 years 8 months, 2 pts classified as stage II and 1 pt as stage III. All patients were assigned to risk group R2. Median follow-up is 2 years 8 months. Group A included 1 girl and 3 boys; median age at diagnosis was 5 years 8 months, 1 pt classified as stage III and 3 pts as stage IV. All patients were assigned to IR group. Median follow-up is 3 years 6 months. In group B all 3 pts are in 1st CR; in group A 3 pts are in 1st CR and 1 pt having Li-Fraumani syndrome died after the 3rd relapse of disease during therapy. In both groups there was no toxic death, myelotoxicity WHO grade III-IV, hepatotoxicity WHO grade II-III. Treatment results of NHL BFM 95 study in our small group of patients are very optimistic. Six patients are in 1st CR and one died due to progression of disease. Despite the small group of patients, the results suggest that NHL BFM 95 protocol is highly effective and safe with regular supportive care.