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Aims. The relationship of tumour volume, radiotherapy treatment time and other prognostic factors affecting prognosis was evaluated. Methods. 184 patients with locally advanced head and neck cancer were treated with radical intensity modulated radiotherapy (IMRT) and compared retrospectively. Results. In the multivariate analysis the overall survival was dependent on gross tumour volume (GTV), clinical stage (CS), radiotherapy treatment time (RTT) and p16 status. Local control was influenced by GTV, overall RTT and age. DFS was significantly affected by GTV, CS, RTT, p16 status and concomitant chemotherapy (CHT). Conclusions. The tumour volume and the radiotherapy treatment time were the most significant prognostic factors with the best outcomes in patients with GTV ≤ 55 cc and RTT ≤ 48 days (mean LC 8.1, DFS 7.1 and OS 6.4 years) and worst outcomes with GTV > 55 cc and RTT >48 days (mean LC 4.4, mean DFS 3.2 and mean OS 2.6 years).

The aim of this retrospective analysis was to evaluate the impact of FDG-PET/CT-based target volume definition on locoregional control and survival, compared to conventional CT-based target volume definition and dose prescription. One hundred and twenty-two patients with squamous cell anal cancer were treated with curative radiotherapy (RT) alone (27%) or with RT with concurrent chemotherapy (73%) and analyzed. Forty-six percent had the early disease (stage I+II) and 54% were stage III. FDG-PET/CT-based staging was performed in 21% of the patients. The mean follow-up time was 60 months. Other risk factors affecting survival were investigated. According to initial staging in both groups (FDG-PET/CT and conventional CT) were 10% of stage IV disease, and they were excluded from radical radiotherapy and treated with palliative intent. Ninety-two percent of the patients achieved complete remission. Significant favorable factors in univariate analysis associated with disease-free survival (DFS) were PET/CT staging, T1/2 and N0 stage, and clinical stage I and II. Locoregional control (LRC) correlated with the T1/2 stage and initial performance status (PS) 0. There were no significant factors affecting overall survival (neither in univariate nor multivariate analysis). In multivariate analysis, the factor associated with better DFS was PET/CT staging and for LRC, PS 0 and concomitant chemoradiation. Acute toxicity was increased in the concurrent chemo-radiotherapy group. Two-, five- and ten-year overall survival rates were 83%, 69%, and 60%; disease-free survival rates were 76%, 73%, 73%; local control rates were 91%, 90%, and 90% and colostomy-free survival was 89%, 86%, and 81%, respectively. PET/CT staging allowed targeted dose escalation to the primary tumor and nodal metastases while decreasing dose to uninvolved regions, resulting in significantly improved DFS without compromising locoregional control.

Allogeneic hematopoietic stem cell transplantation (HSCT) has become a standard part of therapy for a variety of malignant and non-malignant disorders. With improved outcomes after HSCT, increasing attention has been drawn to late complications in long-term survivors. The development of secondary malignancies is recognized as one of the most serious complications. We have evaluated data from 426 patients (272 males, 154 females) who underwent allogeneic transplantation at a median age of 7.9 years from 1989 till 2017 and were alive more than one year after transplantation for the occurrence of secondary solid tumors. We have documented the occurrence of secondary solid tumors in 20 patients (4.7%). The median duration of the development of secondary solid cancer from HSCT was 11.7 (range, 5.4-21.5 years). 18 out of 20 patients (90%) had total body irradiation (TBI) 12-14.4 Gy as a part of a conditioning regimen. All but two had transplantation for malignant disease. All patients underwent surgery and/or chemo-radiotherapy. Eighteen are alive, and two died due to the progression of their secondary malignancy. The most frequent solid cancer was thyroid carcinoma (n=9). Cumulative incidence of secondary solid cancer in all groups was 15.2±3.9%, in a group using TBI based regimen 34.7±8.9%, in non-TBI (only chemo) group was 1.5±1.1%. Overall, the cumulative incidence is statistically significantly different between the TBI based and non-TBI (chemo only) group. The incidence and number of complications following allogeneic HSCT in childhood are increasing in time. The early diagnosis of secondary malignancies is one of the key tasks of long-life multidisciplinary post-transplant care.

Aims. Curative sphincter sparing radiotherapy is a treatment option for early rectal cancer. There are many methods developed for fertility preservation in young patients treated with pelvic radiotherapy. Pregnancy rates after radiotherapy are dependent on the radiation dose to ovaries and uterus. Data on outcomes of total body irradiation suggest a pregnancy is possible following 12-14 Gy TBI, despite elevated rates of preterm deliveries and other complications. Methods. We report a case of full-term delivery of twins after curative chemoradiotherapy for anorectal adenocarcinoma T2 N0 M0 with the total dose 58.6 Gy. The patient underwent laparoscopic laterocranial ovarian transposition before radiotherapy. Results. Long term complete remission was achieved after treatment. Although a spontaneous conception was not successful, the patient underwent an in vitro fertilisation procedure with donor eggs and conceived twins 10 years after the radiotherapy treatment. The mean dose to the uterus was 16 Gy and to the uterine cervix 35 Gy. She reached a full-term pregnancy and delivered two healthy babies by caesarean section at a gestational age of 38 weeks, weighing 2420 g and 2220 g. Conclusion. This is the first case report of the successful pregnancy following sphincter sparing curative pelvic radiotherapy for rectal cancer. Furthermore it allows us to propose an increased limit dose to the uterus enabling fertility sparing beyond the limits achieved from total body irradiation series with 12-14 Gy and accept 16 Gy as uterine body (35 Gy for uterine cervix) limit for IMRT treatment planning in young patients asking for maintaining fertility potential.

Prolongation of radiotherapy worsens the results of treatment of head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to identify the prognostic factors most affected by the prolongation of treatment.184 patients with locally advanced HNSCC were treated with curative chemo-radiation using SIB-IMRT from 2008 to 2016 and the influence of radiotherapy time (RTT) in groups of patients according to prognostic factors was retrospectively evaluated.Median overall survival (OS) was 45 months, median disease-free survival (DFS) was 41 months and median local control (LC) was not reached (mean LRC 68 months). In the multivariate analysis the radiotherapy prolongation negatively affected the LC in stage IV patients, T3/T4, in neck nodes positive disease, in oropharyngeal and oral cavity cancers, after neoadjuvant chemotherapy and in men. The RTT effect on DFS was significant in stage IV patients, patients with neck nodes positive disease and oropharyngeal cancer. RTT prolongation decreased OS within the groups of stage IV and grade 3 tumours.Prolonged RTT was associated with worsened OS and LRC, especially in stage IV patients and/or neck node positive disease and/or oropharyngeal cancer and we recommend that these patients should be prioritized in treatment gap compensation in radical radiotherapy for locally advanced HNSCC.

The treatment of locally advanced head and neck cancer (LAHNC) requires a multimodality approach. Radiotherapy with combination of chemotherapy are demonstrated to be effective, however, the treatment intensification leads to increased toxicity at the same time. The implementation of three-dimensional conformal radiotherapy (3D-CRT) allowed to irradiate the treatment volume more precisely with better surrounding healthy tissue sparing. Intensity modulated radiotherapy (IMRT) facilitated higher conformity in dose shaping to target volume. IMRT with simultaneous integrated boost (IMRT-SIB) offered the possibility to deliver individualized dose levels within one fraction and enabled escalation of the dose per fraction and radiotherapy acceleration. The aim of our study was to compare the technique of 3D-CRT and IMRT-SIB in the treatment of LAHNC and evaluate the treatment outcome and the treatment-related toxicity. 262 patients in 3D-CRT group and 263 patients in IMRT-SIB group underwent the radical treatment for LAHNC between 1/1998 and 12/2016. No statistically significant differences in locoregional control (LCR) and overall survival (OS) were found between the two groups. Acute toxicity and xerostomia were significantly reduced in the patients treated by IMRT-SIB. IMRT-SIB is a safe radiotherapy method where less toxicity was proven without compromising local control and overall survival.

INTRODUCTION: Paediatric high-grade gliomas (HGG) are characterised by the aggressive biological behaviour with dismal prognosis of long-term survival 10-15%. Current molecular-biological diagnostic approaches allow for more precise characterization and determination of new unique subgroups of HGG. Our aim was to identify novel and rare HGG subgroups within our institution cohort. PATIENTS AND METHODS: Our reference centre patients′ cohort consisted of 97 clinically annotated patients with HGG diagnosed between 2000 and 2021. Sanger sequencing was used for screening of the most common HGG-related oncogenic drivers; furthermore we employed whole genome methylation array (Illumina Infinium MethylationEPIC BeadChip) and for selected samples RNA sequencing and expression profiling. RESULTS: Based on H3 status and previous radiotherapy we separated our HGG cases into the RIG, H3mut and H3wt groups. In contrast to H3mut(n=35) and RIG(n=11) that were uniformly fatal, H3wt group contained a proportion of long-term survivors. In the H3wt group we found patients carrying driver mutations in IDH1/2 (n=2) and BRAFV600E (7). Five young patients (under 3) consisted of 3 infant hemispheric gliomas (with NTRK and ROS1 fusions), one gliomatosis cerebri and one brainstem anaplastic astrocytoma with MYB/QKI fusion. We also identified a rare EWSR1-PATZ1 gene fusion in one patient. Importantly, long-term survivors recruited from these subgroups. On the contrary, four cases of MYCN GBM with poor prognosis presented in various locations: one disseminated, one gliomatosis cerebri and two with hemispheric tumour. We identified one patient with “hypermutated” glioblastoma and used targeted therapy with Nivolumab. In three samples of our patients with thalamic glioblastomas, we detected “loss of H3K27-trimethylation” caused by EZHIP overexpression. These tumours proved to be very aggressive with early metastatic recurrence and dismal prognosis. SUMMARY: Detailed characterization of H3 wild-type HGG is very important for further understanding of their biological behaviour, diagnostics, prognostication and identification of therapeutic targets.

Rhabdoid tumour is a fatal disease that can occur in central nervous system as ATRT or in soft tissues or kidneys. The treatment is challenging because of very young age of such patients and aggressiveness of the disease. We aimed to collect demographic and clinical data of patients treated between 2001 and 2018 at our institution. We evaluated survival, molecular features of the tumours and the incidence of rhabdoid tumour predisposing syndrome (RTPS). During the time period we diagnosed 26 patients with rhabdoid tumors; 19 with ATRT, five with mesenchymal rhabdoid tumour (MRT) (mediastinum, urinary bladder, heart, neck) and two with kidney rhabdoid tumour (KRT). Interestingly, two patients with MRT developed ATRT while still on treatment. One patient with ATRT was diagnosed with urinary bladder MRT 6 years after the primary diagnosis. All three patients were confirmed to harbor germ-line SMARCB1 mutation. RTPS was diagnosed in 27% of our patients and was strongly correlated with development of metachronous rhabdoid tumours. Somatic SMARCB1 mutation and/or exonic/whole gene deletions were detected in all patients. Fifteen out of 19 patients with ATRT were treated with curative intent as per EU-RHAB registry protocol (n=8) or other regimens containing chemotherapy +/- radiation (n=7). 5-year progression-free survival was 26,7% and 5-year overall survival 31,2%. Only three long-term survivors recruited from our cohort, all three treated with radiation. Two survivors suffer from severe neurocognitive impairment, whereas the only patient with normal intellectual functioning was treated and irradiated at the age of 15. We can conclude that patients with RTPS need to be surveyed for occurrence of metachronous rhabdoid tumours. Survival of our patients is very poor indicating the urgent need of implementing different treatment strategy.

Li-Fraumeni syndrome (LFS) is a condition characterized by germ-line TP53 mutation and predisposition to various types of malignant neoplasms in childhood. We aimed to characterize spectrum of brain tumours in children associated with LFS. We gathered clinical information on LFS patients treated since 1990 at our department. Where the tissue was available, we performed molecular analysis consisting of whole genome methylation array and/or sequencing. We identified 15 LFS patients diagnosed with brain tumours; six with choroid plexus carcinoma (CPC), four with glioma, three with medulloblastoma, one PNET and one spinal myxopapilary ependymoma. Twelve of these patients presented with brain tumour as their first malignancy. Two patients were previously treated for rhabdomyosarcoma and developed glioma in radiation field. One patient was diagnosed with medulloblastoma after adrenocortical carcinoma. Out of six patients with CPC, three are alive, with two treated with radiation therapy. Gliomas consisted of three diffuse astrocytomas (DA) and one glioblastoma. DAs were diagnosed at later age (14 to 18 years) and molecularly characterized by rare IDH1 R132G mutation. One glioblastoma was classified as GBM_other using NMP2.0. All four patients are alive with median 4 years from diagnosis of glioma, including the patient with glioblastoma. All medulloblastomas were SHH group with tumor location in the cerebellar hemisphere. Two patients treated with combined radiation and chemotherapy died of secondary malignancy 4 and 5 years from the primary diagnosis. Last patient is currently being treated with radiation sparing approach. In our cohort, majority of patients developed brain tumour as their first malignancy. Radiation sparing approaches need to be implemented to decrease risks of secondary cancers. Gliomas and medulloblastomas seem to harbour distinct molecular features compared to their sporadic counterparts.

Summary Background Rindopepimut (also known as CDX-110), a vaccine targeting the EGFR deletion mutation EGFRvIII, consists of an EGFRvIII-specific peptide conjugated to keyhole limpet haemocyanin. In the ACT IV study, we aimed to assess whether or not the addition of rindopepimut to standard chemotherapy is able to improve survival in patients with EGFRvIII-positive glioblastoma. Methods In this randomised, double-blind, phase 3 trial, we recruited patients aged 18 years and older with glioblastoma from 165 hospitals in 22 countries. Eligible patients had newly diagnosed glioblastoma confirmed to express EGFRvIII by central analysis, and had undergone maximal surgical resection and completion of standard chemoradiation without progression. Patients were stratified by European Organisation for Research and Treatment of Cancer recursive partitioning analysis class, MGMT promoter methylation, and geographical region, and randomly assigned (1:1) with a prespecified randomisation sequence (block size of four) to receive rindopepimut (500 μg admixed with 150 μg GM-CSF) or control (100 μg keyhole limpet haemocyanin) via monthly intradermal injection until progression or intolerance, concurrent with standard oral temozolomide (150–200 mg/m 2 for 5 of 28 days) for 6–12 cycles or longer. Patients, investigators, and the trial funder were masked to treatment allocation. The primary endpoint was overall survival in patients with minimal residual disease (MRD; enhancing tumour 2 post-chemoradiation by central review), analysed by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01480479. Findings Between April 12, 2012, and Dec 15, 2014, 745 patients were enrolled (405 with MRD, 338 with significant residual disease [SRD], and two unevaluable) and randomly assigned to rindopepimut and temozolomide (n=371) or control and temozolomide (n=374). The study was terminated for futility after a preplanned interim analysis. At final analysis, there was no significant difference in overall survival for patients with MRD: median overall survival was 20·1 months (95% CI 18·5–22·1) in the rindopepimut group versus 20·0 months (18·1–21·9) in the control group (HR 1·01, 95% CI 0·79–1·30; p=0·93). The most common grade 3–4 adverse events for all 369 treated patients in the rindopepimut group versus 372 treated patients in the control group were: thrombocytopenia (32 [9%] vs 23 [6%]), fatigue (six [2%] vs 19 [5%]), brain oedema (eight [2%] vs 11 [3%]), seizure (nine [2%] vs eight [2%]), and headache (six [2%] vs ten [3%]). Serious adverse events included seizure (18 [5%] vs 22 [6%]) and brain oedema (seven [2%] vs 12 [3%]). 16 deaths in the study were caused by adverse events (nine [4%] in the rindopepimut group and seven [3%] in the control group), of which one—a pulmonary embolism in a 64-year-old male patient after 11 months of treatment—was assessed as potentially related to rindopepimut. Interpretation Rindopepimut did not increase survival in patients with newly diagnosed glioblastoma. Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma. Funding Celldex Therapeutics, Inc.

BACKGROUND: The purpose of the study was to evaluate outcome and pattern of failure in patients with newly diagnosed medulloblastoma treated at the Department of Pediatric Hematology and Oncology in Prague, Czech Republic between 2000–2015. METHODS: Demographics, treatment and survival data were collected in 94 consecutive patients (34 F, 60 M) with histologicaly proven medulloblastoma. Median patient age at the time of diagnosis was 8.43 (0.29 - 17.6) years. Two patients were lost to follow up. Altogether 92 patients were evaluable, Kaplan-Meier analysis was performed to determine survival. Two out of 16 infants (5 metastatic) deceased before the start of any treatment, 14 were treated with chemotherapy only. Older patients (n=75) were treated with radiotherapy and chemotherapy, 44 as a standard risk (SR) and 31 as high risk (HR) group (14 metastatic). One patient with biallelic BRCA2/FANCD1 mutation underwent individualized treatment. RESULTS: The 5-year PFS and OS of all 92 analyzed patients were 66.8% and 72.3%. Survival was higher in older children treated with radiotherapy with 5-year PFS and OS 75.9% and 76.9% respectively. 5-year OS in SR treatment group was 83.0%, in HR group 67.9%. Overall 23 patients have died from all causes. Strikingly, the incidence of secondary malignancies reached 9% (n=9 in 8 patients) and were responsible for 4 deaths. CONCLUSION: The prognosis of medulloblastoma patients is good with over 70% surviving 5 years from the diagnosis with current therapies. Worrisome is a number of SMN. “Supported by the “Project for Conceptual Development of Research Organization 00064203”