Assessment of the effects of treatment of meduloblastoma in children and young adults with three-dimensional conformal radiotherapy

Savremenim multidisciplinarnim lečenjem meduloblastoma hirurgijom, kraniospinalnom radioterapijom i hemioterapijom značajno je poboljšano preživljavanje bolesnika. Cilj rada je bila analiza ishoda lečenja i nezavisnih prognostičkih faktora i analiza trodimenzionalne konformalne radioterapije koja omogućava optimalnu uniformnost i konformalnost distribucije doze u željenom volumenu mete i veću poštedu okolnih zdravih tkiva. Metod: Istraživanje je obuhvatilo grupu od 87 dece sa meduloblastomom koji su lečeni u Institutu za onkologiju i radiologiju Srbije u periodu od januara 2000. do decembra 2013.godine. Rezultati: Srednji uzrast bio je 8,3 godine ( rang 2,5-17,3). Klasični meduloblastom imalo je 61 (70,1%), nodularni/dezmoplastični 23 (26,4%), a krupnoćelijski/anaplastični 3 (3,4%) bolesnika. U odnosu na metastatski stadijum bolesti 62 (71,3%) su bili M0, 12 (13,8%) M1, a 13 (14,9%) M2 i/ili M3. Totalnu resekciju je imao najveći broj 53 (60,9%), a skoro totalnu resekciju 22 (25,3%) bolesnika. 2D radioterapiju imalo je 50 (57,5%), a 3D 37 (42,5%) bolesnika. Hemioterapijom je lečeno 78 (89,7%), neoadjuvantnom 11 (13%), konkomitantnom 9 (10%) i adjuvantnom najveći broj bolesnika 73 (83,9%). Kada je istraživanje završeno 51 (58,6%) je bilo živo, a 31 (35,6%) je umrlo. Pet pacijenata je izgubljeno iz praćenja. Relaps bolesti imalo je 26 (29,9%) bolesnika. Medijana praćenja iznosila je 58 meseci (rang 4-187). Ukupno preživljavanje (OS) iznosi: trogodišnje 76,4%, petogodišnje 66,2% a desetogodišnje 59,2%. Preživljavanje bez znakova bolesti (DFS) iznosi: trogodišnje 75,8%, petogodišnje 62,8% i desetogodišnje 56,6%. Postoji statistički značajna razlika u ukupnom preživljavanju nemetastatskih ( M0) u odnosu na metastatske meduloblastome (M1,M2,M3) ( p=0,003) OS za grupu sa lokalizovanom bolesti (M0) iznosi: trogodišnje 86,4%, petogodišnje 74%, a desetogodišnje 63,1%. OS za grupu sa diseminovanom bolesti (M1,M2,M3) iznosi: trogodišnje 48,9%, petogodišnje 44%, a desetogodišnje 37,7%...Standard treatment for meduloblastoma consists of surgery, craniospinal radiation and chemotherapy. The use of these modalities has resulted in improvement of survival. The aim of this study was to analize survival and independent prognostic factors and to analize three-dimensional conformal radiotherapy who is achieving optimal uniformity and conformality dose distribution in treated volume and to minimize the risk of normal tissue damage. Methods: Da on 87 children diagnosed with meduloblastoma who were treated at the Institute for Oncology and Radiology of Serbia between January 2000 amd December 2013 were analysed. Results: The median age was 8,3 years (range 2,5-17,3). The classis histologic variant was observed in 61 (70,1%), nodular/desmoplastic in 23 (26,4%) and large cell/anaplastic variant was observed in 3 (3,4%) patients. Meningeal dissemination within the subarachnoid space ( cranial M2 or spinal M3) was observed in 13 (14,9%) and microscopic metastases within the CSF ( M1) was observed in 12 (13,8%) patients. Most of the patients (62,71,3%) had no metastatic disease (M0). Gross total resection had the most of the patients 53 (60,9%) and near total had 22 (25,3%) patients. Two-dimensional radiotherapy received 50 (57,5%) and three-dimensional radiotherapy received 37 (42,5%) patients. Chemotherapy was used in 78 (89,7%) patients. Postoperative neoadjuvant chemotherapy was used in 11 (13%), chemotherapy during the raditherapy was used in 9 (10%) patients. The majority of patients (73 83,9%) were treated with adjuvant platinum-based chemotherapy. At the end of the study 51 (58,6%) were alive and 31 (35,6%) had died. Five patients were lost to follow-up. Twenty-six (29,9%) patients relapsed. The median follow-up time was 50 months ( range 4-187)..

Opis przypadku — występujący rodzinnie wewnątrzczaszkowo germinoma

Background. Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurance. Since ICG invades hypothalamus and/or pituitary, the endocrine dysfunction is one of the common determinants of these tumors. We presented two brothers with the history of ICG. Patient 1 is a 25-year-old male who had been suffering from the weakness of the right half of his body at the age of 18. Cranial MRI revealed mass lesion in the left thalamus. He underwent neurosurgery, tumor was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumor after a radiation therapy. At the age of 22 the diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Patient 2 is a 20-year old boy who was presented with diabetes insipidus at the age of 12. MRI detected tumor in the third ventricle and pineal region. After the endoscopic tumor biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy, and treated with GH during childhood. At the age of 18 GH replacement was reintroduced. A six month follow-up during the next two years in both brothers demonstrated the IGF1 normalization with no MRI signs of tumor recurrence. Conclusion. To the best of our knowledge so far, only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside of Japan. They are treated successfully with GH therapy in adult period. Wstęp: Rozrodczaki wewnątrzczaszkowe (intracranial germinomas, ICG) to rzadkie nowotwory mózgu, a szczególnie rzadko stwierdza się ich występowanie rodzinne. W związku z tym, że ICG zajmuje podwzgórze i/lub przysadkę mózgową, zaburzenia endokrynologiczne są jednym z najczęstszych wyznaczników obecności tych guzów. W pracy przedstawiono dwóch braci z ICG. Pacjent 1 to 25-letni mężczyzna, u którego w wieku 18 lat wystąpiło osłabienie mięśni po lewej stronie ciała. Badanie metodą rezonansu magnetycznego (MRI) czaszki ujawniło masę w lewym wzgórzu. Chorego poddano zabiegowi neurochirurgicznemu, podczas którego guz został całkowicie usunięty. Badania histopatologiczne i immunohistochemiczne potwierdziły rozpoznanie czystej postaci rozrodczaka. Po radioterapii nastąpiła całkowita remisja guza. W wieku 22 lat u chorego zdia­gnozowano izolowany niedobór hormonu wzrostu (isolated growth hormone deficiency, IGHD) i wdrożono terapię zastępczą hormonem wzrostu (growth hormone, GH). Genetyczna analiza molekularna tkanki guza wykazała mutację w eksonie 2 w genie KRAS. Pacjent 2 to 20-letni mężczyzna, u którego w wieku 12 lat stwierdzono moczówkę prostą. W badaniu MRI wykryto guz w okolicy trzeciej komory i szyszynki. Po ocenie histopatologicznej materiału pobranego za pomocą biopsji endoskopowej postawiono diagnozę czystego rozrod­czaka. U chorego zastosowano chemioterapię, a następnie radioterapię, a także podawano GH w okresie dzieciństwa. W wieku 18 lat u chorego wznowiono terapię GH. Sześciomiesięczna obserwacja obu braci w następnych 2 latach wykazała normalizację IGF1 przy braku objawów nawrotu guza w badaniu MRI. Wnioski: Według najlepszej wiedzy autorów dotychczas opublikowano 6 doniesień na temat rodzinnego występowania ICG. Przed­stawieni w niniejszej pracy bracia są pierwszym opisanym przypadkiem rodzinnego ICG poza Japonią. W okresie dorosłym chorzy są leczeni GH z dobrym skutkiem

Clinical case seminar - familial intracranial germinoma

Background: Intracranial germinomas (ICG) are uncommon brain neoplasms with extremely rare familial occurrence. Because ICG invades the hypothalamus and/or pituitary, endocrine dysfunction is one of the common determinants of these tumours. We present two brothers with a history of ICG. Patient 1 is a 25-year-old male who suffered from weakness of the right half of his body at the age of 18 years. Cranial MRI revealed a mass lesion in the left thalamus. He underwent neurosurgery, and the tumour was removed completely. Histopathological (HP) and immunohistochemical analyses verified the diagnosis of pure germinoma. He experienced complete remission of the tumour after radiation therapy. At the age of 22 years a diagnosis of isolated growth hormone deficiency (IGHD) was established and GH replacement was initiated. Molecular genetic analysis of the tumour tissue detected the mutation within exon 2 in KRAS gene. Patient 2 is a 20-year-old man who presented with diabetes insipidus at the age of 12 years. MRI detected tumour in the third ventricle and pineal region. After endoscopic tumour biopsy the HP diagnosis was pure germinoma. He received chemotherapy followed by radiotherapy and was treated with GH during childhood. At the age of 18 years GH replacement was reintroduced. A six-month follow-up during the subsequent two years in both brothers demonstrated the IGF1 normalisation with no MRI signs of tumour recurrence. Conclusion: To the best of our knowledge, so far only six reports have been published related to familial ICG. The presented two brothers are the first report of familial ICG case outside Japan. They have been treated successfully with GH therapy in adulthood

Radical radiotherapy for paediatric solid tumour metastases:An overview of current European protocols and outcomes of a SIOPE multicenter survey

Purpose/objective: About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. Materials/methods: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating >= 50 children annually were invited to participate in an online survey. Results: Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. Conclusion: Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST. (C) 2020 The Author(s). Published by Elsevier Ltd

Assessment of the effects of treatment of meduloblastoma in children and young adults with three-dimensional conformal radiotherapy

Savremenim multidisciplinarnim lečenjem meduloblastoma hirurgijom, kraniospinalnom radioterapijom i hemioterapijom značajno je poboljšano preživljavanje bolesnika. Cilj rada je bila analiza ishoda lečenja i nezavisnih prognostičkih faktora i analiza trodimenzionalne konformalne radioterapije koja omogućava optimalnu uniformnost i konformalnost distribucije doze u željenom volumenu mete i veću poštedu okolnih zdravih tkiva. Metod: Istraživanje je obuhvatilo grupu od 87 dece sa meduloblastomom koji su lečeni u Institutu za onkologiju i radiologiju Srbije u periodu od januara 2000. do decembra 2013.godine. Rezultati: Srednji uzrast bio je 8,3 godine ( rang 2,5-17,3). Klasični meduloblastom imalo je 61 (70,1%), nodularni/dezmoplastični 23 (26,4%), a krupnoćelijski/anaplastični 3 (3,4%) bolesnika. U odnosu na metastatski stadijum bolesti 62 (71,3%) su bili M0, 12 (13,8%) M1, a 13 (14,9%) M2 i/ili M3. Totalnu resekciju je imao najveći broj 53 (60,9%), a skoro totalnu resekciju 22 (25,3%) bolesnika. 2D radioterapiju imalo je 50 (57,5%), a 3D 37 (42,5%) bolesnika. Hemioterapijom je lečeno 78 (89,7%), neoadjuvantnom 11 (13%), konkomitantnom 9 (10%) i adjuvantnom najveći broj bolesnika 73 (83,9%). Kada je istraživanje završeno 51 (58,6%) je bilo živo, a 31 (35,6%) je umrlo. Pet pacijenata je izgubljeno iz praćenja. Relaps bolesti imalo je 26 (29,9%) bolesnika. Medijana praćenja iznosila je 58 meseci (rang 4-187). Ukupno preživljavanje (OS) iznosi: trogodišnje 76,4%, petogodišnje 66,2% a desetogodišnje 59,2%. Preživljavanje bez znakova bolesti (DFS) iznosi: trogodišnje 75,8%, petogodišnje 62,8% i desetogodišnje 56,6%. Postoji statistički značajna razlika u ukupnom preživljavanju nemetastatskih ( M0) u odnosu na metastatske meduloblastome (M1,M2,M3) ( p=0,003) OS za grupu sa lokalizovanom bolesti (M0) iznosi: trogodišnje 86,4%, petogodišnje 74%, a desetogodišnje 63,1%. OS za grupu sa diseminovanom bolesti (M1,M2,M3) iznosi: trogodišnje 48,9%, petogodišnje 44%, a desetogodišnje 37,7%...Standard treatment for meduloblastoma consists of surgery, craniospinal radiation and chemotherapy. The use of these modalities has resulted in improvement of survival. The aim of this study was to analize survival and independent prognostic factors and to analize three-dimensional conformal radiotherapy who is achieving optimal uniformity and conformality dose distribution in treated volume and to minimize the risk of normal tissue damage. Methods: Da on 87 children diagnosed with meduloblastoma who were treated at the Institute for Oncology and Radiology of Serbia between January 2000 amd December 2013 were analysed. Results: The median age was 8,3 years (range 2,5-17,3). The classis histologic variant was observed in 61 (70,1%), nodular/desmoplastic in 23 (26,4%) and large cell/anaplastic variant was observed in 3 (3,4%) patients. Meningeal dissemination within the subarachnoid space ( cranial M2 or spinal M3) was observed in 13 (14,9%) and microscopic metastases within the CSF ( M1) was observed in 12 (13,8%) patients. Most of the patients (62,71,3%) had no metastatic disease (M0). Gross total resection had the most of the patients 53 (60,9%) and near total had 22 (25,3%) patients. Two-dimensional radiotherapy received 50 (57,5%) and three-dimensional radiotherapy received 37 (42,5%) patients. Chemotherapy was used in 78 (89,7%) patients. Postoperative neoadjuvant chemotherapy was used in 11 (13%), chemotherapy during the raditherapy was used in 9 (10%) patients. The majority of patients (73 83,9%) were treated with adjuvant platinum-based chemotherapy. At the end of the study 51 (58,6%) were alive and 31 (35,6%) had died. Five patients were lost to follow-up. Twenty-six (29,9%) patients relapsed. The median follow-up time was 50 months ( range 4-187)..

Postoperative craniospinal radiotherapy of medulloblastoma in children and young adults

PURPOSE The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy). PATIENTS AND METHODS During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study end-points. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days). Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7%) patients. The majority of them (46 73%) received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years). Five-year overall survival (OS) was 51% and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p=0.0023) (Graph 2). Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p=0.0116). Significantly poorer survival was found in patients with meningitis developing in the postoperative period, with no patient living longer than two years (p=0.0134) (Graph 3). By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i. e. positive CSF cytology was not obtained, which was of statistical importance for survival (p=0.8207). Neither shunt placement nor shunt type showed any impact on survival (p=0.5307 and 0.7119, respectively). Children younger than three years had significantly poorer survival compared to those older than 16 years (p=0.0473). Although there was a better survival rate in females than in males this was not statistically significant (p=0.2386).The analysis results of treatment showed that significantly better survival occurred in patients in whom total or subtotal tumor removal was possible (p=0.0022) (Graph 4). Patients who started radiotherapy within two months after surgery have better survival, but again this was not statistically significant, probably due to the small number of patients receiving delayed radiotherapy (p=0.2231)(Graph5). CONCLUSION Based on this factors standard and high risk group could be defined. Combined chemotherapy should to be investigated particularly for high risk subgroup. Future research should be done to define new therapeutic modalities (gene therapy, compounds active in tumor antiangiogenesis etc)

Living unrelated donor kidney transplantation: A fourteen-year experience

Background. In countries without a national organization for retrieval and distribution of organs of the deceased donors, problem of organ shortage is still not resolved. In order to increase the number of kidney transplantations we started with the program of living unrelated - spousal donors. The aim of this study was to compare treatment outcome and renal graft function in patients receiving the graft from spousal and those receiving ghe graft from living related donors. Method. We retrospectively identified 14 patients who received renal allograft from spousal donors between 1996 and 2009 (group I). The control group consisted of 14 patients who got graft from related donor retrieved from the database and matched than with respect to sex, age, kidney disease, immunological and viral pretransplant status, the initial method of the end stage renal disease treatment and ABO compatibility. In the follow-up period of 41 ± 38 months we recorded immunosuppressive therapy, surgical complications, episodes of acute rejection, CMV infection and graft function, assessed by serum creatinine levels at the beginning and in the end of the follow-up period. All patients had pretransplant negative cross-match. In ABO incompatible patients pretransplant isoagglutinine titer was zero. Results. The patients with a spousal donor had worse HLA matching. There were no significant differences between the groups in surgical, infective, immunological complications and graft function. Two patients from the group I returned to hemodialysis after 82 and 22 months due to serious comorbidities. Conclusion. In spite of the worse HLA matching, graft survival and function of renal grafts from spousal donors were as good as those retrieved from related donors