Severe complications of nivolumab monotherapy in an adolescent with malignant melanoma.

This study presents a case of a 17-year-old female patient who had previously undergone surgical resection of melanoma in the right periscapular area. She was administered adjuvant treatment with the PD-1 inhibitor nivolumab as monotherapy. The mechanism of action of this drug is based on increased stimulation of the immune system. The patient developed a series of complications including capillary leak syndrome and hypothyroidism after the fifth cycle of therapy, as a result of dysregulation of immunity. Nivolumab treatment had to be discontinued and glucocorticosteroids were administered as a salvage therapy. After several months, two relapses developed in the subcutaneous tissue - first in the left and then in the right iliac region, confirmed as distant metastases of malignant melanoma, treated with resections of the lesions and intensity-modulated radiation therapy. Follow-up imaging studies and clinical examinations showed no metastases or pathologically enlarged lymph nodes.

Evaluation of Renal Function in Pediatric Patients After Treatment for Wilms' Tumor.

BACKGROUND: Wilms' tumor is the most common kidney cancer in children. Treatment consists of pre- and post-operative chemotherapy, surgery and in some cases radiotherapy. The treatment of nephroblastomas is very effective. Hence, the population of adult patients cured of this cancer in their childhood is steadily growing, generating a need for long-term health assessment, including renal function, due to the specifications of the therapy and the location of the tumor. OBJECTIVES: The aim of the study was to evaluate nephrological complications after treatment for nephroblastoma. MATERIAL AND METHODS: The study group consisted of 50 children treated in the Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation at Wroclaw Medical University (Poland) from 2002 to 2012. An analysis of the patients' medical histories was carried out. The glomerular filtration rate estimated by the Schwartz formula (GFR by Schwartz), serum creatinine levels, urea and electrolyte concentrations; the results of urinalysis and blood pressure were assessed. Each of these analyses was performed at the time of diagnosis, at the end of therapy, as well as 6 months, one year and two years after its completion. RESULTS: The study showed that, in most cases, implemented therapy had no significant impact on the deterioration of renal parameters in the two-year period following treatment for Wilms' tumor. However, the group of patients treated with cyclophosphamide and carboplatin required more careful monitoring, due to a higher risk of renal function deterioration. CONCLUSIONS: The study shows that the problem of nephrotoxicity after treatment for Wilms' tumor is more frequent than indicated in other studies; however, the deterioration of kidney function in most cases is not serious. Additional attention should be paid to patients treated with cyclophosphamide and carboplatin. Assessment of the early and late effects of the treatment is a key element in improving the quality of the patients' life.

The recovery of immune system parameters in children following lymphoblastic leukemia therapy - preliminary report.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric neoplasm. Long-term survival is achieved in approximately 80% of patients. One of the more common complications of ALL treatment is immunosuppression. OBJECTIVES: The aim of the study is to assess the reconstruction rate of the most important immune system parameters in children after ALL treatment. MATERIAL AND METHODS: The study included 47 children (22 boys, 25 girls) diagnosed and treated for ALL in Department of Pediatric Hematology and Oncology at Wroclaw Medical University. The study used peripheral blood collected at the time treatment was completed and in the first, second, third and sixth months following treatment, then at yearly intervals up to 10 years after treatment. In order to determine the immune status of the tested samples the following parameters were assessed: white blood cell count, absolute lymphocyte count, the proportions of individual subpopulations of lymphocytes - T (CD3 +), Th (CD4 +), Ts (CD8 +), B (CD19 +), NK (CD16 + 56 +), the concentration of immunoglobulins A, G and M, interleukin 10 activity, as well as the expression of ICAM-1 adhesion molecules. RESULTS: At the end of anti-neoplastic therapy a reduction in both the absolute number leukocytes and various subpopulations of lymphocytes was observed. The lower limits of normal range were achieved about two years after the end of treatment. The concentrations of immunoglobulin IgA, IgG and IgM at the end of treatment were within low normal limits. Normal concentrations of immunoglobulin levels and stability were observed about two years after the end of treatment. There was a slow, steady increase in the production of interleukin-10 and the expression of ICAM-1 adhesion molecules. These results confirm previous observations that after ALL treatment children are in an immunocompromised state for up to 12 months, in terms of both humoral and cellular immunity. CONCLUSIONS: Knowing the average growth trends for the main immune system parameters after ALL treatment can be important in clinical practice for children in whom immune reconstruction proceeds slowly. Predicting the expected time required to restore immune function could be of help, for example in combating infections and planning vaccinations.

Clinical factors in relapses of Wilms' tumor--results for the Polish Pediatric Solid Tumors Study Group.

BACKGROUND: The risk factors responsible for recurrences of Wilms' tumor (nephroblastoma) are still under discussion. The aim of the study was to analyze the relationship between relapses of Wilms' tumor and the patients' clinical history. MATERIAL AND METHODS: Clinical data from children registered in the Polish Pediatric Solid Tumors Study Group were analyzed. The clinical stages (CS), pathology variants (high risk: HR, intermediate risk: INT, and low risk: LOW) and chemotherapy regimens were correlated with the outcomes. RESULTS: Recurrences developed in 34 out of 288 (11.8%) patients with Wilms' tumor treated in accordance with International Society for Pediatric Oncology 2001 (SIOP 2001) protocols. Of these 34 patients, 11 initially had CS I, seven were at CS II, four were at CS III, 11 were at CS IV and one had CS V. There were eight patients with second recurrences; of these, seven were in the INT risk group and one in the high histological risk group. There was no correlation between age (p=0.256) or gender (p=0.538) and the risk of tumor recurrence. In the study group, seven out of 10 patients with local recurrences are alive; as are 13 out of 22 patients with distant recurrences (p=0.703). Those who died due to disease progression comprised six out of 26 patients with a first recurrence (four HR, two INT), and seven out of eight with a second recurrence (one HR, six INT). CONCLUSIONS: The prognosis after relapse in initially metastatic patients did not differ from that in patients who had primarily localized disease. The pathology variants probably had more significance.

Advances and changes in the treatment of children with nephroblastoma.

Wilms' tumor or nephroblastoma is the most common malignant tumor stemming from kidney cells and second only to neuroblastoma when it comes to extracranial solid tumors in children. The results of nephroblastoma treatment are a perfect example of therapeutic success resulting from an interdisciplinary approach to the problem and the cooperation of pediatric surgeons, pediatric oncologists, pathologists, radiologists and radiotherapists leading to precise diagnoses and the selection of the optimal treatment. At the end of the sixties, international research teams began studying the best treatment for this tumor in children. In Europe, it was the International Society of Paediatric Oncology (SIOP), which has used the working name SIOP- RTSG (Renal Tumor Study Group - Group for the Study of Kidney tumors) since 2008 and in North America NWTS (National Wilms' Tumor Study - The National Committee for Research on Wilms' tumor). Summarizing the experience and knowledge on the treatment of nephroblastoma, it should be noted that, despite years of research and information exchange, uniform guidelines have not yet been developed, and there are still differences in treatment of this tumor. The biggest differences are between the "American" treatment recommended by the NWTS and the "European" by SIOP. In the first it is recommended to start treatment from the surgical removal of the tumor, even in the case of disseminated disease with the presence of metastases in the lungs. The treatment method is chosen by the institution managing the patient; for this reason on the American continent in Brazil, Wilms' tumor is treated according to the recommendations of "European" protocols (SIOP) and some institutions in Europe, for example in Italy, treat patients with nephroblastoma according to the "American" protocols recommended by the NWTS; until recently, focal disease was treated with primary nephrectomy in the UK.

Adult Wilms tumour.

BACKGROUND: Wilms tumour is the most common renal tumour in children, accounting for above 90% of cases and comprising 8% of paediatric solid tumours. In adults, it is extremely rare and represents only 0.5% of all renal tumours. We reviewed 9 patients older than 16 years: three were treated in the Department of Paediatric Surgery and three in the Department of Urology; additionally, 3 patients were referred to us for consultation with regard to further treatment after having been operated on previously in other centres. Clinical presentation, stage distribution, histology, treatment, and prognosis of all the patients are presented. PATIENTS AND METHODS: The age of 9 patients ranged from 17 to 32 years: there were 8 men and 1 women. Tumour stages were defined according to SIOP classification: 4 were of local stage II, 3 of stage III, and 2 of stage IV with metastases to lungs and bones. Three of them were treated according to the paediatric protocol of the Society of Paediatric Oncology (SIOP 93-01 protocol)-all after a fine-needle biopsy which confirmed nephroblastoma, received preoperative chemotherapy of two drugs (VCR + ACT D) during 4 weeks. Histological studies revealed a low-risk cystic tumour in one case, intermediate-risk tumour in 2 patients, and high-risk tumour with blastemal predominance or with the presence of diffuse anaplasia in 5 patients. One tumour was defined as a mixed high-risk tumour: renal cell carcinoma with nephroblastoma of blastemal predominance. RESULTS: Complete remission was achieved in 3 patients. Three relapsed after complete remission of 6-30 months. A second-line therapy was undertaken in these patients as well as in those who had undergone the initial treatment elsewhere. But the second-line therapy proved ineffective. CONCLUSIONS: Adult patients with Wilms tumour have more aggressive histology and poorer prognosis than children.

Thymic carcinoma in children: a report from the Polish Pediatric Rare Tumors Study.

BACKGROUND: Invasive thymomas and thymic carcinomas are rare tumors jointly accounting between 0.2% and 1.5% of malignancies in adults. They are usually at an advanced stage when diagnosed and have both high recurrence and poor survival rates. In this report, the aim is to explore our experience in the treatment of thymic carcinomas in Polish children. PROCEDURE: The clinical data of nine children with thymic carcinomas, treated between 1992 and 2008 in the Polish oncological and surgical centers was retrospectively analyzed. RESULTS: In five cases, presenting symptoms resulted from the compression of the respiratory ways by the mediastinal tumor. In two children paraneoplastic autoimmune syndromes were associated with thymic carcinoma. In accordance with the Masaoka classification, two patients had stage II, five had stage III, and two had stage IV of the disease. Diagnostic biopsy of mediastinal tumor was performed on eight patients and one underwent complete primary resection and subsequently received radiotherapy; he has passed 11 years since the conclusion of therapy. Six patients received multi-drug chemotherapy with or without steroids. Delayed surgery was performed in four children (R0-2, R1-1, and R2-1). After complete resection, one child received chemotherapy. In three patients, chemotherapy and radiotherapy was administered. Seven patients died, including six due to progression of the disease with the other as a result of complications following chemotherapy; only two patients classed at stage II remain alive. CONCLUSIONS: Most thymic tumors in pediatric patients are inoperable at diagnosis, which results in poor prognosis. Improved chemotherapy approaches are needed.

[Evaluation of selected endocrine complications in patients treated with auto- and allo-haematopoietic stem cell transplantation]. / Ocena wybranych powiklan endokrynologicznych u pacjentów po autologicznym i allogenicznym przeszczepie krwiotwórczych komórek macierzystych.

AIM: The aim of this study was to evaluate the endocrine complications, in particular disorders of growth and thyroid function and glucose metabolism dysfunctions in patients treated with allo- and auto-haematopoietic stem cell transplantation (HSCT). MATERIAL AND METHODS: The investigated group consisted of: I. 16 patients after auto-HSCT (6 girls, 10 boys) aged 3-20 years (average 10,8+/-) because of acute myelogenous leukaemia (n=5), non Hodgkin lymphoma (n=3), neuroblastoma (n=3), embryonal cancer (n=2), medulloblastoma (n=1), Ewing's sarcoma/PNET (n=1), hyper eosinophilic syndrome (n=1). High dose chemiotherapy (HDC/T) included: BU/MEL (busulfan/melfalan) (n=7), BEAM (carmustine, eteposide, cytosine arabinose, melfalan) (n=3). II. 30 patients after allo-HSCT (20 girls, 10 boys) aged 3-17 years (average 9,56). Indication for HSCT was acute lymphoblastic leukaemia (n=11), acute myelogenous leukaemia (n=5), chronic myeloid leukaemia-CML (n=6), myelodysplastic syndromes (n=2), non Hodgkin lymphoma (n=1), juvenile myelomonocytic leukemia (n=1), severe aplastic anaemia (n=1), Blackfan-Diamond anaemia (n=1), severe combined immune deficiency (n=1), rhabdomyosarcoma (n=1). The patients underwent the following types of transplantation: HSCT of matched sibling donor (n=13), HSCT of matched unrelated donor (n=11) and HLA-mismatched related donor (n=6). The preparative regimens consisted of HDC/T usually BU/MEL (n=3); BU/CY/VP (busulfan, cyclophosphamide, etoposide) (6); BU/CY/ATG (anti-thymocyte globulin) (n=5), VP/ATG/TBI (total body irradiation) (n=3). 19 children received CI (cranial irradiation) prior to grafting: auto-HSCT (n=6) and allo-HSCT (n=13) and 6 patients underwent TBI. 18 children received high steroid doses at least 28 days before transplant, 4 patients in the auto-HSCT group, and in the allo-HSCT group 14 patients before and 20 after HSCT procedure. The analysis of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), hemoglobin A1c (HbA1c), prolactine (PRL), oral glucose tolerance test, growth hormone (GH test) and thyrotropin releasing hormone (TRH) test was performed in each case. RESULTS: Hypothyroidism was found in 5 patients (3 after allo-HSCT, 2 after auto-HSCT). Thyroid hormone substitution was applied. No case of hyperthyroidism was diagnosed. Growth deficit was found in 8 patients (6 girls, 2 boys) between 13 to 70 months after allo-transplantation (average 36 months). Three children from the above group received CI. Growth hormone substitution was applied in 1 girl (ALL, HLA MM REL, CI). An impaired excretion of GH after stimulation was diagnosed in 14 pts (10 after allo-HSCT, 4 after auto-HSCT). The growth process should still be observed in this subgroup. Glucose intolerance was found in 7 patients: in 4 treated with auto-HSCT and in 3 after allo-HSCT. Diabetes mellitus was diagnosed in none of them. An impaired glucose tolerance curve with increased excretion of insulin was diagnosed in 12 children. CONCLUSIONS: Early endocrinological care is necessary in patients treated both with auto-HSCT and allo-HSCT due to high risk of hormonal disorders.

[Thymoma and thymic carcinoma--review of literature and clinical characteristics based on the Polish Paediatric Solid Tumours Study Group experience]. / Grasiczaki i raki grasicy--przeglad pismiennictwa i charakterystyka kliniczna w oparciu o dane Polskiej Pediatrycznej Grupy Guzów Litych.

Thymomas and thymic carcinomas are rare neoplasms derived from the epithelial tissue of thymus, very infrequently developing in young adults and children. The estimation of thymomas' invasiveness has been the matter of discussion for many years reflected by numerous clinical and histological classifications. In 1999 the WHO classification was created, joining all the most important issues present in previously used systems. It is believed that histological structure is the most important prognostic factor in thymic carcinomas while in less aggressive types of thymomas the clinical stages influence the outcome. Staging of thymomas is most commonly based on the Masoka classification. Independent evaluation of the stage and histological aggressiveness are necessary to predict the clinical course and outcome in thymomas. Thus the term 'malignant thymoma' has been replaced by 'invasive thymoma' in clinical practice. The treatment strategy depends on the clinical stages of thymoma. Complete resection of the tumour is the treatment of choice with supplementing radiotherapy in more advanced clinical stages. Chemotherapy in invasive thymomas has been reported to play an increasingly important role as induction, supplementing and palliative therapy. It has been proved that combined treatment improves the outcome in invasive thymomas, especially in thymic carcinomas. This paper reviews the literature data concerning the histology, clinical issues and treatment of thymomas and thymic carcinomas. The clinical data on nine children with thymic carcinomas treated between 1992 and 2006 in the Polish oncological and surgical centres were also analysed and presented. Based on multicentre data we were able to conclude the following: 1. Thymic carcinomas in children are very rare and that is why early diagnosis is often difficult. 2. At diagnosis most cases are already inoperable, which results in poorer prognosis. 3. Complex adjuvant chemo- and radiotherapy in childhood thymic carcinomas seem to prolong overall survival. 4. Further detailed analysis in all the cases of thymic carcinomas in children is recommended in order to estimate the optimal strategy of treatment.

[What to improve in approach to diagnose and treat pediatric myelodysplastic syndromes and juvenile myelomonocytic leukemia in Poland?]. / Jak poprawic diagnostyke i leczenie dzieciecych zespolów mielodysplastycznych i mlodzienczej bialaczki mielomonocytowej w Polsce?

Group of heterogeneous clonal hematopoietic disorders usually associated with other genetic disorders called for myelodysplastic syndromes (MDS) are occurring less common in children. The WHO classification based on French-American-British (FAB) MDS morphology is widely accepted in adults but does substantially differe from the one applicable in children. The differencies have recently been published. In our national retrospective study we analyzed 99 children with MDS and JMML diagnosed between 1989 and 2003 in Poland. Chemotherapy is generally, not useful in childhood MDS. With a few exceptions hematopoieitic stem cell transplantation (HSCT) is the only curative treatment for children with MDS. In this nationalexperience use of a relative or an unrelated donor results are almost comparable to the internationally published ones. Successful management of the disease needs to be run on a basis of cooperative efforts between clinicians and scientists involved in pediatric MDS. This includes need for centralized update and morphologic re-evaluation of all patients in the country as well as appointments on a regular basis for all individuals involved in treatment of MDS for quality control.

[Analysis of some risk factors for abnormal growth velocity in children treated with haematopoetic stem cell transplantation]. / Analiza wybranych czynników ryzyka zahamowania tempa wzrastania u dzieci po przeszczepie komórek hematopoetycznych.

BACKGROUND: Late effects following haematopoietic stem cell transplantation occur both in children and adults. Endocrine impairment may cause abnormal growth velocity and impaired growth in children. OBJECTIVE: To assess the influence of preparative regimen-high dose chemotherapy and/or cranial irradiation as risk factors for growth impairment. MATERIAL AND METHODS: 30 children underwent haematopoetic stem cell transplantation (19 girls, 11 boys) aged 2-20 years, with autologous (N=9) or allogeneic (N=21) maneuver. 14 children received cranial irradiation prior to grafting: 18 Gy (N=10) and 24 Gy (N-4), high doses chemotherapy included Busulfan/Melphalan (N=6), Cyclophosphamide/Busulfan/ Etoposide (N=6) and total body irradiation with 12 Gy (N=2). Thyroid function was evaluated prior to and after grafting. Growth hormone secretion with standard provocative test were analyzed. Bone age was estimated. State of nutrition 12 to 5 months before and after transplantation, WLI (weight-for-length index) and BMI (body mass index) were evaluated. Abnormal growth velocity denotes decrease > or =1 SD. RESULTS: 1. Cyclophosphamide statistically significantly blunted growth velocity 4 (n=28; p=0.046; r=0.4). 2. Significant correlation (n=28; p=0.0184; r=0.45) was found between abnormal gonadal function and Busulfan. 3. Cranial irradiation prior to preparative regimen impaired growth more significantly than high dose chemotherapy (n=28; p=0.0044). 4. Evaluated WLI determined short stature after transplantation (n=26; p<0.001). CONCLUSION: Hematopoietic stem cell transplantation causes long term endocrine complications especially impaired growth.

[Rare tumours--are they really rare in the Polish children population?]. / Nowotwory rzadkie--czy rzeczywiscie rzadkie w populacji polskich dzieci?

Clear statement that pediatric neoplasms are really rare is not easy. Thus the incidence of rare tumours in children has not been defined so far. The paper efforts to assess the topic of rare tumours of childhood in the Polish population. Following two categories are proposed: tumours typical for adults, but possible in children (neoplasms of epithelial origin--mainly carcinomas, melanomas, carcinoids) and paediatric tumours consisting less than 10% of cases in corresponding clinical groups according to the ICCC classification. Data on 317 patients aged 0-18 years treated in centres associated in the Polish Paediatric Group for Solid Tumours (PPGST) were analysed. Classical adult malignancies were registered in 130 patients: carcinomas in 90 (mean age 12.6 +/- 4.5 years), melanomas in 25 (mean age 9.4 +/- 4.9) and carcinoids in 9 (mean age 14.5 +/- 1.2 years). Non epithelial neoplasms were registered in 187 patients (mean age 10.4 +/- 5.5). That group included rare tumours of soft tissue, CNS, bones and other organs. Treatments of certain groups were specified by separate therapeutic protocols within PPGST. Rare malignancies of adult-type among children under 18 years of age in Poland comprised 1.5% of all pediatric neoplasms. The incidence of adult-type neoplasms increased with age until 14 years. In patients over 15 years of age the number of registered cases decreased. It may suggest a first peak of incidence in early adolescence or an underestimation of number of patients with carcinoma aged over 15 years. In the analyzed group, the mean age of patients with carcinomas and other epithelial and unspecified tumours significantly exceeded the age of children with rare neoplasms of non-epithelial origin (12.1 +/- 4.7 vs 10.4 +/- 5.5 years; p<0.05). A very young age at diagnosis of malignant melanomas (mean 9.4 years) and numerous cases of carcinomas affecting the digestive tract (n=24; 27% of all carcinomas), especially those located in colorectal region (n=10), seem surprising. The preliminary analysis of the collected data on rare neoplasms in Poland encourage to undertake a prospective study, meant to link the epidemiology and characteristics of rare epithelial tumours in childhood with diagnostic and therapeutic suggestions for these types that are not coordinated within Polish Paediatric Group of Solid Tumours.