Predictors of pulmonary metastases on chest computed tomography in children and adolescents with osteosarcoma-tips for qualifying patients for thoracotomy.

BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Lungs are the most frequent and often the only site of metastatic disease. The presence of pulmonary metastases is a significant unfavourable prognostic factor. Thoracotomy is strongly recommended in these patients, while computed tomography (CT) remains the gold imaging standard. The purpose of our study was to create tools for the CT-based qualification for thoracotomy in osteosarcoma patients in order to reduce the rate of useless thoracotomies. METHODS: Sixty-four osteosarcoma paediatric patients suspected of lung metastases on CT and their first-time thoracotomies (n = 100) were included in this retrospective analysis. All CT scans were analysed using a compartmental evaluation method based on the number and size of nodules. Calcification and location of lung lesions were also analysed. Inter-observer reliability between two experienced radiologists was assessed. The CT findings were then correlated with the histopathological results of thoracotomies. Various multivariate predictive models (logistic regression, classification tree and random forest) were built and predictors of lung metastases were identified. RESULTS: All applied models proved that calcified nodules on the preoperative CT scan best predict the presence of pulmonary metastases. The rating of the operated lung on the preoperative CT scan, dependent on the number and size of nodules, and the total number of nodules on this scan were also found to be important predictors. All three models achieved a relatively high sensitivity (72-92%), positive predictive value (81-90%) and accuracy (74-79%). The positive predictive value of each model was higher than of the qualification for thoracotomy performed at the time of treatment. Inter-observer reliability was at least substantial for qualitative variables and excellent for quantitative variables. CONCLUSIONS: The multivariate models built and tested in our study may be useful in the qualification of osteosarcoma patients for metastasectomy through thoracotomy and may contribute to reducing the rate of unnecessary invasive procedures in the future.

Application of array comparative genomic hybridization (aCGH) for identification of chromosomal aberrations in the recurrent pregnancy loss.

Spontaneous abortion occurs in 8-20% of recognized pregnancies and usually takes place in the first trimester (7-11 weeks). There are many causes of pregnancy loss, but the most important (about 75%) is the presence of chromosomal aberrations. We present the results of oligonucleotide array application in a cohort of 62 miscarriage cases. The inclusion criteria for the study were the loss after 8th week of pregnancy and the appearance of recurrent miscarriages. DNA was extracted from trophoblast or fetal skin fibroblasts. In the 62 tested materials from recurrent miscarriages, the detection rate was 56.5% (35/62). The most commonly found were aneuploidies (65%) (chromosomal trisomy 14, 16, 18, 21, and 22), Turner syndrome, and triploidy (17.1%). Other chromosomal abnormalities included pathogenic and likely pathogenic structural aberrations: 1) pathogenic: deletion 7p22.3p12.3 and duplication 9p24.3p13.2 inherited from the normal father, deletion 3q13.31q22.2 and deletion 3q22.3q23 of unknown inheritance and duplication of 17p12 inherited from father with foot malformation; 2) likely pathogenic variants: deletion 17p13.1 inherited from normal mother, deletion 5q14.3 of unknown inheritance and de novo deletion 1q21.1q21.2. Among these aberrations, six CNVs (copy number variants) were responsible for the miscarriage: deletion 7p22.3p12.3 and duplication 9p24.3p13.2, deletion 3q13.31q22.2 and deletion 3q22.3q23, and deletion 17p13.1 and deletion 1q21.1q21.2. Other two findings were classified as incidental findings (deletion 5q14.3 and 17p12 duplication). Our research shows that 17% of the aberrations (6/35 abnormal results) that cannot be identified by the routine kariotype analysis are structural aberrations containing genes important for fetal development, the mutations of which may cause spontaneous abortion.

Predicting Ewing Sarcoma Treatment Outcome Using Infrared Spectroscopy and Machine Learning.

BACKGROUND: Improved outcome prediction is vital for the delivery of risk-adjusted, appropriate and effective care to paediatric patients with Ewing sarcoma-the second most common paediatric malignant bone tumour. Fourier transform infrared (FTIR) spectroscopy of tissues allows the bulk biochemical content of a biological sample to be probed and makes possible the study and diagnosis of disease. METHODS: In this retrospective study, FTIR spectra of sections of biopsy-obtained bone tissue were recorded. Twenty-seven patients (between 5 and 20 years of age) with newly diagnosed Ewing sarcoma of bone were included in this study. The prognostic value of FTIR spectra obtained from Ewing sarcoma (ES) tumours before and after neoadjuvant chemotherapy were analysed in combination with various data-reduction and machine learning approaches. RESULTS: Random forest and linear discriminant analysis supervised learning models were able to correctly predict patient mortality in 92% of cases using leave-one-out cross-validation. The best performing model for predicting patient relapse was a linear Support Vector Machine trained on the observed spectral changes as a result of chemotherapy treatment, which achieved 92% accuracy. CONCLUSION: FTIR spectra of tumour biopsy samples may predict treatment outcome in paediatric Ewing sarcoma patients with greater than 92% accuracy.

Malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like tumor of the gastrointestinal tract) of the small intestine in a 12-year-old boy.

The aim of this paper is a clinical and anatomopathological demonstration of a malignant lesion, a gastrointestinal neuroectodermal tumor (GNET), as an exceedingly rare cause of ileus in the pediatric population. Specifically, we present the case of a 12-year-old boy who showed dramatic weight loss, hypochromic anemia, fever, dehydration, exaggerated granulation of the terminal ileum, and mechanical ileus due to the obstruction by an intramural tumor of the small intestine. A 50cm-long part of the small intestine with pathological stricture was surgically removed, sampled and routinely fixed and stained with hematoxylin and eosin. The additional immunostains that were preformed were: PAS, S-100, HMB-45, NSE, LCA, CK AE1 / AE3, desmin, SMA, vimentin, CD99, NSE, synaptophysin, WT-1, calretinin, and DOG-1. Moreover, fluorescent in situ hybridization (FISH) with the EWSR1 Break Apart FISH Probe was applied. The neoplasm was composed of nests and alveolar patterns of frankly malignant clear cells with immunoreactivity to S-100, vimentin, and CD 99. The FISH technique detected chromosomal breaking at 22q12. The tumor metastasized to both the mesenteric lymph nodes and a number of hepatic segments. With several chemotherapy protocols, repeat laparotomies, and liver thermal ablations, the patient had a 1.5-year-long survival from the moment of diagnosis. The diagnosis of this malignancy requires both histopathological evaluation and molecular analysis, and the follow-up is based on careful clinical imaging of the neoplastic spread in order to apply proper surgical and oncological treatments. In conclusion, the clinical course of GNET was highly aggressive.

The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults.

Ezrin is a protein that functions as a cross-linker between actin cytoskeleton and plasma membrane. Its clinical role in osteosarcoma is unclear. The aim of this study was to investigate, in osteosarcoma, the prognostic value of ezrin expression at biopsy and changes in expression levels after preoperative chemotherapy. Thirty-eight newly diagnosed osteosarcoma patients aged 6-23 years were included. At diagnosis, 20 patients had localized disease, the others had distant metastases. Median follow-up was 75 months (range 13-135). Ezrin expression was assessed immunohistochemically in biopsy tissue and primary tumour specimens resected after chemotherapy. The influence on survival of changes in ezrin expression after chemotherapy was analysed. Ezrin expression was significantly higher after preoperative chemotherapy and changes compared to biopsy tissue were significantly lower in patients with early progression than in patients with relapse or no further evidence of disease (p = 0.006 and p = 0.002, respectively). Similarly, ezrin expression was higher after preoperative chemotherapy and exhibited less change in expression in deceased patients compared to patients surviving more than 5 years (both p = 0.001). Ezrin expression at biopsy was significantly associated with both histopathological aggressiveness (p < 0.001) and tumour size (p = 0.037). The results of this study provide evidence that changes in overexpression of ezrin due to preoperative chemotherapy could be a useful predictive and prognostic marker in patients with osteosarcoma.

Giant congenital melanocytic nevi: selected aspects of diagnostics and treatment.

BACKGROUND: Treatment of giant melanocytic nevi (GMN) remains a multidisciplinary challenge. We present analysis of diagnostics, treatment, and follow- up in children with GMN to establish obligatory procedures in these patients. MATERIAL/METHODS: In 24 children with GMN, we analyzed: localization, main nevus diameter, satellite nevi, brain MRI, catecholamines concentrations in 24-h urine collection, surgery stages number, and histological examinations. The t test was used to compare catecholamines concentrations in patient subgroups. RESULTS: Nine children had "bathing trunk" nevus, 7 had main nevus on the back, 6 on head/neck, and 2 on neck/shoulder and neck/thorax. Brain MRI revealed neurocutaneous melanosis (NCM) in 7/24 children (29.2%), symptomatic in 1. Among urine catecholamines levels from 20 patients (33 samples), dopamine concentration was elevated in 28/33, noradrenaline in 15, adrenaline in 11, and vanillylmandelic acid in 4. In 6 NCM children, all catecholamines concentrations were higher than in patients without NCM (statistically insignificant). In all patients, histological examination of excised nevi revealed compound nevus, with neurofibromatic component in 15 and melanoma in 2. They remain without recurrence/metastases at 8- and 3-year-follow-up. There were 4/7 NCM patients with more than 1 follow-up MRI; in 1 a new melanin deposit was found and in 3 there was no progression. CONCLUSIONS: Early excision with histological examination speeds the diagnosis of melanoma. Brain MRI is necessary to confirm/rule-out NCM. High urine dopamine concentration in GMN children, especially with NCM, is an unpublished finding that can indicate patients with more serious neurological disease. Treatment of GMN children should be tailored individually for each case with respect to all medical/psychological aspects.

Suspicion of Recurrent Osteosarcoma in a Patient with Pseudotumour Adjacent To the Endoprosthesis.

Purpose: Pseudotumor is a rare complication after arthroplasty, most often of the hip joint, in response to metal particles present in the implant. There are merely sporadic reports of pseudotumor in patients with bone sarcoma after sparing surgery with endoprosthesis implant. The aim of this study is to present the characteristic imaging features of pseudotumor. Case report: We present a case of a 21-year-old male patient in whom a scheduled follow-up ultrasound revealed a painless lesion suspected of local recurrence at the border of the endoprosthesis and the bone stump 3.5 years after the end of treatment for osteosarcoma of the femur. Histopathology of the biopsy specimen revealed that the lesion was a pseudotumor. Conclusions: Although pseudotumor is sporadic in patients treated with endoprosthesis for bone sarcoma, their prolonged survival could bear the risk of such a complication. Imaging studies, in particular ultrasound, may be helpful in differentiating from local recurrence of sarcoma, however, the histopathology of the specimen obtained by open biopsy at a reference center is crucial for the final diagnosis.

A prognostic evaluation of vascular endothelial growth factor in children and young adults with osteosarcoma.

BACKGROUND: The potential role of VEGF in osteosarcoma has been evaluated in several studies. The majority of them included heterogeneous and limited series of patients, giving conflicting results. The aim of presented study is to evaluate the prognostic role of VEGF-A in biopsy samples of clinically homogeneous group of osteosarcoma patients with at least 5 years of follow up. MATERIALS AND METHODS: VEGF-A was assessed immunohistochemically in the pre-treatment biopsy samples of 91 patients (mean age 14 years; range, 4-23 years) with primary, high-grade, non-metastatic osteosarcoma localized in extremities. The survival of each patient was assessed after at least 5-year follow-up period. RESULTS: VEGF-A over 50% of positive tumor cells was observed in 39% of cases and was linked to patients age below 14-year old (P = 0.025) and tumor size more than 8 cm (P = 0.054). VEGF-A was associated with a significantly decreased both overall survival (P = 0.006) and progression-free survival (P = 0.011). In the Cox proportional hazard model it was confirmed that VEGF-A expression in the biopsy samples was an independent prognostic factor of unfavorable survival in osteosarcoma (HR 2.51; 95% CI: 1.12-5.66). CONCLUSION: The expression of VEGF-A in the biopsy sample is the potential marker for predicting the course and outcome of osteosarcoma.

The retrospective molecular analysis of large or giant congenital melanocytic nevi in a group of Polish children.

BACKGROUND: Large and giant congenital melanocytic nevi (CMN), benign naevomelanocytic proliferations derived from neural crests, with a projected adult size (PAS) ≥ 20 cm, are connected to a high risk of melanoma and neurocutaneous melanosis. Among several factors, genetic alterations seem to be involved in tumorigenesis. The aim of the present study was to analyse the mutation status of NRAS and BRAF genes in resection specimens from large or giant CMN in a group of Polish patients. MATERIAL AND METHODS: The formalin-fixed, paraffin-embedded resection specimens from 18 patients, fixed in the years of 2006 to 2017, were included in the study. The regions containing the highest load of melanocytes were macrodissected prior to DNA isolation. The NRAS and BRAF mutation status was evaluated using qPCR. RESULTS: We detected activating mutations in NRAS gene (codons: 12 and 61) in 7 out of the 18 (38.9%) patients. No BRAF mutations were found. CONCLUSION: Our study, the first molecular analysis of large/giant CMN in Polish patients, supports the hypothesis that NRAS mutation in codon 61 are frequent, recurrent mutations in large/giant CMN. Moreover, we show, for the first time, that NRAS mutations in codon 12 (p.Gly12Asp) can be also detected in giant CMN. The exact role of these genetic alterations in CMN formation remains to be elucidated.

Post-zygotic diploidization of triploidy in human is possible? - a case of triploid partial molar pregnancy resulting in a premature live-born diploid female infant.

OBJECTIVE: During the treatment of our patient we found that reports covering possible complications and their treatment are very scarce. Due to advancement in ultrasound diagnosis most of molar pregnancies are terminated in first trimester of pregnancy. There is the gap in knowledge concerning pregnancy complications in case of partial mole discovered in advanced pregnancy. This is why we incorporated extensive and up-to-date review of literature in our manuscript. METHOD: We described a case of previously healthy, 25 year old primigravida who delivered live daughter at 27 weeks of gestation, complicated with unusual ultrasound appearance of the placenta, severe hypotrophy, and subsequent post-partum eclampsia. RESULTS: Healthy diploid female infant, now two years old and healthy mother taking care of her. CONCLUSIONS: In clinical practice early diagnosis of this complication usually lead to pregnancy termination. In modern medicine, decisions should be based on evidence and patient-doctor mutual understanding. Termination of pregnancy with suspicion of molar placenta can be specially difficult in gestation in older nulliparous women or after ART. We sincerely hope that this report will be useful for physicians across the world in counseling and treating their patients.

Distinguishing Ewing sarcoma and osteomyelitis using FTIR spectroscopy.

The differential diagnosis of Ewing sarcoma and osteomyelitis can be challenging and can lead to delays in treatment with possibly devastating results. In this retrospective, small-cohort study we demonstrate, that the Fourier Transformed Infrared (FTIR) spectra of osteomyelitis bone tissue can be differentiated from Ewing sarcoma and normal bone tissue sampled outside tumour area. Significant differences in osteomyelitis samples can be seen in lipid and protein composition. Supervised learning using a quadratic discriminant analysis classifier was able to differentiate the osteomyelitis samples with high accuracy. FTIR spectroscopy, alongside routine radiological and histopathological methods, may offer an additional tool for the differential diagnosis of osteomyelitis and ES.

Prediction of Ewing Sarcoma treatment outcome using attenuated tissue reflection FTIR tissue spectroscopy.

Ewing sarcoma is the second most common type of primary bone cancer and predominantly affects children and young people. Improved outcome prediction is key to delivering risk-adjusted, appropriate and effective care to cancer patients. Advances in the Fourier Transform Infrared (FTIR) spectroscopy of tissues enable it to be a non-invasive method to obtain information about the biochemical content of any biological sample. In this retrospective study, attenuated tissue reflection FTIR spectroscopy of biopsy samples from paediatric patients reveals spectral features that are diagnostic for Ewing Sarcoma. Furthermore, our results suggest that spectral features such as these may be of value for the prediction of treatment outcome independent to well-known, routinely used risk factors.

Management and follow-up of Ewing sarcoma patients with isolated lung metastases.

BACKGROUND: Ewing sarcoma (ES) is the second most common pediatric malignant bone tumor with a wide spectrum of clinical presentations. Although metastatic disease to the lungs is often the cause of death, isolated lung metastases at diagnosis are not frequent. The specific role of chemotherapy, surgery, and lung radiation has not been clearly defined. We investigated prognostic factors and the impact of the different treatment modalities in a cohort of patients with ES with isolated lung metastases. MATERIALS AND METHODS: Thirty-eight patients with ES and isolated lung metastases were treated using modern multimodal therapy during the period 2000-2014. According to the imaging characteristics of lung nodules patients were allocated into one of four treatment groups: "0" without nodules, "1" one solitary nodule of <0.5cm or several nodules of <0.3cm, "2" solitary nodule of 0.5-1cm or multiple nodules of 0.3-0.5cm, "3" one pulmonary/pleural nodule of >1cm, or more than one nodule of >0.5cm. Factors predictive of outcome were analyzed. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. RESULTS: Treatment of the lung metastases was performed in 23 cases (60.5%): twenty patients underwent lung surgery, 6 of them received additional postoperative whole lung radiation; three patients received lung radiation only. Malignant cells were found in all lung nodules of patients from group "3", in 5 (62.5%) patients from group "2", and none of the group "1". There was a correlation between histological response of the primary tumor and outcome. Three-year estimates of EFS and OS were 45.19% and 60.7%, respectively. Patients with good response measured by chest CT had significantly better EFS than patients with poor response (81% vs. 27.66%, respectively, p=0.006). CONCLUSIONS: Metastatectomy may have a role in the treatment of highly selected patients with ES and isolated lung metastases depending on the histologic response to therapy. Further studies are needed to better define the use of surgery and the response-adapted criteria in the upfront management of this population.

[Neuroblastoma: epidemiology, pathomorphological and molecular diagnosis, prognosis]. / Neuroblastoma--epidemiologia, diagnostyka patomorfologiczna i molekularna, prognoza.

Neuroblastoma is the third most common neoplasm of childhood. About 70% of cases occurs by 5 years old and around 95% cases in the patients younger than 10 years old. Neuroblastoma is part of the spectrum of the family neuroblastic tumors. The family consists of heterogeneous group of tumors, difficult to classify. Additionally some cases of neuroblastoma show tendency to self-maturation and regression. The family consists of neuroblastoma (NB), ganglio-neuroblastoma (GNB) and ganglineuroma (GN). In recent years there has been considerable development in the classification concepts from purely histological to clinico-pathological one. These schemes include clinical, pathological and molecular features od tumors which allow more accurate prognostication.

Neurocutaneous melanosis in children with giant congenital melanocytic nevi.

Twenty-four children with giant congenital melanocytic nevi underwent brain MRI at 1.5 T scanner. Melanin deposits in the brain were found in seven children (29.2%) located in temporal lobes, thalamus, cerebellum, and pons. One patient showed leptomeningeal involvement. Six patients were asymptomatic, and one had epilepsy. As opposed to previous reports, localization of skin nevi on anterior part of trunk was correlated to central nervous system involvement. In all patients with brain involvement skin nevi showed picture of compound nevus with neurofibromatic component.

Congenital glioblastoma coexisting with vascular developmental anomaly.

Congenital central nervous tumours form a unique group of neoplasms. They are different from other tumour groups not only due to the onset time but also to their histopathology, anatomic location, and biologic behaviour. Congenital glioblastoma is one of the rarest types of congenital brain tumours and is uncommon in the prenatal period. We report a rare case of congenital glioblastoma detected prenatally by ultrasound examination and magnetic resonance imaging at 26 gestational weeks. Based on MRI findings and consultation of a team of specialists, pregnancy was terminated at 28 weeks. The newborn presented hydrops foetal. The child died shortly after birth due to cardiorespiratory insufficiency. At autopsy a large tumour with a spongy-like appearance was found. The tumour involved nearly the whole right cerebral hemisphere and led to marked hydrocephalus. In the histological and immunohistochemical examination, the tumour presented features of glioblastoma. Neoplastic cells were immunopositive for GFAP, S-100 protein and negative for neuronal markers. Frequent mitoses and high MIB-1 labelling index were seen in the tumour areas. The coexistence of tumour and vascular developmental anomaly was stated. The conglomerates of numerous, distended, thin-walled foetal-like blood vessels were located beside the tumour tissue, which presented disturbance in differentiation and maturation of the vascular net. Such coexistence of malignant glioma with vascular developmental anomaly is unique.

Case report. Cervical spinal tuberculosis.

Cervical spinal tuberculosis is a rare variant of extra-pulmonary tuberculosis. We present the case of Vietnamese woman, aged 48, who was admitted to the Department of Neurosurgery because of a cervical spine (C7) compression fracture. Several months earlier, the patient complained of neck pain and numbness of the hands. On physical examination, the woman was subfebrile and complained of pain over the cervical spinal area. Neurological examination revealed no focal motor weakness. The roentgenograms of chest, pelvis and cranium were without pathological changes. Abdominal ultrasonography was normal. Radioisotope bone-scanning showed abnormal accumulation of isotope in the lower cervical region, thoracic vertebra, as well as in the articulations of knees and shoulders and in the left tibial bone. An MRI scan revealed compression fracture of the C7 vertebral body with infiltration of paraspinal tissues at the vertebral column with indentation of osseous masses into the spinal canal. The lesion resembled neoplasm metastasis. The neoplasm infiltrating vertebral body C7, two discs, C6-C7 and C7-Th1, and ligament were removed surgically. Neuropathological examination of the removed material showed typical granulomatous inflammation with characteristic infiltrate of lymphocytes, epithelioid macrophages and Langhans-type multi-nucleated giant cells. The spoligotyping method confirmed the presence of Mycobacterium tuberculosis complex in the specimens.