How we treat endocrine complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), and have emerged as a powerful new tool for oncologists. As these immune checkpoints are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects. Endocrine complications are among the most common, including hypophysitis, thyroid dysfunction, diabetes mellitus and primary adrenal insufficiency, while autoimmune polyendocrine syndrome type 2 (APS-2) may also present. The aim of this article is to critically appraise the literature and present (i) the biological role and function of the main ICs, (ii) the use of ICIs in the treatment of various cancer types, (iii) the endocrine complications of cancer immunotherapy with ICIs and (iv) practical recommendations for screening and management of patients with such endocrinopathies in everyday clinical practice.

Differential diagnosis of Spitzoid melanocytic neoplasms.

Atypical Spitzoid neoplasms represent a controversial and incompletely defined diagnostic category for lesions with intermediate architecture and cytomorphology between Spitz nevus and melanoma. The vast majority of these neoplasms have a good overall prognosis. Only a small proportion of patients will end up developing distant metastases and death. The distinction between Spitz tumours with atypical features and Spitzoid melanoma remains difficult on clinical and histological grounds and the prediction of the biological behaviour of those tumours even with sentinel lymph node biopsy is impossible. Tools such as immunohistochemistry, genetic analysis, mutation analysis and mass spectometry have contributed to the better understanding of those tumours and may be useful in the differential diagnosis of Spitzoid tumours.

miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas.

In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.

MicroRNA expression profiles in pediatric dysembryoplastic neuroepithelial tumors.

Among noncoding RNAs, microRNAs (miRNAs) have been most extensively studied, and their biology has repeatedly been proven critical for central nervous system pathological conditions. The diagnostic value of several miRNAs was appraised in pediatric dysembryoplastic neuroepithelial tumors (DNETs) using miRNA microarrays and receiving operating characteristic curves analyses. Overall, five pediatric DNETs were studied. As controls, 17 samples were used: the FirstChoice Human Brain Reference RNA and 16 samples from deceased children who underwent autopsy and were not present with any brain malignancy. The miRNA extraction was carried out using the mirVANA miRNA Isolation Kit, while the experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction was performed to validate the expression profiles of miR-1909* and miR-3138 in all samples initially screened with miRNA microarrays. Our findings indicated that miR-3138 might act as a tumor suppressor gene when down-regulated and miR-1909* as a putative oncogenic molecule when up-regulated in pediatric DNETs compared to the control cohort. Subsequently, both miRNA signatures might serve as putative diagnostic biomarkers for pediatric DNETs.

Epidemiology of pediatric brain tumors in Greece (1991-2008). Experience from the Agia Sofia Children's Hospital.

BACKGROUND: We set out to determine the epidemiology of pediatric brain tumors in a single Greek institute. METHODS: We reviewed all cases of brain tumors in children, under the age of 15 years, that were treated surgically in the Neurosurgical Department of Children's Hospital "Agia Sofia", between January 1991 and December 2008. RESULTS: From January 1991 through December 2008, we encountered 335 cases of pediatric brain tumors. The mean age was 7.2 years and there was a slight male predominance. Astrocytomas made up the largest component, with pilocytic astrocytomas accounting for 25.6% of all tumors. The second most common entity was medulloblastoma, accounting for 18% of all tumors, whereas ependymomas were the third most frequent tumor. There was an increase in the total number of brain tumors during the last decade. Furthermore, examining low-grade astrocytoma, medulloblastoma and ependymoma trends over the last 2 decades, we found a trend for a decrease of low-grade astrocytomas and an increase of the more aggressive medulloblastomas and ependymomas. CONCLUSION: This study presents the first epidemiological data of pediatric brain tumors in Greece. Astrocytomas were the most common tumor followed by medulloblastomas and ependymomas. Furthermore, a trend for an increase of malignant tumors over the last decade has been observed.

Malignant progression of a pleomorphic xanthoastrocytoma in a child.

Pleomorphic xanthoastrocytoma (PXA) is a recently recognized rare cerebral neoplasm that predominantly affects young patients. We report on the case of a 3-year-old boy who presented with a 2-week history of headaches and seizures. Radiological investigation revealed a lesion in the right parietal-occipital lobe. The lesion was excised and histology disclosed the presence of a PXA with anaplastic features. 1 year later follow-up magnetic resonance imaging (MRI) revealed tumor relapse. An MRI of the spine was also performed and demonstrated leptomeningeal dissemination. The patient underwent a second operation. Histology revealed that the presence of a malignant PXA with anaplastic features. The patient received radiotherapy and 9 months later on follow-up MRI a new tumor recurrence was noted. A third craniotomy was performed and the tumor removed. Histological examination revealed dedifferentiation to glioblastoma multiforme. The patient was referred to the oncology department and received chemotherapy with temozolamide. 8 months later the patient was stable without tumor recurrence. PXAs require close follow-up because of their unpredictable biological behaviour.

Gastric fibrolipoma causing bleeding in a child.

Gastrointestinal lipomas are uncommon benign tumors usually occurring in the colon and rarely in the stomach. We report a case of a 10-year-old boy who presented with a two-week history of epigastric abdominal pain and several episodes of melena. Gastroscopy revealed a soft, elevated, broad based, polypoid lesion on the posterior wall, without superficial erosion or ulceration. One week later the patient was readmitted with melena and hematemesis, followed by a significant drop of hematocrit levels. A laparotomy was carried out and the mass was excised. Histological findings were consistent with a submucosal gastric fibrolipoma resected IN TOTO. The clinical presentation, diagnosis and management of this condition are discussed.

Spontaneous ovulation in a true hermaphrodite with normal male phenotype and a rare 46,XX/47,XXY Klinefelter's mosaic karyotype.

BACKGROUND: Most true hermaphrodite patients--characterized by the presence of both ovarian and testicular tissue--demonstrate ambiguous genitalia and are diagnosed at birth, most commonly bearing a 46,XX karyotype. PATIENT AND METHODS: We report on a 13-year-old boy presenting with left scrotal hemorrhage. He had a left inguinal hernia, a palpable testis in the right, normal male external genitalia and significant gynecomastia. During operation, the left gonad and adjacent tissue were removed for histological examination, which revealed the presence of a normal ovary, rich in follicles and a ruptured corpus luteum, suggestive of spontaneous ovulation, with a normal ipsilateral adnexa and semi-uterus. Biopsy of the right gonad revealed a dysgenetic testicle. Endocrinological assessment postoperatively depicted high FSH, pubertal testosterone and low estradiol levels. Cytogenetic analysis in peripheral blood lymphocytes and FISH of the right gonad revealed a 46,XX (70-60%)/47,XXY (30-40%) karyotype, respectively, while molecular analysis verified the presence of SRY and azoospermia factor genes. CONCLUSION: The importance of full histological, cytogenetic and molecular investigation and of interdisciplinary approach in every single patient with sex differentiation disorders is highlighted by this rare case of spontaneous ovulation in a true hermaphrodite with normal male external genitalia and Klinefelter mosaicism.

Bcl-2 and Bax in congenital naevi.

BACKGROUND: Melanocytes represent a static component of the epidermis, and the role of apoptosis in basal melanocyte function and melanocytic tumour formation has not been fully elucidated. OBJECTIVES: The aim of this study was to investigate the expression of Bcl-2 anti-apoptotic and Bax apoptotic proteins in congenital naevi in correlation with p-27 protein and Ki-67 proliferative index. METHODS: Our material comprised 30 congenital naevi (eight giant) excised from children aged from 15 days to 14 years old. The immunohistochemical streptavidin-biotin method was performed on paraffin sections for the detection of Bcl-2 (cl100/D5), Bax (cl2D2) , Ki-67 (MIB-1) and p-27 (1B4) proteins with monoclonal antibodies. RESULTS: Bcl-2 protein was detected in all cases showing a strong diffuse cytoplasmic expression in >70% of the naevocytes and was preserved in the deeper parts of the naevi. On the other hand, Bax was detected in 13 of the cases, showing a fainter cytoplasmic expression in 40-50% of the naevocytes without any particular topographic distribution. Ki-67 was detected in all cases showing a limited expression in 1-2% of the nuclei mainly in the junctional and upper dermal components. p-27 protein showed a broad diffuse nuclear expression (>70% of the nuclei) in all cases with a particular increase in the deeper parts of the naevi. Bcl-2 expression showed a parallel correlation with p-27 protein. CONCLUSIONS: Broad Bcl-2 expression in congenital naevi suggests that suppression of apoptosis may play an important role in the maintenance of naevocytes despite the low proliferative activity.

Subcutaneous fat necrosis associated with severe hypocalcaemia in a neonate.

Subcutaneous fat necrosis (SFN) of the newborn is an uncommon disorder of the adipose tissue, mostly affecting full-term or post-term newborns who experience perinatal distress. The lesions of SFN typically occur during the first six weeks of life; they are usually self-limited and no specific therapy is required. The disorder may be rarely complicated with hypercalcaemia. We present the case of a neonate with perinatal asphyxia who manifested SFN followed by hypocalcaemia instead of hypercalcaemia and a biochemical profile of pseudohypoparathyroidism four weeks after the eruption of skin lesions. The infant was treated with alfacalcidiol. Blood biochemistry was normalized within one week and serum parathyroid hormone levels declined to normal over the next two months. It is suggested that perinatal asphyxia was the common etiopathogenetic factor for the development of both SFN and pseudohypoparathyroidism.

Diffuse intraabdominal desmoplastic small round cell tumor: a ten-year experience.

BACKGROUND: Intraabdominal desmoplastic small round cell tumors (IDSRCT) are rare in children and predominantly affect male adolescents and young adults. We present our experience in the management of five children with diffuse IDSRCT, managed with aggressive chemotherapy, surgery, radiotherapy and peripheral blood stem cell transplantation. MATERIAL AND METHODS: During the last decade five patients, four males and one female (mean age 9.6 years), with diffuse IDSRCT were managed in our department. The main symptoms were abdominal distention, vague abdominal pain, and vomiting. Three patients with inoperable tumor on admission were submitted initially to open biopsy followed by aggressive chemotherapy. Regression of the tumor was followed by a second laparotomy and radical excision of any macroscopically distinguishable masses, followed by chemotherapy. In the remaining two patients a debulking procedure was done initially, followed by chemotherapy. The accurate diagnosis of the disease was established by immunohistochemistry, additionally confirmed in the last two patients by molecular analysis. RESULTS: Three patients who had radical excision of the tumor and adjuvant chemotherapy had recurrence after two to six months. In the remaining two patients, recurrence was evident after two and eighteen months, respectively, following debulking. In addition, one patient with recurrence received radiotherapy and two others underwent peripheral blood stem cell transplantation. All but one patient died within three years from diagnosis. The last patient, who was submitted to a debulking procedure, is still alive eight months after the operation. CONCLUSIONS: Intrabdominal desmoplastic small round cell tumor is a highly aggressive malignancy with a very poor prognosis. Multiagent chemotherapy usually leads initially to a temporary regression of the tumor, but recurrence is the rule. Radical surgical excision, radiotherapy and peripheral blood stem cell transplantation does not seem to improve prognosis significantly. Despite all therapeutic modalities the outcome is dismal and surgical efforts can be considered only as palliative.

Actinic granuloma successfully treated with acitretin.

Actinic granuloma is a rare skin disorder that develops in an area of actinic elastosis. The pathogenesis of the disease is obscure but the most accepted hypothesis implicates the solar radiation as the triggering factor. Typically the disease presents in middle-aged individuals with significant past sun-exposure and involves mainly the sun-exposed skin. It manifests as asymptomatic annular patches with elevated borders and central atrophy and shows little tendency to regression. Several treatments have been tried with variable success. We present a 74-year-old male who consulted our department for annular atrophic plaques involving his forehead and nose, present for 8 months and insidiously spreading but otherwise asymptomatic. A biopsy confirmed the clinical suspicion of actinic granuloma and excluded other possibilities. Our patient was commenced on acitretin 25 mg/day and showed a remarkable improvement within a year; the lesions stopped spreading and almost disappeared.

Low serum insulin values in children with multiple lesions of granuloma annulare: a prospective study.

BACKGROUND: The relationship between granuloma annularae (GA) and diabetes mellitus (DM) is controversial. OBJECTIVE: To investigate the relationship between multiple lesions of GA and carbohydrate metabolism in children. SUBJECTS AND METHODS: Fifteen children (seven boys, eight girls, mean age 4.8 years) with five or more lesions of GA were evaluated. A personal and family history of DM or other autoimmune diseases was obtained and the glycaemic and insulin response during an oral glucose tolerance test (OGTT) was determined. Thirteen children with a negative personal and family history of DM served as controls for the OGTT and 100 other children as 'clinical controls'. RESULTS: At the 30-min sampling of the OGTT the mean insulin values were comparable in GA children and controls (P=0.1), while the mean glucose values were significantly higher in GA children than in controls (P=0.005). All other insulin values during the OGTT were significantly lower in GA children than in controls, while all other glucose values were comparable in GA children and controls with all indices applied. Eleven out of 15 GA children had a positive family history of DM (73.3% vs. 16% of the clinical controls; P<0.0001). CONCLUSION: Multiple lesions of GA in children are associated with significantly lower serum insulin values than in controls and mildly impaired glucose tolerance.

Desmoplastic infantile ganglioglioma: MRI and histological findings case report.

Desmoplastic infantile gangliogliomas (DIG) are rare intracranial tumors occurring during the 1st year of life. They arise invariably in the supratentorial region and have a great size at presentation, commonly involving more than one lobe. They are composed of a solid peripheral component of variable size, which involves the superficial cerebral cortex and the leptomeninges, and a large cystic part. Despite the great size at presentation and occasional mitotic activity in the variable undifferentiated component, this entity constitutes a distinct clinicopathological entity with benign prognosis. We hereby present the MRI and histological findings of two cases of DIG in infants aged 9 and 10 months, respectively.

Kinetics of quiescent cord blood stem/progenitor cells with high proliferative potential in stem-cell expansion culture.

BACKGROUND: The most primitive engrafting hematopoietic stem cell (HSC) resides mainly in a tumor growth factor-beta (TGF-beta)-dependent quiescent phase of the cell cycle. In this study, ex vivo expansion of UC blood (UCB) HSCs has been investigated, with the aim of showing whether quiescent HSCs can be recovered from expansion culture. METHODS: AC133(+) stem/progenitor cells from six full term-pregnancies UCB-samples were immunomagnetically selected, followed by ex vivo expansion culture in the presence of thrombopoietin (TPO), c-kit ligand (KL), flt-3 ligand (FL) and IL-6. Quiescent HSCs were detected by a clonogenic assay that allows the detection of multipotent and committed single- lineage quiescent stem/progenitor cells, named mHPP-Q and cHPP-Q, respectively, by means of a TGF-beta blocking Ab. RESULTS: Expansion culture of fresh selected AC133(+) cells for 1 week caused maintenance rather than expansion of mHPP-Q cells and a 1-fold increase in cHPP-Q cells. A further week culture initiated with 7-day expanded AC133(+) cells resulted in an additional 1.5-fold expansion of cHPP-Q while no mHPP-Q cells could be detected. Amplification of cHPP-Q cells in long-term expansion cultures initiated with 14-day expanded AC133(+) cells was observed for at least a further 4 weeks. DISCUSSION: A small proportion of HPP-Q cells recovered from 7-day expansion cultures retain their multilineage potential: longer culturing of these cells results in the loss of multilineage potential while they maintain quiescent behavior and high proliferative potential.