Investigating the cardiac pathology of SCO2-mediated hypertrophic cardiomyopathy using patients induced pluripotent stem cell-derived cardiomyocytes.

Mutations in SCO2 are among the most common causes of COX deficiency, resulting in reduced mitochondrial oxidative ATP production capacity, often leading to hypertrophic cardiomyopathy (HCM). To date, none of the recent pertaining reports provide deep understanding of the SCO2 disease pathophysiology. To investigate the cardiac pathology of the disease, we were the first to generate induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) from SCO2-mutated patients. For iPSC generation, we reprogrammed skin fibroblasts from two SCO2 patients and healthy controls. The first patient was a compound heterozygote to the common E140K mutation, and the second was homozygote for the less common G193S mutation. iPSC were differentiated into cardiomyocytes through embryoid body (EB) formation. To test the hypothesis that the SCO2 mutation is associated with mitochondrial abnormalities, and intracellular Ca2+ -overload resulting in functional derangements and arrhythmias, we investigated in SCO2-mutated iPSC-CMs (compared to control cardiomyocytes): (i) the ultrastructural changes; (ii) the inotropic responsiveness to ß-adrenergic stimulation, increased [Ca2+ ]o and angiotensin-II (AT-II); and (iii) the Beat Rate Variability (BRV) characteristics. In support of the hypothesis, we found in the mutated iPSC-CMs major ultrastructural abnormalities and markedly attenuated response to the inotropic interventions and caffeine, as well as delayed afterdepolarizations (DADs) and increased BRV, suggesting impaired SR Ca2+ handling due to attenuated SERCA activity caused by ATP shortage. Our novel results show that iPSC-CMs are useful for investigating the pathophysiological mechanisms underlying the SCO2 mutation syndrome.

Fortuitous administration of denosumab in breast carcinoma with osteoclastic giant cells.

Breast carcinoma with osteoclastic giant cells (OGCs) is a rare entity characterized by an admixture of giant cells and malignant epithelial cells within an inflammatory and vascular stroma. Denosumab is a monoclonal antibody that targets the pathway for osteoclast formation and activation, indicated for the prevention of skeletal-related events in patients with bone metastases, as well as for the treatment of giant cell tumor of bone. We report a patient who presented with aggressive bone recurrence of breast cancer 12 years after her original diagnosis, showing a transformed histology that included multinucleated OGCs, and that was refractory to traditional therapy. Misdiagnosed with a tumor-to-tumor metastasis of breast cancer to a giant cell tumor of bone, she was treated with denosumab for her presumed primary bone disease and had a remarkable clinical and radiological response. To the best of our knowledge, this is the first report of breast cancer with OGCs occurring initially in a metastasis while absent in the original tumor and the first description of its successful treatment with denosumab. This case sheds light on the development of giant cells in the tumor microenvironment and suggests the potential use of denosumab in the management of cancers with giant cell elements.

Metastatic rhabdoid meningioma with BRAF V600E mutation and good response to personalized therapy: case report and review of the literature.

Rhabdoid meningioma is an aggressive phenotype of meningioma, associated with a poor prognosis. We present a very rare case of high-grade meningioma with rhabdoid features that eventually expressed in a coma state. Comprehensive genomic profiling using a Next Generation Sequencing (NGS) assay revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. After treatment with BRAF inhibitor (dabrafenib), the child's clinical condition improved progressively. After seven months, an MEK inhibitor was added (trametinib).

Previously unrecognized pattern of central nervous system hemangiopericytoma with pseudoglandular spaces.

Central nervous system hemangiopericytoma (HPC) is an uncommon extraaxial tumor with controversial terminology, histogenesis, and grading. Herein, we report a unique example in a 64-year-old woman with a 3.2 cm extra-axial right frontal lobe mass. Histologic sections showed an HPC with increased mitotic activity and elevated proliferation index, interspersed with gland-like spaces lined by epithelioid cells with apical blebs and filled with proteinaceous material. Both spindled and epithelioid cells expressed BCL-2, CD99, and nuclear STAT6, but were negative for CD34, AE1/AE3, CAM5.2, and epithelial membrane antigen. A diagnosis of anaplastic HPC with pseudoglandular spaces was rendered. To our knowledge, this is the first pathologically and molecularly well-documented example in the literature. This pattern has only been reported once in 1983 and is not widely known. Differential diagnosis included synovial sarcoma, anaplastic meningioma with epithelial metaplasia, malignant peripheral nerve sheath tumor, and metastatic carcinosarcoma. Accurate diagnosis depends on recognition of this pattern, along with appropriate immunohistochemical and molecular work-up.

Alkaline phosphatase level change in patients with osteosarcoma: its role as a predictive factor of tumor necrosis and clinical outcome.

BACKGROUND: In osteosarcoma the histological response, measured by the percentage of tumor necrosis, constitutes one of the most significant predictive factors, with better survival in patients whose tumor necrosis is > or = 90%. OBJECTIVES: To determine if the decrease rate of serum alkaline phosphatase (SAP) levels during the first month of neoadjuvant chemotherapy could serve as a predictive indicator of tumor necrosis and clinical outcome. METHODS: We analyzed the medical files of 53 osteosarcoma patients (19 females, 34 males) (median age 16 years, range 8-24); the disease was metastatic in 12 and localized in the other 41. RESULTS: The histological responses were good in 38 patients (71.7%) and poor in 15 (28.3%). At a median follow-up of 50 months, 34 patients (64.2%) had no evidence of disease and 19 (35.8%) had died from the disease. High levels of SAP at diagnosis correlated with worse survival (P = 0.002). There was no difference in overall survival between patients whose SAP decrease rate was > 25% and those with a rate < 25% (P = 0.14). Among female patients, "rapid" SAP responders had better survival than "slow" responders (P= 0.026). In patients with metastases the SAP decrease rate was positively correlated with survival (P = 0.042). CONCLUSIONS: There was no evidence that "rapid" SAP responders had a higher percentage of tumor necrosis than "slow" responders, although female "rapid" SAP responders had a better prognosis than "slow" responders. Patients with metastases at presentation and "rapid" SAP response had better prognoses.

Anaplastic ganglioglioma in the spinal cord: case report and literature review.

Anaplastic ganglioglioma (AGG) is a rare tumor. A PubMed database search yielded only a few case reports and fewer case series. An even rarer entity is AGG arising in the spinal cord. We present a case of a pediatric patient with a pathological diagnosis of spinal AGG.

Improvement of cerebral metabolism mediated by Ro5-4864 is associated with relief of intracranial pressure and mitochondrial protective effect in experimental brain injury.

PURPOSE: To investigate the possible impact of reduction of mitochondrial membrane permeabilization by modulation of the 18 kDa translocator protein mediated by Ro5-4864 over post-traumatic cerebral edema and metabolic crisis. METHODS: Cerebral microdialysis and intracranial pressure (ICP) monitoring were performed in Sprague-Dawley rats treated by intraperitoneal injection of either dimethylsulfoxide (vehicle) or Ro5-4864 following cortical contusion and further correlated with quantitative assessment of mitochondrial damage, water content in the injured tissue, modified neurological severity score, and lesion size. RESULTS: Ro5-4864 resulted in a profound decrease in ICP that correlated with improved cerebral metabolism characterized by significantly higher glucose and pyruvate and lower lactate concentrations in the pericontusional area in comparison with vehicle-treated animals. Reduced ICP correlated with reduced water content in the injured tissue; improved metabolism was associated with reduced mitochondrial damage evidenced by electron microscopy. Both effects were associated with a profound and significant reduction in glycerol release and lesion size, and correlated with improved neurological recovery. CONCLUSIONS: The present study shows that Ro5-4864 has a favorable effect on the fate of injured brain, presumably mediated by improvement of metabolism. It further suggests that improvement of metabolism may contribute to ICP relief.

Undifferentiated sarcoma of the thyroid in a child.

The most common malignant tumor of the thyroid is papillary carcinoma. Sarcoma of the thyroid is encountered very rarely; its therapy is complex and poses significant problems due to the problematic location of the tumor. A 14-year-old female was diagnosed with undifferentiated sarcoma of the thyroid and received combined therapy comprising surgery, chemo- and radiotherapy without significant side effects. This case underlines the fact that undifferentiated thyroid sarcoma may be a diagnostic possibility in children with malignant masses of the neck and may be successfully treated with modern therapeutic strategies.

Osteogenic sarcoma in a child with familial expansile osteolysis syndrome: an accidental association?

We present the first reported case of a child with familial expansile osteolysis syndrome (FEO) who developed osteogenic sarcoma (OS) of the iliac bone. A 17-year-old adolescent presented with pain and a mass on the left pelvis. He was from a family with several members who had been diagnosed with FEO, from which he also suffered. The median life expectancy of affected members of the family was reported as 25 to 30 years, with death ensuing as a result of various respiratory and cardiac complications of severe skeletal deformations, characteristic of increased bone turnover as seen in FEO. Biopsy of the patient's mass revealed chondroblastic OS. He was treated according to the P9754 protocol for patients with newly diagnosed nonmetastatic OS. Chemotherapy consisted of HD-MTX, ifosfomide, doxorubicin, and cisplatin. Complete resection of the tumor was carried out, but the patient subsequently developed metastatic disease and died (histologic response to neoadjuvant chemotherapy-85%). The patient's alkaline phosphatase level that was highly elevated before the start of chemotherapy, dropped significantly during treatment, with repeated elevation soon after definitive surgery, while he was recuperating and not on treatment. We speculate that chemotherapy affected not only the malignant cells of OS but normal osteoblasts as well, with a decreasing level of alkaline phosphatase even in the absence of any clinical and radiographic signs of OS. We also think that increased bone turnover, characteristic of a condition such as FEO, may facilitate de novo development of OS.

Primary cardiac chondrosarcoma with rapid MFH-like recurrence: case report and review of tumor type.

We present a case report of a patient with a rare primary cardiac tumor, chondrosarcoma. After initial excision, a locally advanced recurrence appeared within six weeks at a different site in the heart with the histological features of a high-grade sarcoma. We discuss the background, management and prognosis of these rare tumors.

Plasma heparanase as a significant marker of treatment response in children with Hodgkin lymphoma: pilot study.

INTRODUCTION: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with Hodgkin lymphoma and to investigate whether this parameter provides prognostic information for response to treatment after induction therapy. PATIENTS AND METHODS: HP levels of 19 pediatric patients (mean age: 10.3 years (y) (range, 4-18 y), 9 girls, 10 boys) with Hodgkin lymphoma were assayed at diagnosis and at restaging. HP levels were determined using an ELISA anti-human heparanase immunoassay kit. According to diagnosis, CAT scan and/or FDG/ PET-CT fusion were performed to assess response to treatment after 2-3 courses of chemotherapy. Two patients received VAMP protocol (1 stage IA, 1 stage IIA), 1 received AV-PC (nonbulky stage IIA), 4 received COPP/ABV (3 stage IIA bulky, 1 stage IIIA nonbulky), 4 received ABVE-PC (2 stage IIB, 1 stage IIA bulky, 1 stage IIIA bulky), 2 received ABVD (1 stage IIA bulky, 1 stage IIIA), and 6 received escalated BEACOPP (1 stage IIIB, 3 stage IVA, 2 stage IVB). RESULTS: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1019 pg/mL (range, 141-5733 pg/mL), decreasing at restaging to 588 pg/mL (range, 62-3267 pg/mL) (p = .034). At diagnosis, the average HP of the 16 patients in CR or VGPR was 1104 pg/mL; it had decreased at restaging to 586 pg/mL (p = .032). At diagnosis, the average HP level for the 3 patients with TP or PR was 1704 pg/mL; it had increased to 1938 pg/mL at restaging (p = .166). Due to the small number of patients, no correlation was observed between HP levels at diagnosis, staging, or any other clinical prognostic factor. CONCLUSIONS: Changes in plasma HP levels correlated with response to treatment for children diagnosed with Hodgkin lymphoma. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group, using the test for clinical trials of antiangiogenic therapies.

Accelerated pulmonary nodulosis and sterile pleural effusion in a patient with psoriatic arthropathy during methotrexate therapy: a case report.

Pulmonary nodulosis and sterile pleural exudates are well-known extra-articular manifestations in rheumatoid arthritis patients with a positive rheumatoid factor. In some patients, treatment with methotrexate has been postulated as the trigger of these complications. We report a patient with psoriatic arthropathy, negative RF, negative anticyclic citrulinated peptide antibodies but positive antibodies to cardiolipin who developed massive sterile pleural empyema and multiple cavitary pulmonary nodules during methotrexate treatment. We suggest that awareness of methotrexate-induced lung and pleural complications should be extended to other than rheumatoid arthritis diseases, not necessarily accompanied by rheumatoid factor or anticyclic citrulinated peptide antibodies.

Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties.

Recent experimental data have shown that hyperbaric oxygen therapy (HBOT) was associated increased Bcl-2 expression at the injury site that correlated with reduced apoptosis. We hypothesized that HBOT mediated enhancement of Bcl-2 expression and increased intracellular oxygen bio-availability may both contribute to preserve mitochondrial integrity and reduce the activation of the mitochondrial pathway of apoptosis. For this purpose, a cortical lesion was created in the parietal cortex of Sprague-Dawley rats by dynamic cortical deformation (DCD) and outcome measures in non-treated animals were compared with that of HBOT treated rats. Morphological analysis showed a profound reduction in neuronal counts in the perilesional area and a marked rarefaction of the density of the axonal-dendritic network. In treated animals, however, there was a significant attenuation of the impact of DCD over perilesional neurons, characterized by significantly higher cell counts and denser axonal network. In mitochondria isolated from injured brain tissue, there was a profound loss of mitochondrial transmembrane potential (Deltapsi(M)) that proved to be substantially reversed by HBOT. This finding correlated with a significant reduction of caspases 3 and 9 activation in HBOT treated animals but not of caspase 8, indicating a selective effect over the intrinsic pathway of apoptosis. All together, our results indicate that the neuroprotective effect of HBOT may represent the consequence of preserved mitochondrial integrity and subsequent inhibition of the mPTP and reduction of the mitochondrial pathway of apoptosis.

Ultrasound imaging of fasciitis due to body-building supplement.

BACKGROUND: Fascia and soft tissues, rich in collagen, receptors of pain and capable of significant distention, may be targets of autoimmune inflammatory diseases. We observed fasciitis due to the protein supplement Pure Whey, which has not been reported previously. METHODS: Sonography (Sonosite-Titan, 5 to 10 MHz, L-38) was performed on a patient (age, 26 years; body mass index, 38 kg/m2) with protein fasciitis. He had developed compact swelling of his forearms, hands, and legs, with skin irregularity and severe disability (without peripheral eosinophilia, normal Ig and ESR 18/hr) after taking Pure Whey, containing L-tryptophan (1.4 g per 100 g of protein). A deep skin biopsy was performed. The thickness of the brachioradial fascia (BRF) was measured and compared with 10 healthy control subjects (men ages 36.7 +/- 8.3 years; body mass index, 26.4 +/- 6.5 kg/m2). RESULTS: The deep skin biopsy showed severe fat interlobular and fascial thickening with mononuclear (noneosinophilic) infiltrate and fibrosis associated with fasciitis. BRF of the 10 healthy men had a thickness of 0.75 +/- 0.19 mm, compared with the patient's 2.4 mm thickened and cleaved BRF. After 2.5 months of corticosteroid therapy (30 mg/d with tapering) and discontinuation of the protein supplement, the patient's BRF returned to a monolayer appearance. Its thickness reduced to normal (0.8 mm), with significant clinical improvement. CONCLUSIONS: This case of noneosinophilic fasciitis associated with ingestion of L-tryptophan-containing protein supplement responded favorably to corticosteroid therapy. Sonography proved to be an effective method to visualize and confirm the fasciitis and to follow the course and therapy.

Cerebral Liposarcoma Embolus From Heart Metastasis Successfully Treated by Endovascular Extraction Followed by Cardiac Surgery.

The current case presents a patient with a tumor emboli stroke as a presenting symptom of a liposarcoma metastasis to the heart that was treated successfully with endovascular mechanical retrieval, followed by subsequent cardiac surgery. The patient is still alive, under chemotherapy treatment, 3 years following the interventions. This scenario should be considered as a part of the differential diagnosis of oncology patients presenting with new central neurological symptoms. This active approach can be an effective treatment if the patient is fit and there is no evidence of widespread disease.

Post-traumatic cytotoxic edema is directly related to mitochondrial function.

Cerebral edema represents a major threat following traumatic brain injury. However, therapeutic measures for control of intracranial pressure alone have failed to restore cerebral metabolism and improve neurological outcome. Since mitochondrial damage results in ATP depletion and deactivation of membrane ionic pumps, we hypothesized that modulation of ATP bioavailability may directly affect cytotoxic edema. Intracranial pressure measurements were performed in Sprague-Dawley rats treated by intraperitoneal injection of dimethylsulfoxide (vehicle), cyclosporine A (CsA), or Oligomycin B (OligB) following cortical contusion and further correlated with water content, mitochondrial damage, and electron microscopic assessment of neuronal and axonal edema. As hypothesized, ultra-structural figures of edema closely correlated with intracranial pressure elevation, increased water content and mitochondrial membrane permeabilization expressed by loss of transmembrane mitochondrial potential. Further, mitochondrial damage evidenced ultra-structurally by figures of swollen mitochondria with severely distorted cristae correlated with both cytotoxic edema and mitochondrial dysfunction. Importantly, cerebral edema and mitochondrial impairment were significantly worsened by treatment with OligB, whereas a noticeable improvement could be observed in animals that received injections of CsA. Since OligB and CsA are responsible for symmetrical and opposite effects on oxidative metabolism, these findings support the hypothesis of a causative relationship between edema and mitochondrial function.

Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome.

Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients' fibroblasts. RNA sequencing of Ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.

Relative effects of mannitol and hypertonic saline on calpain activity, apoptosis and polymorphonuclear infiltration in traumatic focal brain injury.

The purpose of this study was to compare the relative effects of mannitol and hypertonic saline (HTS) on calpain activity, apoptosis and neuroinflammatory response induced by experimental cortical contusion. Four groups of 5 Sprague-Dawley male rats were submitted to focal brain injury produced by exposing the parietal cortex to dynamic cortical deformation. Groups were defined by rescucitation fluids administered 30 min post-injury as follows: group 1-0.9% normal saline 2 ml/kg; group 2-mannitol 20% 0.5 g/kg; group 3-HTS 2 ml/kg; group 4-HTS 4 ml/kg. At 72 h, animals were sacrificed. Paraffin-mounted sections of were stained for mu-Calpain, TUNEL, active caspase 3 and myeloperoxidase. There was no difference in the lesion size between the different groups. In contrast, there was a significant reduction in calpain and apoptosis activity and in the neuroinflammatory response in animals receiving HTS. Although mannitol proved to significantly decrease the neuroinflammatory response and calpain activity, it did not affect apoptosis, and its effect was significantly less than that of HTS. Importantly, the effect of HTS was mostly independent from the infused volume. Our results show that HTS promotes cell survival and reduces secondary brain damage following TBI. This protective effect was evidenced at rather small infused volumes, proved to encompass several cellular and molecular mechanisms involved in secondary cell death and could not be related to relief of intracranial pressure. These findings suggest that the high osmolality of HTS may have protective effects besides its impact on brain edema.

Acute cytomegalovirus infection associated with the onset of inflammatory bowel disease.

A 29-year-old man was admitted with high-grade fever, crampy abdominal pain, and watery diarrhea that had persisted for 2 weeks before his admission. Symptomatic treatment (acetaminophen only) was of no benefit. On physical examination, there was diffuse abdominal tenderness. Laboratory tests showed a leukomoid reaction with atypical lymphocytosis, and serology tests revealed acute cytomegalovirus infection. Abdominal computed tomography and colonoscopy revealed an inflammatory process involving the large intestine. On histologic examinations of intestinal biopsy samples, there was an active inflammation with no inclusion bodies. The patient was treated with ganciclovir with only mild improvement. Adding 5-aminosalicylic acid caused little further improvement. Repeated colonoscopy performed 2 months later showed severe chronic ulcerative colitis. Only the addition of systemic steroids caused complete resolution of the symptoms. On review of the literature (Medline search for cytomegalovirus colitis in immunocompetent patients), 18 cases were found. On follow-up, 10 of these patients were found to have inflammatory bowel disease.