Successful management of unsuspected retroperitoneal paraganglioma via the use of combined epidural and general anesthesia: a case report

INTRODUCTION: Similar to pheochromocytomas, paragangliomas can secrete catecholamines, although they are usually non-functional and clinical presentation is non-specific. We present a case of accidental, intra-operatively diagnosed neuroendocrine-active sympathetic paraganglioma, which was suspected and confirmed during elective retroperitoneal tumor removal. CASE PRESENTATION: A 25-year-old Caucasian Croatian man, American Society of Anesthesiologists status 1, underwent elective surgery for retroperitoneal tumor removal. The tumor had been discovered by chance during a routine examination and was suspected to be a sarcoma. Our patient had no history of previous medical conditions nor did he have symptoms characteristic of a neuroendocrine secreting tumor. The results of ultrasound and magnetic resonance imaging studies showed a large, well demarcated retroperitoneal tumor mass in his upper abdomen localized between the aorta and vena cava, measuring approximately 9×6×4.5cm. In the operating room an epidural catheter was inserted at the T7 to T8 level prior to induction of general anesthesia. Epidural analgesia was maintained by an infusion pump with local anesthetic and opiate mixture. During the surgical excision of the tumor, hemodynamic changes occurred, with hypertension (205/110mmHg) and tachycardia (up to 120 beats/minute). In spite of the fact that the surgical field of work did not include adrenal glands whose direct manipulation could explain this occurrence, there was a high degree of suspicion for the presence of a neurosecreting tumor. His clinical symptoms were relieved after administration of urapidil, esmolol and magnesium sulfate. After tumor excision, our patient developed severe hypotension. Hemodynamic stability was reinstated with aggressive volume replacement, with crystalloids and colloids, vasopressors and hydrocortisone. His post-operative course was unremarkable and on the eighth post-operative day our patient was discharged from hospital, with no consequences or symptoms on follow-up two years after surgery. CONCLUSIONS: Our patient’s case emphasizes the need to consider the presence of extra-adrenal paragangliomas in the differential diagnosis of retroperitoneal tumors, despite their rare occurrence. In our patient’s case, invasive hemodynamic monitoring during combined general anesthesia and epidural analgesia and early recognition of catechol-induced symptoms raised suspicion of the existence of a paraganglioma, and this led to an adequate therapeutic approach and favorable outcome of the surgery. Pre-operative recognition of paragangliomas could lead to better pre-operative preparation, but even high clinical suspicion in undiagnosed forms during surgery and the availability of rapid and short-acting vasodilatators, α-blockers and β-blockers might favor good outcome

New insight into the role of PTCH1 protein in serous ovarian carcinomas.

The Hedgehog (Hh) signaling pathway is essential for normal embryonic development, while its hyperactivation in the adult organism is associated with the development of various cancers. The role of the Hh signaling pathway in ovarian cancer has not been sufficiently investigated. Therefore, the present study investigated the role of protein patched homolog 1 (PTCH1), a component of the Hh signaling pathway, and changes in the promoter methylation status of the corresponding gene in a cohort of low‑(LGSC) and high‑grade serous ovarian carcinomas (HGSC) and HGSC cell lines (OVCAR8 and OVSAHO). PTCH1 protein expression level was analyzed using immunohistochemistry in tissue samples and immunofluorescence and western blotting in cell lines. DNA methylation patterns of the gene were analyzed using methylation‑specific PCR. PTCH1 protein expression was significantly higher in HGSCs and LGSCs compared with controls (healthy ovaries and fallopian tubes). Similarly, ovarian cancer cell lines exhibited significantly higher PTCH1 protein expression compared with a normal fallopian tube non‑ciliated epithelial cell line (FNE1). PTCH1 protein fragments of different molecular weights were detected in all cell lines, indicating possible proteolytic cleavage of this protein, resulting in the generation of soluble N‑terminal fragments that are translocated to the nucleus. DNA methylation of the gene promoter was exclusively detected in a proportion of HGSC (13.5%) but did not correlate with protein expression. PTCH1 protein was highly expressed in serous ovarian carcinoma tissues and cell lines, while promoter methylation was only detected in HGSC. Further investigation is required to elucidate the possible mechanisms of PTCH1 activation in serous ovarian carcinomas.This research was co‑financed by the European Union through the Europe Regional Development Fund, Operational Programme Competitiveness and Cohesion (grant no. KK.01.1.1.01.0008; Reproductive and Regenerative Medicine‑Exploring New Platforms and Potentials)

NEOANGIOGENESIS AND MICROVASCULAR DENSITY IN MYELODYSPLASTIC SYNDROME – A SINGLE CENTER EXPERIENCE

Angiogenesis has a significant part in the pathogenesis of hematological malignancies, such as leukemia and myelodysplastic syndromes (MDS). We evaluated the relationship between morphometric, morphological and clinical features of MDS. Blood vessels of 31 newly diagnosed MDS bone marrow biopsies were immunohistochemically analyzed using CD34 and compared with 8 controls and 13 chronic myelomonocytic leukemias (CMML). MDS were categorized into three risk groups: low-, intermediate- and high-risk MDS. Microvascular density (MVD) and major and minor axis length were analyzed using digital image analysis. Overall, MDS had significantly higher MVD and lower minor axis values than the control group and CMML. High-risk MDS had significantly higher MVD compared to the controls, while all MDS risk groups had lower minor axis values than the control group. Increased minor and major axis values were prognostic predictors of shorter overall survival in all MDS risk groups and CMML patients. In conclusion, angiogenesis presents one of the essential factors in MDS pathogenesis and progression characterized by descriptive marrow microvascular network transformation. The size-related features are powerful indicators of survival in MDS patients

WNT5A, β‑catenin and SUFU expression patterns, and the significance of microRNA deregulation in placentas with intrauterine growth restriction

Placental insufficiency is a common cause of intrauterine growth restriction (IUGR). It affects ~10% of pregnancies and increases fetal and neonatal morbidity and mortality. Although Wnt and Hh pathways are crucial for embryonic development and placentation, their role in the pathology of IUGR is still not sufficiently explored. The present study analyzed the expression of positive regulators of the Wnt pathway, WNT5A and β‑catenin, and the expression of the Hh pathway negative regulator suppressor of fused (SUFU). Immunohistochemical and reverse transcription‑quantitative PCR (RT‑qPCR) assays were performed on 34 IUGR and 18 placental tissue samples from physiologic singleton‑term pregnancies. Epigenetic mechanisms of SUFU gene regulation were also investigated by methylation‑specific PCR analysis of its promoter and RT‑qPCR analysis of miR‑214‑3p and miR‑378a‑5p expression. WNT5A protein expression was higher in endothelial cells of placental villi from IUGR compared with control tissues. That was also the case for β‑catenin protein expression in trophoblasts and endothelial cells and SUFU protein expression in trophoblasts from IUGR placentas. The SUFU gene promoter remained unmethylated in all tissue samples, while miR‑214‑3p and miR‑378a‑5p were downregulated in IUGR. The present results suggested altered Wnt and Hh signaling in IUGR. DNA methylation did not appear to be a mechanism of SUFU regulation in the pathogenesis of IUGR, but its expression could be regulated by miRNA targeting

Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital

Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement

Dishevelled family proteins in serous ovarian carcinomas: A clinicopathologic and molecular study

Dishevelled family proteins (DVL1, DVL2 and DVL3) are cytoplasmic mediators involved in canonical and non-canonical Wnt signaling that are important for embryonic development. Since Wnt signaling promotes cell proliferation and invasion, its increased activation is associated with cancer development as well. To get deeper insight into the behavior of Dishevelled proteins in cancer, we studied their expression in serous ovarian carcinomas [both low- (LGSC) and high-grade (HGSC)], and HGSC cell lines OVCAR5, OVCAR8 and OVSAHO. DVL protein expression in serous ovarian carcinomas tissues was analyzed using immunohistochemistry while DVL protein and mRNA expressions in HGSC cell lines were analyzed using western blot and quantitative real-time PCR. DVL1 protein expression was significantly higher in LGSC compared with normal ovarian tissue, while DVL3 was overexpressed in both LGSC and HGSC. DVL2 and DVL3 protein expression was higher in HGSC cell lines when compared with normal control cell line while DVL1, DVL2, and DVL3 mRNA expression was significantly increased only in OVSAHO cell line. Survival analysis revealed no significant impact of DVL proteins on patients' outcome. Our data show an active involvement of Dishevelled family proteins in serous ovarian carcinomas. Further studies should confirm the clinical relevance of these observations.European Union through the Europe Regional Development Fund, Operational Programme Competitiveness and Cohesion, under grant agreement No. KK.01.1.1.01.0008 Qatar University: QUSD-CMED-2018-

Fourier Transform Infrared Spectroscopy Reveals Molecular Changes in Blood Vessels of Rats Treated with Pentadecapeptide BPC 157

Recently, it was found that when confronted with major vessel occlusion and vascular failure, stable gastric pentadecapeptide BPC 157 therapy might rapidly functionally improve minor vessels to take over the function of disabled major vessels, reorganize blood flow, and compensate failed vessel function. We focused on the BPC 157 therapy effect obtained by giving 10 ng/kg ip to rats 5 min before sacrifice on the rat thoracic aorta, which we assessed with Fourier transform infrared spectroscopy (FTIR) 90 min thereafter. We applied a principal component analysis (PCA). The PCA model showed, with a clear distinction being mostly due to the PC1 score, differences between the spectra of BPC 157- and saline-treated rats. The comparison of the averaged spectra of these two groups with their differential spectrum and PC loadings allowed us to identify the parts of the FTIR spectra that contributed the most to the spectral separation of the two observed groups. The PC1 loadings and the differential spectrum showed that the main bands affecting the separation were the amid I band around 1650 cm−1, the amid II band around 1540 cm−1, and the vibrational band around 1744 cm−1. Fitting the spectral range between 1450 and 1800 cm−1 showed changes in protein conformation and confirmed the appearance of the vibrational band at 1744 cm−1. Controls had a substantially more intense vibrational band at 1744 cm−1. These spectral results showed the cells from saline-treated (control) rats to be in the early stage of cell death, while the samples from BPC 157-rats were protected. Thus, BPC 157 therapy changed the lipid contents and protein secondary structure conformation, with a rapid effect on vessels, within a short time upon application

Therapy Effect of the Stable Gastric Pentadecapeptide BPC 157 on Acute Pancreatitis as Vascular Failure-Induced Severe Peripheral and Central Syndrome in Rats

We revealed the therapy effect of the stable gastric pentadecapeptide BPC 157 (10 μg/kg, 10 ng/kg ig or po) with specific activation of the collateral rescuing pathways, the azygos vein, on bile duct ligation in particular, and acute pancreatitis as local disturbances (i.e., improved gross and microscopy presentation, decreased amylase level). Additionally, we revealed the therapy’s effect on the acute pancreatitis as vascular failure and multiorgan failure, both peripherally and centrally following “occlusion-like” syndrome, major intoxication (alcohol, lithium), maintained severe intra-abdominal hypertension, and myocardial infarction, or occlusion syndrome, and major vessel occlusion. The application-sacrifice periods were ligation times of 0–30 min, 0–5 h, 0–24 h (cured periods, early regimen) and 4.30 h–5 h, 5 h–24 h (cured periods, delayed regimen). Otherwise, bile duct-ligated rats commonly presented intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension, gross brain swelling, hemorrhage and lesions, heart dysfunction, lung lesions, liver and kidney failure, gastrointestinal lesions, and severe arterial and venous thrombosis, peripherally and centrally. Unless antagonized with the key effect of BPC 157 regimens, reversal of the inferior caval and superior mesenteric vein congestion and reversal of the failed azygos vein activated azygos vein-recruited direct delivery to rescue the inferior-superior caval vein pathway; these were all antecedent to acute pancreatitis major lesions (i.e., acinar, fat necrosis, hemorrhage). These lesions appeared in the later period, but were markedly attenuated/eliminated (i.e., hemorrhage) in BPC 157-treated rats. To summarize, while the innate vicious cycle may be peripheral (bile duct ligation), or central (rapidly developed brain disturbances), or peripheral and central, BPC 157 resolved acute pancreatitis and its adjacent syndrome

Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle

First, we review the definitively severed myotendinous junction and recovery by the cytoprotective stable gastric pentadecapeptide BPC 157 therapy, its healing that might combine both transected and detached tendon and transected muscle, ligament and bone injuries, applied alone, as native peptide therapy, effective in rat injury, given intraperitoneally or in drinking water or topically, at the site of injury. As a follow up, we reviewed that with the BPC 157 therapy, its cytoprotective ability to organize simultaneous healing of different tissues of and full recovery of the myotendinous junction might represent the particular muscle therapy against distinctive etiopathology muscle disabilities and weakness. In this, BPC 157 therapy might recover many of muscle disabilities (i.e., succinylcholine, vascular occlusion, spinal cord compression, stroke, traumatic brain injury, severe electrolyte disturbances, neurotoxins, neuroleptics, alcohol, serotonin syndrome and NO-system blockade and tumor-cachexia). These might provide practical realization of the multimodal muscle-axis impact able to react depending on the condition and the given agent(s) and the symptoms distinctively related to the prime injurious cause symptoms in the wide healing concept, the concept of cytoprotection, in particular. Further, the BPC 157 therapy might be the recovery for the disabled heart functioning, and disabled smooth muscle functioning (various sphincters function recovery). Finally, BPC 157, native and stable in human gastric juice, might be a prototype of anti-ulcer cytoprotective peptide for the muscle therapy with high curing potential (very safe profile (lethal dose not achieved), with suited wide effective range (µg-ng regimens) and ways of application)