Georgios Karkavelas

Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis

Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Delivery of BMSCs in the cerebrospinal fluid via intracerebroventricular (ICV) transplantation is a useful tool to identify mechanisms underlying the migration and function of these cells. In the current study, BMSCs were ICV administered in severe and mild EAE, as well as naive animals; neural precursor cells (NPCs) served as cellular controls. Our data indicated that ICV-transplanted BMSCs significantly ameliorated mild though not severe EAE. Moreover, BMSCs exerted significant anti-inflammatory effect on spinal cord with concomitant reduced axonopathy only in the mild EAE model. BMSCs migrated into the brain parenchyma and, depending on their cellular density, within brain parenchyma formed cellular masses characterized by focal inflammation, demyelination, axonal loss and increased collagen-fibronectin deposition. These masses were present in 64% of ICV BMASC-transplanted severe EAE animals whereas neither BMSCs transplanted in mild EAE cases nor the NPCs exhibited similar behavior. BMSCs possibly exerted their fibrogenic effect via both paracrine and autocrine manner, at least partly due to up-regulation of connective tissue growth factor (CTGF) under the trigger of TGFb1. Our findings are of substantial relevance for clinical trials in MS, particularly regarding the possibility that ICV transplanted BMSCs entering the inflamed central nervous system may exhibit - under conditions - a local pathology of yet unknown consequences.

Dermatofibrosarcoma protuberans with fibrosarcomatous transformation of the head and neck

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous neoplasm associated with a high cure rate. We present a case of aggressive DFSP with fibrosarcomatous areas in the head and neck. A 28-year-old Mediterranean female presented with a 45-day history of rapidly growing cutaneous lesion of the face. Surgical biopsy confirmed the diagnosis of DFSP. Subsequently, the patient underwent wide local surgical resection, followed by reconstruction. Histopathology report revealed fibrosarcomatous transformation and the patient underwent adjuvant radiotherapy. The patient continues to be disease free at the 35-month follow-up.Although DFSP behave as non-aggressive malignancy, surgery with complete removal of the affected area is the intervention of choice. Moreover, adjuvant treatment and follow-up of the patient is essential in order to prevent recurrence.

The effect of subconjunctival ranibizumab on primary pterygium: a pilot study.

Purpose: A prospective interventional pilot study was performed to estimate the effect of ranibizumab injection on the clinical and histological picture of primary pterygium. Methods: Five patients with primary pterygia received a single subconjunctival injection of ranibizumab (0.3 mg), whereas 5 nontreated pterygia served as controls. The treated pterygia were surgically removed 3 days, 1 week, 2 weeks, 1 month, and 2 months after the injection, respectively. Digital photographs of the pterygia were taken immediately before injection, 1 week after, and on the day of operation. Results: Ranibizumab was well tolerated by all patients, and no side effects were reported. However, it had no effect on the extent of vascularization of pterygium, regardless of the interval between injection and operation. No regression of pterygium vessels was noted in any of the patients. Immunohistochemical analysis also showed no particular differences in the number of vessels stained positive for vascular endothelial growth factor A, in the intensity of vessel staining among the treated pterygia, and between the treated and the nontreated pterygia. Conclusions: Subconjunctival ranibizumab at a single dose of 0.3 mg was not associated with any side effects but had no effect on the extent of vascularization of primary pterygium in our study.

Somatostatin receptor expression in non-medullary thyroid carcinomas.

OBJECTIVEPeptide receptor radionuclide therapy (PRRT) is dependent upon binding of radiolabelled peptides to their respective receptor expressing cells. The main objective of this study was to characterize the expression of somatostatin receptor (SSTR) subtypes in non-medullary thyroid cancers in order to be able to recommend the use of PRRT as a treatment option in patients with progressive local or metastatic disease.DESIGNWe constructed tissue microarrays from paraffin blocks prepared from 47 cases of non-medullary thyroid carcinomas and related normal thyroid tissue. Immunohistochemical staining was performed with five different polyclonal SSTR antibodies.RESULTSSSTR subtypes sst2 and sst3 were expressed in all non-medullary thyroid carcinomas, sst1 and sst5 in 75%, and sst4 in 38%. Coexpression of more than three subtypes was detected in 36 of the 47 cases. The expression of SSTR sub-types in normal thyroid tissue was low or absent.CONCLUSIONSNon-medullary thyroid carcinomas frequently express all SSTR subtypes. This expression provides a basis for further studies with the aim of exploring PRRT as a possible new treatment for iodine-131 refractory metastatic non-medullary thyroid carcinomas.

Relative expression of human telomerase catalytic subunit (hTERT) transcripts in astrocytic gliomas

Human telomerase catalytic subunit (hTERT) expression has been reported as a marker for malignancy in various tumor systems. The aim of the present study was to investigate the relative expression of hTERT (relhTERT) and its transcripts A+B+ (contained in the full-length product), Adel and Bdel in astrocytic gliomas (grades I–IV, n=38). relhTERT was assessed by duplex reverse transcription-PCR and the expression profile of Adel, Bdel and A+B+ transcripts by nested real time-PCR. relhTERT and A+B+ presence correlated well with each other (P<0.001) and with histological grading [grades I–II (low) vs III–IV (high), PrelhTERT=0.002 and PA+B+<0.001]. A+B+ was detected in one out of seven hTERT-positive low-grade tumors, while it was present in 96.3%, and predominantly expressed in 59.3% of high-grade tumors. Bdel predominance was observed only in three cases, irrespective of grading, while Bdel levels equal or close to those of A+B+ were found in 30.4% of grade IV tumors. In situ hybridization with specific Bplus and Bdel probes revealed positive signals for both mRNAs in association with relhTERT and respective variant profiles. In addition, this method was useful in assessing hTERT expression in cases where sampling errors for RT-PCR were unavoidable. Our findings show that except for differences in relhTERT, low- and high-grade astrocytic gliomas exhibit distinct hTERT variant profiles, most of which seem to be in line with the role attributed to hTERT regarding its contribution to the acquisition of malignant potential during astrocyte carcinogenesis. Low-grade tumors mainly express Adel and Bdel. High-grade tumors, especially grade IV, always express A+B+, mostly but not always in predominance over Adel and Bdel. In this same group, profiles with Bdel predominance or relatively equal A+B+/Bdel expression are also observed, and Adel is often missing. Whether these differences characterize tumors with different biological behavior remains to be elucidated.

Clinicopathological correlations in a series of adult patients with non-alcoholic fatty liver disease

Possible correlations among clinical data, serum aminotransferase levels and histological features were assessed in a series of 37 adult patients with non‐alcoholic fatty liver disease (NAFLD), consisting of nine patients with fatty liver (FL) and 28 with non‐alcoholic steatohepatitis (NASH). In each liver biopsy, the NAFLD activity score (NAS) and the stage of fibrosis were determined. Additionally, the number of Kupffer cell aggregates (microgranulomas) per centimeter of biopsy length (MG/cm ratio) was assessed on immunohistochemical stains for CD68 antigen. Definite NASH (NAS ≥ 5) was strongly correlated with serum aspartate aminotransferase (AST) level (P= 0.003), stage of fibrosis (P= 0.003) and age (P= 0.014). On multivariate analysis, age >46 years and AST level above normal values were found to be independent clinical predictors of established NASH. The MG/cm ratio increased from control liver to FL to NASH (P < 0.001), and was correlated with the NAS (P= 0.003) and with the stage of fibrosis (P= 0.004), but not with the serum aminotransferase levels. In conclusion, persistent AST elevation in patients with suspected NAFLD should be an indication for liver biopsy, in order to determine the severity of necroinflammatory activity and the stage of fibrosis. Microgranuloma counting may represent a useful complementary marker of necroinflammatory activity in patients with NAFLD.

A rare tumoral combination, synchronous lung adenocarcinoma and mantle cell lymphoma of the pleura

BackgroundCoexistence of adenocarcinoma and mantle cell lymphoma in the same or different anatomical sites is extremely rare. We present a case of incidental discovery of primary lung adenocarcinoma and mantle cell lymphoma involving the pleura, during an axillary thoracotomy performed for a benign condition.Case presentationA 73-year old male underwent bullectomy and apical pleurectomy for persistent pneumothorax. A bulla of the lung apex was resected en bloc with a scar-like lesion of the lung, which was located in proximity with the bulla origin, by a wide wedge resection. Histologic examination of the stripped-off parietal pleura and of the bullectomy specimen revealed the synchronous occurrence of two distinct neoplasms, a lymphoma infiltrating the pleura and a primary, early lung adenocarcinoma. Immunohistochemical and fluorescence in situ hybridization assays were performed. The morphologic, immunophenotypic and genetic findings supported the diagnosis of primary lung adenocarcinoma (papillary subtype) coexisting with a non-Hodgkin, B-cell lineage, mantle cell lymphoma involving both, visceral and parietal pleura and without mediastinal lymph node involvement. The neoplastic lymphoid cells showed the characteristic immunophenotype of mantle cell lymphoma and the translocation t(11;14). The patient received 6 cycles of chemotherapy, while pulmonary function tests precluded further pulmonary parenchyma resection (lobectomy) for his adenocarcinoma. The patient is alive and without clinical and radiological findings of local recurrence or distant relapse from both tumors 14 months later.ConclusionThis is the first reported case of a rare tumoral combination involving simultaneously lung and pleura, emphasizing at the incidental discovery of the two coexisting neoplasms during a procedure performed for a benign condition. Any tissue specimen resected during operations performed for non-tumoral conditions should be routinely sent for pathologic examination.

Effect of Ramipril Alone Compared to Ramipril with Eplerenone on Diabetic Nephropathy in Streptozocin-Induced Diabetic Rats

Background/Aims: We studied the effect of the combined treatment with an angiotensin-converting enzyme (ACE) inhibitor (ramipril) and eplerenone compared with ramipril alone in streptozocin-induced diabetic rats. Methods: Wistar rats were divided into 4 groups: nondiabetic controls, streptozocin-treated diabetic rats (50 mg/kg), diabetic rats receiving ramipril (1 mg/kg) and diabetic rats treated with the combination of ramipril (1 mg/kg) and eplerenone (100 mg/kg) for 8 weeks. Our model produced early-stage diabetic nephropathy. Results: The diabetic rats developed polyuria, proteinuria, hyperfiltration (assessed by creatinine clearance) and histopathological evidence of renal injury including glomerular hypertrophy and mesangial expansion. Ramipril reduced proteinuria but its combination with eplerenone did not produce any greater benefit. Both treatment approaches prevented glomerular hypertrophy. Addition of eplerenone to ramipril prevented glomerular hyperfiltration. Conclusion: Whether eplerenone should be used in addition to an ACE inhibitor or an angiotensin receptor blocker at an early stage of diabetic nephropathy remains questionable.

Classic (Mediterranean) Kaposi's sarcoma of the true vocal cord: a case report and review of the literature.

Kaposi’s sarcoma (KS) is a rare subcutaneous lesion linked mainly with patients suffering from acquired immunodeficiency syndrome. The aim of the present study is to present the first documented case of classic Kaposi’s sarcoma (CKS) located in the right true vocal cord. A 62 year old male presented with cough and hoarseness for 2 months. Clinical examination revealed a nodule on the right vocal cord. The patient underwent surgery and the lesion was removed and biopsied. The histopathology report showed that the lesion was KS but with no complete removal of the lesion, since the surgical margins of the nodule were not healthy. The patient, although fully informed, refused any further treatment. Further laboratory tests were performed, revealing an HIV-negative immunodeficiency profile. Although (Mediterranean) CKS is not an aggressive malignancy, surgery with complete removal of the affected area is indicated when it is applicable. Moreover, conservative treatment and follow up of the patient is essential in order to prevent relapse or other primary lesions.

Sialadenoma papilliferum of bronchus

Salivary gland-type tumours of the bronchi include a variety of neoplasms with identical histological features to tumours of the major and minor salivary glands [4, 8, 9]. These lesions are uncommon and presumably arise from bronchial glands. Sialadenoma papilliferum (SP) is a rare tumour that has mostly been described in minor salivary glands of the mouth [3, 5]. In an extensive search of the literature, we have not found any mention of this neoplasm in the larynx, trachea or bronchi. We present a case of an endobronchial papillary tumour with histological and immunohistochemical features of SP. The patient was a 53-year-old man who was found to have a radiopaque lesion in the right lung on a routine Xray examination. The patient had a 40-year history of heavy smoking (40–60 cigarettes per day). He had noticed deterioration of the morning cough, accompanied by increased sputum production during the 4 months preceding admission. He also complained of dyspnea on exertion and mild weight loss. Chest radiographs showed a radiopaque lesion in the parahilar region of the lower lobe of the right lung (Fig. 1A). The cardiopulmonary index was within normal range. Bronchoscopy showed occlusion of the apical bronchus of the right lower lobe, which contained purulent and necrotic material. Cytological examination of a bronchial wash showed squamous cells without evidence of malignancy. Histological examination of a bronchial biopsy showed findings consistent with a benign papillary lesion. Computed tomography (CT) scan of the chest revealed an area of bronchial thickening and consolidation accompanied by parenchymal changes suggestive of inflammation (Fig. 1B). Brain, abdominal and retroperitoneal CT scans, as well as bone nuclear scan, were normal. Pulmonary function tests included: