Search

Nutritional status is strongly associated to prognosis in metastatic gastrooesophageal junction (mGOJ)/gastric cancer (GC) patients. The aim of the present study was to develop an immune-checkpoint inhibitor (ICI)-specific nutritional index (NI).Ten serum and anthropometric nutritional markers derived from blood tests or CT scans were analyzed at baseline in patients treated with second-line ICI and correlated with overall survival (OS). An ICI-specific NI (the NUTRIICI) was developed with its specificity assessed in an independent group of patients treated with standard second-line chemotherapy.From June 2014 to December 2018, 57 mGOJ/GC patients (14 females, 43 males) with a median(m) age of 61 years (range 29-85) received ICI as second-line therapy (Pembrolizumab n=26, Nivolumab n=16, Avelumab n=15). Among the 10 analyzed variables, Onodera's prognostic NI (PNI) ≤33 and waist-to-hip (WHR)1 were independent predictors of OS and used to build the NUTRIICI. Patients with both favorable factors (i.e., PNI33 and WHR ≥1, comparator group) had a mOS of 18.0NUTRIICI is the first ICI-specific NI for mOGJ/GC patients receiving second-line ICI. A validation in larger cohorts is strongly encouraged.

Background We describe a case of leucocytoclasic vasculitis induced by Sofosbuvir and its disappearence after the end of the therapy. The hepatitis C virus, firstly described in 1989, is a major global health problem, with high morbidity and mortality. We observed a temporal relationship between the treatment and the onset of vasculitis. We emphasize the multidisciplinary approach to the patients with liver disease to improve the quality of life of these patients. Case presentation A 53-year-old Caucasian man with a history of hepatitis C virus genotype 1 infection was examined at our Department of Dermatology for the occurrence of palpable purpura. The patient referred that the first appearance of the dermatoses was about one month after initiation of therapy with Sofosbuvir for hepatitis C. Conclusions Vasculitis appeared after the beginning of Sofosbuvir and, even though it was treated with different medications proved to be effective, it disappeared only after the conclusion of the therapy, giving a strong evidence to be a drug eruption.

Simple Summary Neurofibromatosis type 1 is a genetic disease that predisposes to tumors of the nervous system, primarily the neurofibroma. Plexiform neurofibromas (Pnfs) are of the greatest concern because of location, size, and frequent progression to malignancy. Although research is making great progress, the lack of in-depth understanding of the molecular mechanisms driving neoplastic progression results in the absence of prognostic indicators and therapeutic targets. We document that cell–cell cooperativity and the dynamics of the extracellular matrix play important roles in the growth and transformation of Pnf cells, directly through the cooperation of RAS and focal adhesion kinase (FAK) signaling. In turn, we found that treatment of Pnf cells with both MEK and FAK inhibitors is effective in abolishing the transforming ability of these cells. Abstract Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+/− milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell–cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.

Marfan syndrome (MFS) is a connective tissue disease caused by mutations in the FBN1 gene, leading to alterations in the extracellular matrix microfibril assembly and the early formation of thoracic aorta aneurysms (TAAs). Non-genetic TAAs share many clinico-pathological aspects with MFS and deregulation of some microRNAs (miRNAs) has been demonstrated to be involved in the progression of TAA. In this study, 40 patients undergoing elective ascending aorta surgery were enrolled to compare TAA histomorphological features, miRNA profile and related target genes in order to find specific alterations that may explain the earlier and more severe clinical outcomes in MFS patients. Histomorphological, ultrastructural and in vitro studies were performed in order to compare aortic wall features of MFS and non-MFS TAA. MFS displayed greater glycosaminoglycan accumulation and loss/fragmentation of elastic fibers compared to non-MFS TAA. Immunohistochemistry revealed increased CD133+ angiogenic remodeling, greater MMP-2 expression, inflammation and smooth muscle cell (SMC) turnover in MFS TAA. Cultured SMCs from MFS confirmed higher turnover and &alpha, smooth muscle actin expression compared with non-MFS TAA. Moreover, twenty-five miRNAs, including miR-26a, miR-29, miR-143 and miR-145, were found to be downregulated and only miR-632 was upregulated in MFS TAA in vivo. Bioinformatics analysis revealed that some deregulated miRNAs in MFS TAA are implicated in cell proliferation, extracellular matrix structure/function and TGF&beta, signaling. Finally, gene analysis showed 28 upregulated and seven downregulated genes in MFS TAA, some of them belonging to the CDH1/APC and CCNA2/TP53 signaling pathways. Specific miRNA and gene deregulation characterized the aortopathy of MFS and this was associated with increased angiogenic remodeling, likely favoring the early and more severe clinical outcomes, compared to non-MFS TAA. Our findings provide new insights concerning the pathogenetic mechanisms of MFS TAA, further investigation is needed to confirm if these newly identified specific deregulated miRNAs may represent potential therapeutic targets to counteract the rapid progression of MFS aortopathy.

In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.

Osteoarthritis (OA) is the most common joint disease characterized by destruction of articular cartilage. OA-induced cartilage degeneration causes inflammation, oxidative stress and the hypertrophic shift of quiescent chondrocytes. Clusterin (CLU) is a ubiquitous glycoprotein implicated in many cellular processes and its upregulation has been recently reported in OA cartilage. However, the specific role of CLU in OA cartilage injury has not been investigated yet. We analyzed CLU expression in human articular cartilage in vivo and in cartilage-derived chondrocytes in vitro. CLU knockdown in OA chondrocytes was also performed and its effect on proliferation, hypertrophic phenotype, apoptosis, inflammation and oxidative stress was investigated. CLU expression was upregulated in human OA cartilage and in cultured OA cartilage-derived chondrocytes compared with control group. CLU knockdown reduced cell proliferation and increased hypertrophic phenotype as well as apoptotic death. CLU-silenced OA chondrocytes showed higher MMP13 and COL10A1 as well as greater TNF-α, Nox4 and ROS levels. Our results indicate a possible cytoprotective role of CLU in OA chondrocytes promoting cell survival by its anti-apoptotic, anti-inflammatory and antioxidant properties and counteracting the hypertrophic phenotypic shift. Further studies are needed to deepen the role of CLU in order to identify a new potential therapeutic target for OA.

Highlights • Clear Cell Hidradenoma (CCH) is a benign tumor of the sweat glands that very rarely appear on the hand. • CCH needs to be considered as a possible diagnosis for small subcutaneous masses on the extremities in all ages. • Accurate surgical excision is the treatment of choice, to avoid recurrence. • Histological analysis is fundamental for a correct diagnosis., Introduction Clear cell hidradenoma (CCH) is a superficial adnexal tumor of the sweat glands. It generally appears on the trunk or scalp and is uncommon on the upper and lower limbs; it is extremely rare on the hand. CCH tend to be benign, with low malignancy risk. Treatment is based on complete surgical excision. We report a rare case of a CCH of the palm of the hand in an 83-year old patient. Presentation of case An 83-year old male patient presented with a small mass on the palmar surface of his left hand, which was progressively increasing over 5 years. The tumor was surgically excised after sonography and sent for histologic examination, based on which diagnosis of CCH was made. Three months after surgery, the patient had no recurrence and was symptom free. Discussion CCH is a rare tumor of the distal extremities and to the best of our knowledge, only one case of this tumor on the hand has been reported. Our case represents a rare CCH located at the palm of the hand, which was successfully surgical excised without recurrence. Therefore, CCH needs to be considered in the differential diagnosis when encountering masses on the distal extremities. Hidradenocarcinoma is the malignant variant that arises from the same cells. Conclusion We report the second case of CCH on the palmar surface of the hand. Treatment of choice is surgical excision, followed by histological analysis and close follow-up for recurrence.

Background In recent years, new treatments with novel action mechanisms have been explored for advancer lung cancer. Retinoids were shown to promote cancer cell differentiation and death of and their action is mediated from specific cytoplasmic and nuclear receptors.Objective The purpose of this study was to investigate the effect of Cellular retinol binding Protein I (CRBPI) transfection in H460 human non-small cell lung cancer cell line normally not expressing that receptor.Methods H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBPI gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans retinoic acid ( at RA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array. Results were analysed using d by one-way analysis of variance (ANOVA) followed from a Bonferroni post hoc test or with t-student test.Results CRBPI + showed a reduced proliferation and viability in basal condition and after at RA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBPI + H460 cells associated to the down-regulation of pAKT/pERK/pEGFR genes. In particular, gene array documented in CRBPI + H460 cells the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, Foxo3, p21, p27, pTen, Jun.Conclusion Restoration of CRBPI expression in H460 cells reduced proliferation and viability in both basal condition and after at RA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBPI-related intracellular pathways contribute to counteract non-small cell lung carcinoma progression in order to suggest a potential tool to improve efficacy of retioid anti lung cancer adjuvant therapy.

Background Ventriculoperitoneal (VP) shunt is the most frequent treatment for hydrocephalus. VP shunt malfunction is a very common problem in neurosurgical practice, often requiring shunt revision procedures. In some cases, complete removal of a VP shunt may present difficulties, leading the surgeon to leave the ventricular catheter in situ. This decision is often made to avoid possible adverse events, primarily risk of life-threatening hemorrhage. However, a nonfunctioning catheter left in the ventricular system may lead to further complications. Case Description We report the case of an adult man who presented with a tumor-like cystic lesion, with mural and nodular postcontrast enhancement, caused by a huge granuloma formed around the tip of a retained ventricular catheter. Conclusions This occurrence is extremely rare, and this is the first reported case in the literature. Preoperative differential diagnosis was challenging and included infection, metastasis, dysembryogenetic lesions, and rare reversible porencephalic cysts. According to several physiopathogenetic theories recently reported in the literature, the granuloma may develop as the result of persistent chronic inflammatory reactions between the ventricular catheter left in situ and the brain parenchyma. Application of neuroendoscopic techniques is improving management of VP shunt revisions, allowing safe removal of catheters stuck or lost in the ventricular system. Neuroendoscopy may represent an additional option to avoid possible complications related to retained ventricular catheters.

Soft-tissue hematomas are a common clinical entity often associated with trauma, surgery, and bleeding disorders. In the majority of cases, soft-tissue hematomas acutely appear and spontaneously resolve, but sometimes, they present as swellings that slowly expand and progressively increase with time. We present a case of a 70-year-old man with chronic expanding hematoma of the left flank without any history of recent trauma or other medical disease. The diagnosis could not be confirmed on imaging features alone, so the patient was taken to surgery for open biopsy and excision. In patients with slowly growing extremity masses without recent trauma or chronic medical disorders, the differential diagnosis becomes challenging, and chronic expanding hematoma should be considered in addition to soft-tissue sarcomas and other malignancies.

We report a case of a 72-year-old male admitted in our Unit with anemia and a 10 cm liver neoplasm. Computed tomography scan showed 2 lesions respectively in the II, III and, VIII segment of the liver. Surgical resection of the larger liver mass was performed and the tumor appeared as a solid-cystic mass and a diagnosis of malignant mesenchymal tumor not otherwise specified, was made. One month later a Computed tomography scan detected a dishomogeneous gastric mass, 6 cm in diameter, in the greater curvature, confirmed by esophagogastroduodenoscopy. The pathological diagnosis from endoscopic biopsy revealed a mesenchymal tumor requiring surgical removal for accurate diagnosis. The patient underwent relaparotomy and gastric resection and the pathological findings gave a diagnosis of a rare malignant glomic tumor of the stomach confirmed by the revision of previously performed hepatic resection classified as secondary lesion. Keywords: Glomus tumor, Liver metastases, Gastric mesenchymal Neoplasms

Psoriasis is a diffuse chronic skin disorder characterized from accelerated epidermal turnover and inflammatory cell infiltrate. Retinoids influence keratinocyte proliferation and differentiation as well as inflammatory response. Cellular retinol binding protein (CRBPI) regulates intracellular vitamin A bioavailability and contributes to maintain skin homeostasis. The aim of present study was to investigate the expression of CRBPI and its role in the pathogenesis of skin psoriasis. Immunohistochemistry revealed more diffuse and increased CRBPI expression in all epidermal layers of human psoriatic lesions except in the stratum corneum. An imiquimod-induced psoriatic-like model documented the increase of skin lesional area and severity index score as well as of the severity of microscopic features as parakeratosis, papillomatosis and spongiosis in CRBPI-knockout compared to wild-type mice, associated to the increased keratinocyte CK17 and Ki-67 expression and the reduction of CK1, CRABPII and RXRα. Gene array of imiquimod-induced psoriatic skin documented the greater up-regulation of EGF/PDGF-related genes and down-regulation of EGR1 and pro-inflammatory IL-related genes in CRBPI-knockout compared to wild-type mice. Finally, CRBPI transfection in HaCaT cells increased AKT and NF-κB-related genes and proteins and down-regulated IL-2, IL-6 and IL-8 pro-inflammatory signalling. Although not recognized as a psoriatic susceptibility gene in our cohort of patients, the present data strongly supported the potential role of CRBPI to sustain keratinocyte proliferation and differentiation and to counteract pro-inflammatory genes expression in psoriatic lesions.

Osteoporosis (OP) and osteoarthritis (OA) are the most common joint diseases, with a high incidence in the elderly population. OP is characterized by trabecular bone remodeling and reabsorption, whereas articular cartilage and subchondral bone remodeling are major features of OA. Although classically considered as independent or even conflicting processes, clinical coexistence of OP and OA was recently described. Transglutaminase 2 (TG2) expression is considered a biomarker of OA, but its role in osteoporotic bone remodeling is still uncertain. We investigated TG2 and bone biological markers (Osteocalcin, Osteopontin, and Sclerostin) in osteoporotic and osteoarthritic osteocartilagineous tissue (n = 54) and human chondrocyte cultures in vitro by immunohistochemistry, immunofluorescence and RT-PCR. Histomorphometric evaluation of bone trabecular remodeling was also performed. In cartilage, TG2 expression was faint in control and OP and significantly less than in OA and OP + OA chondrocytes; the opposite was found for Osteocalcin, whereas Osteopontin and Sclerostin expression was similar. In the subchondral trabecular bone, osteocytes/osteoblasts TG2 expression was slight and similar comparing control, OP, OA, and OP + OA group, whereas Osteocalcin and Osteopontin expression was lower in OP compared to control, OA and OP + OA. Increased TG2 and reduced Osteocalcin expression were maintained in human osteoarthritic chondrocytes in vitro. Histomorphometric analysis confirmed reduced trabecular bone mass in OP and OP + OA compared with OA patients. TG2 represented a suitable biomarker of osteoarthritic chondrocyte activation, whereas osteocalcin and osteopontin characterized osteoporotic osteocyte/osteoblast changes; differences were lost in OP + OA patients, suggesting careful consideration when coexistence of the two diseases occurs.

Background Acute hemorrhagic occurrence of pilocytic astrocytomas is extremely rare but has become increasingly recognized and often presents in clinically emergent situations. The precise significance of hemorrhage in these tumors and its pathogenetic mechanisms have not yet been defined. Nothing is known about the natural history of bleeding pilocytic astrocytomas. Case Description A 21-year-old man presented with acute biventricular hydrocephalus for repeat bleeding of a midbrain lesion that had been diagnosed 18 years earlier after a similar acute hemorrhagic episode. The patient had been initially treated conservatively, considering the high risk of surgery. He underwent urgent biventricular external shunt surgery and, subsequently, total removal of the lesion. Histopathological analysis revealed pilocytic astrocytoma. Including the present case, 59 cases were analyzed and reviewed, including 5 cases with a pilomyxoid variant. Different pathogenetic mechanisms have been proposed, including histological characteristics, rupture of the bridging veins torn by the neoplastic mass, and vascular instability determined by overexpression of vascular endothelial growth factor. Conclusions To the best of our knowledge, the presented case is completely unique owing to the long-term observational follow-up data available. The hemorrhagic potential did not decrease over time, representing a specific feature of this tumor. The occurrence of bleeding might not reflect either malignancy or aggressiveness. However, the worse prognosis is related to the clinical behavior, with life-threatening complications often associated. Surgery remains the standard treatment and will influence the final prognosis.

We report the case of a seventy-four-year-old man with a slow-growing 2 cm mass on the back that arose near the surgical scar of previously excised melanoma, invasive to a Breslow depth of 3 mm. Preoperative clinical diagnosis was “in-transit” melanoma metastasis. After surgical excision, histopathologic examination revealed a dermal nodular proliferation of spindle cells arranged in storiform pattern, with mild pleomorphism, infiltrating around appendages and into the subcutaneous tissue. Immunohistochemical investigation documented diffuse positivity for CD34 and vimentin of spindle cells. Scattered dendritic cells, containing dark pigment in varying proportion and positive for S100, Melan-A and HMB-45, were also observed. A final diagnosis of Bednar tumour was formulated. Subsequently, the patient developed numerous metastases from the primary melanoma and died after 18 months. Bednar tumour is a rare pigmented variant of dermatofibrosarcoma protuberans of intermediate malignant potential. The presence of pigmented cells in Bednar tumour requires careful differential diagnosis with malignant or benign pigmented skin tumours. The clinical history of a Bednar tumour developing close to the scar of a previous melanoma gives the opportunity of a critical and intriguing discussion about the potential origin of pigmented cells in this rare variant of dermatofibrosarcoma protuberans.

Objectives Primary mediastinal germ cell tumors (PMGCTs) are rare, which often makes them difficult to treat. Herein, we examined patients with PMGCTs who underwent multimodal treatment. Methods We examined 6 patients (median age: 25 years, range: 19–27 years) with PMGCTs who underwent multimodal treatment between April 2001 and March 2015. Three patients had seminomas, 2 patients had yolk sac tumors, and 1 patient had choriocarcinoma. The median observation period was 32.5 months (range: 8–84 months). Results Three of the 6 patients received initial operation followed by 3-4 courses of chemotherapy (bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP)). One patient developed multiple lung metastases 17 months after surgery; received salvage chemotherapy with vinblastine, ifosfamide, and cisplatin; and achieved complete remission. The remaining 3 patients received initial BEP and EP chemotherapy. Multiple lung metastases and supraclavicular lymph node metastases were detected in 2 of these patients at the initial diagnosis. The patients underwent resections to remove residual tumor after treatment, and no viable tumor cells were found. Conclusions Reliable diagnosis and immediate multimodal treatments are necessary for patients with PMGCTs. The 6 patients treated in our hospital have never experienced recurrence after the multimodal treatment.

Several immune-related markers have been implicated in basal cell carcinoma (BCC) pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL)-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ) treatment or photodynamic therapy (PDT). IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular) from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT). Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response during IMQ and MAL-PDT treatments.

We describe the case of a 44-year-old man with congenital cystic adenomatoid malformation. Both computed tomographic (CT) scan findings with perfusion protocol and histological biopsy led to diagnosis. CT scan showed multiple terminal bronchiolar-like uniform cysts smaller than 2 cm and CT perfusion allowed to make a differential diagnosis with an usual interstitial pneumonia. In order to make a definite diagnosis, an open lung biopsy confirmed the CT findings.

Objective: Aging represents a major risk factor for vascular disease development. With aging, changes of the biological properties of vascular smooth muscle cells (SMCs) are observed. Stem marker expression characterizes SMCs during developmental growth and atherosclerosis, but the contribution of SMCs with stem features to the age-related arterial remodeling remains largely unknown. Methods and results: Immunostaining revealed rare vascular growth factor receptor-1(+) (flt-1(+)) and c-kit(+) cells in tunica media of grossly normal human young (17-30 years old) large arteries and 2-month old rat aorta, whereas CD133(+) cells were absent. In large arteries of human aged donors (64-77 years), flt-1(+) and c-kit(+) cell number increased in the intimal thickening and tunica media. Double immunofluorescence revealed that 30.6 +/- 3% of flt-1(+) intimal cells co-expressed alpha-smooth muscle actin. Immunostaining, blots and RT-PCR documented the increased expression of flt-1 and c-kit in 20-24-month old rat aortic media. In vitro, old rat aortic SMCs proliferated and migrated more with greater flt-1, c-kit, NF-kappa B, VCAM-1, IAP-1 and MCP-1 levels and less alpha-smooth muscle actin and myosin compared to young SMCs. Old SMCs were also more susceptible to all-trans retinoic and NF-kappa B inhibition-induced apoptosis compared to young SMCs. Anti-flt-1 blocking antibody reduced migration and placental growth factor-induced but not serum and PDGF-BB-stimulated proliferation of old SMCs. Conclusions: The increase of flt-1(+) and c-kit(+) SMCs characterizes large arteries of aged donors; the blocking of flt-1 signaling influences the behavior of old SMCs, suggesting that the accumulation of SMCs with a stem phenotype contributes to the age-dependent adverse arterial remodeling. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

Primary cardiac sarcomas are rare and represent 20% of all primary cardiac tumors. Symptoms depend on the chambers and the cardiac structures involved. Transthoracic echocardiography is commonly used to identify a cardiac mass. The diagnosis of cardiac sarcoma requires adequate sampling and the careful use of ancillary diagnostic techniques. In the most recent histologic classification, angiosarcoma is the most common malignant tumor of the heart with recognizable differentiation. Undifferentiated sarcomas account for one-third of all cardiac sarcomas and have been incorporated in the malignant fibrous histiocytoma/pleomorphic sarcoma subgroup. Elective cardiac sarcoma therapy includes complete surgical excision when possible, followed by radio and chemotherapeutic regimen, the latter preferably containing anthracyclines, ifosfamide, or taxanes. Prognosis of cardiac sarcomas is very poor, with mean survival ranging from 9.6 to 16.5 months. A less-aggressive course seems related to the left atrium location, a low histologic grading with scarce cellular pleomorphism and low-mitotic activity, absence of necrosis, myxoid tumor appearance, and absence of metastasis at diagnosis.

Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15 KDa cytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodelling processes. In the last years, the role of CRBP-1-related retinoid signalling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers. Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cellsin vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients’ screening for a more personalized and efficacy retinoid therapy.

Aim of the study Stillman's cleft is a mucogingival triangular-shaped defect on the buccal surface of a root with unknown etiology and pathogenesis. The aim of this study is to examine the Stillman's cleft obtained from excision during root coverage surgical procedures at an histopathological level. Materials and method Harvesting of cleft was obtained from two periodontally healthy patients with a scalpel and a bevel incision and then placed in a test tube with buffered solution to be processed for light microscopy. Results Microscopic analysis has shown that Stillman's cleft presented a lichenoid hand-like inflammatory infiltration, while in the periodontal patient an inflammatory fibrous hyperplasia was identified. Conclusion Stillman's cleft remains to be investigated as for the possible causes of such lesion of the gingival margin, although an inflammatory response seems to be evident and active from a strictly histopathological standpoint.

PURPOSE: Adenocarcinoma, the most common non-small cell lung cancer is a leading cause of death worldwide, with a low overall survival (OS) despite increasing attempts to achieve an early diagnosis and accomplish surgical and multimodality treatment strategies. Cellular retinol binding protein-1 (CRBP-1) regulates retinol bioavailability and cell differentiation, but its role in lung cancerogenesis remains uncertain. EXPERIMENTAL DESIGN: CRBP-1 expression, clinical outcome and other prognostic factors were investigated in 167 lung adenocarcinoma patients. CRBP-1 expression was evaluated by immunohistochemistry of tissue microarray sections, gene copy number analysis and tumor methylation specific PCR. Effects of CRBP-1 expression on proliferation/apoptosis gene array, protein and transcripts were investigated in transfected A549 lung adenocarcinoma cells. RESULTS: CRBP-1(High) expression was observed in 62.3% of adenocarcinomas and correlated with increased tumor grade and reduced OS as an independent prognostic factor. CRBP-1 gene copy gain also associated with tumor CRBP-1(High) status and dedifferentiation. CRBP-1-transfected (CRBP-1(+)) A549 grew more than CRBP-1(-) A549 cells. At >1μM concentrations, all trans-retinoic acid and retinol reduced viability more in CRBP-1(+) than in CRBP-1(-) A549 cells. CRBP-1(+) A549 cells showed up-regulated RARα/ RXRα and proliferative and transcriptional genes including pAkt, pEGFR, pErk1/2, creb1 and c-jun, whereas RARβ and p53 were strongly down-regulated; pAkt/pErk/ pEGFR inhibitors counteracted proliferative advantage and increased RARα/RXRα, c-jun and CD44 expression in CRBP-1(+) A549 cells. CONCLUSION: CRBP-1(High) expression in lung adenocarcinoma correlated with increased tumor grade and reduced OS, likely through increased Akt/Erk/EGFR-mediated cell proliferation and differentiation. CRBP-1(High) expression can be considered an additional marker of poor prognosis in lung adenocarcinoma patients.

Objectives— Clusterin is a heterodimeric glycoprotein which is implicated in several biological processes. The nuclear (n-CLU) and cytoplasmic secreted (s-CLU) isoforms have recently been described, but their role is still unclear. The aim of this study is to investigate the expression of clusterin and its isoforms during proliferative arrest and apoptosis of vascular smooth muscle cells (SMCs). Methods and Results— Clusterin expression was evaluated by immunohistochemistry and Western blotting in human arteries and rat aortas. In human diffuse myointimal thickening, clusterin was detected in cell cytoplasm and extracellular space, whereas it was practically absent in the media. In rat aortas 15 days after ballooning, intimal cells (IT cells) overexpressed s-CLU and n-CLU, the latter mainly in the inner neointima; clusterin expression decreased at 60 days. In vitro, IT cells maintained high clusterin expression and its antisense markedly reduced proliferation and increased apoptosis. Western blotting showed that all- trans retinoic acid-induced proliferative arrest and increased α-smooth muscle actin expression did associate to s-CLU and B-myb reduction, whereas bax-related apoptosis was associated to a shift from the s-CLU to n-CLU isoform. Conclusions— Clusterin overexpression characterized neointimal SMCs; s-CLU expression decreased in IT cells during all- trans retinoic acid-induced proliferative arrest and redifferentiation, whereas n-CLU overexpression was characteristic of apoptosis.

Objective : Myocardial fibrosis contributes to the impairing of cardiac function and characterizes ageing, but is also a consequence of atherosclerotic ischemic disease. Since atherosclerosis is a slow progressive disease, which prevails in elderly populations, the aim of this study was to distinguish the contribution of ageing and atherosclerosis to cardiac fibrosis. Methods : Coronary atherosclerosis was induced in 5–6-year-old rabbits by a hyperlipemic diet for 9 months. Left ventricular (LV) collagen was quantified by densitometric analysis after Sirius-Red staining; an immunohistochemical investigation of the interstitium was also performed. Results : Atherosclerosis was associated to a marked increase of left ventricular interstitial collagen with the appearance of fibrotic foci and a decrease of coronary vessel endothelial nitric oxide synthase (eNOS) expression. In fibrotic foci, abundant macrophages co-localized with transforming growth factor beta-1 (TGFβ-1)-positive myofibroblasts and vascular cell adhesion molecule-1 (VCAM-1) positive microvessels (52.3±3.9%). In normocholesterolemic rabbits, ageing resulted in a fourfold increase of myocardial interstitial collagen, with alpha-smooth muscle actin and TGFβ-1 negative fibroblasts and VCAM-1 positive microvessels (19.4±1.2%) without macrophages, suggesting a role of endothelial dysfunction in age-related fibrosis. Conclusions : There is a distinct difference between ageing and coronary atherosclerosis-induced cardiac fibrosis, although the effects may be cumulative. In the cascade of events leading to myocardial remodeling, reparative fibrosis with TGFβ-1-positive myofibroblasts and interstitial inflammation were the major findings in atherosclerotic old rabbits, whereas with ageing alone, interstitial fibrosis with TGFβ-1 negative fibroblasts and VCAM-1 positive microvessels prevailed.

Pericytic tumours is a new category recently introduced in soft tissue pathology describing those entities sharing evidence of myoid differentiation and a tendency of spindle or more rounded cells to grow in a perivascular fashion. The great majority of pericytic tumours are benign but recurrence has been described as well as very rare malignant cases with an aggressive behaviour. Although pericytic tumours arise most commonly in the subcutaneous tissue of distal extremities in middle age patients, additional cases have been recently described in many other organs. Here we describe a case of a 57-year-old man with an 8.5 cm mass of the liver hilus diagnosed as myopericytoma, with particular reference to its biological potential and differential diagnosis. It is important for the pathologists to take this diagnosis into consideration as well for a better management of patient care.

Cellular retinol binding protein-1 regulates retinol bioavailability and contributes to cell differentiation maintenance, but its role in ovarian carcinogenesis remains uncertain. We investigated CRBP-1 expression in ovarian tumors and CRBP-1 signaling-regulated pathways.We performed immunohistochemistry, methylation-specific PCR, gene copy number analysis in ovarian tumors and proliferation/apoptosis evaluation, gene array, blot and real-time PCR in CRBP-1-transfected A2780 ovarian cancer cells.CRBP-1 expression was reduced or absent in G2 and G3 ovarian carcinomas. CRBP-1 silencing in 60% of G2 and 66.7% of G3 carcinomas was due to CRBP-1 promoter methylation. A2780 CRBP-1-transfected cells showed increased retinol-induced apoptosis, retinoid-induced reduced clonogenicity and down-regulation of proliferation and transcription genes, including AKT1, AKT3, EGFR, FOS, JUN, STAT1 and STAT5A.CRBP-1 loss in G2/G3 ovarian carcinomas and increased apoptotic susceptibility to retinoids in CRBP-1-transfected-A2780 cells suggest CRBP-1 screening as a target to ensure efficacy of an adjuvant retinoid therapy.