Erratum: Author Correction: Health and sustainability in post-pandemic economic policies.

[This corrects the article DOI: 10.1038/s41893-020-0563-0.].

Histologic and Radiographic Analysis of Nonhealing Extraction Sockets Treated with Bio-Oss Collagen After a 4-Month Healing Period: A Prospective Descriptive Study in Humans.

Healing of extraction sockets may sometimes result in formation of fibrous tissue instead of bone, even after 4 months, an occurrence that may hinder implant placement. The aim of this preliminary observational study was to histologically evaluate quality and amount of bone regeneration after treating nonhealing sockets with a bovine-derived xenograft enriched with porcine collagen (Bio-Oss Collagen, Geistlich) without barrier membranes. Biopsy specimens were collected during implant placement, 4 months after grafting. A total of 10 cases were treated and evaluated. In all cases, correct implant placement was possible and no implant failure occurred up to 6 months after loading. The histologic analysis demonstrated new bone formation in all specimens. The percentage of newly formed bone was 29.1% (SD 20.71%; range 5% to 48%). Xenograft particles in direct contact with newly formed bone were visible, and mature lamellar bone was observed in 8 cases.

Immunohistochemical expression of basement membrane proteins of verrucous carcinoma of the oral mucosa.

Squamous cell carcinoma (SCC) of the oral cavity is an extremely invasive tumour of stratified squamous epithelium that spreads throughout degradation of the basement membrane (BM) and extra-cellular matrix. Oral verrucous carcinoma (VC) is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. It also has a different clinical behaviour from classical oral SCC. We investigated the immunohistochemical expression of laminin, laminin-5, collagen IV and fibronectin in VC, severe epithelial dysplasia (SED) and SCC in order to analyse if the pattern of these molecules expression contributes to the differences in the biological behaviour of these diseases. The staining pattern of laminin was less intensive in SCC compared with SED and VC, and collagen IV expression was increased in VC compared with SED. Discontinuities of laminin, collagen IV and fibronectin were more evident in SED than in VC. This study indicates that VC has a biological behaviour different from SED or SCC, observable by immunohistochemistry in the BM zone.

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas.

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.

Gorham-Stout syndrome: a monocyte-mediated cytokine propelled disease.

UNLABELLED: We studied the biological features and the immunophenotype of a cell culture established from the lesion of soft tissues of a woman affected by Gorham-Stout syndrome. We found that these cells belonged to a monocytic lineage with some characteristics of immature osteoclasts and were able to release large amounts of osteoclastogenic and angiogenic molecules that may contribute to disease progression. INTRODUCTION: Gorham-Stout syndrome is a rare disease characterized by osteolysis and proliferation of vascular or lymphatic vessels, with a severe outcome. Its etiology and the identification of the cell types involved are completely unknown. MATERIALS AND METHODS: A cell culture from a lesion of soft tissues was established, and its behavior in vitro and in immunodeficient mice was studied. We analyzed (1) the cell phenotype by flow cytometry; (2) the adhesive and migratory properties on different substrates; (3) the ability to differentiate into mature osteoclasts; (4) the production of osteclastogenic and angiogenic molecules; (5) the in vivo angiogenic activity of the cells subcutaneously implanted in mouse in a Matrigel plug; and (6) the ability to recapitulate the disease when transplanted in nude mice. RESULTS AND CONCLUSIONS: The established culture consisted of a morphologically homogeneous cell population belonging to a monocytic lineage having some features of an osteoclast-like cell type. Cells had an invasive phenotype, were angiogenic, and produced osteoclastogenic (IL-6, TGF-beta1, IL-1beta) and angiogenic (vascular endothelial growth factor-A [VEGF-A], CXCL-8) molecules when challenged with inflammatory cytokines. Immunodeficient mice injected with these cells did not show any bone lesions or vascular alteration, but had high amounts of circulating human IL-6 and VEGF-A. Cells isolated from a cutaneous lymphangiomatosis did not show any of these findings. These data suggest that cells of monocyte-macrophage lineage play an essential role in the pathogenesis of Gorham-Stout disease, whose progression is propelled by cytokine circuits that accelerate angiogenesis and osteoclastogenesis.

Toluidine blue uptake in potentially malignant oral lesions in vivo: clinical and histological assessment.

To assess the histological features of in vivo toluidine blue (TB) uptake in potentially malignant oral lesions (PML) and to determine whether any were related to clinical Dark versus Pale Royal Blue stain and/or to the malignant/dysplastic nature of the lesions. Frozen sections were used to evaluate TB extra- and intra-epithelial distribution, depth of penetration and nuclear or extra-nuclear uptake. Eighteen lesions were studied. The clinical appearance of a Dark Royal Blue stain was significantly related to the nuclear uptake of the dye. Conversely Pale Royal Blue staining was unrelated to any histological feature. Dark Royal Blue-malignant lesions had more nuclear uptake than benign lesions. The results suggest that Dark Royal Blue staining is the true positive outcome of a TB test and showed that Dark Royal Blue-malignant and Dark Royal Blue-benign lesions have a different histological pattern of uptake.

Biological factors involved in the osseointegration of oral titanium implants with different surfaces: a pilot study in minipigs.

BACKGROUND: The stability of titanium implants is determined by the rigid load-bearing connections that are formed by the bone, a process that involves a complex network of cells, pro- and anti-inflammatory mediators, and growth factors. The osseointegration processes at the interfaces of machined and porous implants were studied using molecular and histological techniques. METHODS: Two machined and two porous titanium implants were inserted into the tibiae of four minipigs. The animals were sacrificed at 15, 30, 60, and 90 days post-implantation. The levels of bone morphogenetic protein (BMP)-4, transforming growth factor (TGF)-beta1, and tumor necrosis factor (TNF)-alpha were quantified in the peri-implant osseous samples. The levels of interleukin (IL)-1beta, IL-6, IL-10, and TNF-alpha in the serum were also assessed. RESULTS: Histomorphological analysis showed evidence of bone ossification around the porous implant at 60 days. Surrounding the machined implants, highly sclerotic fibrous pads started the healing response at 90 days, and the levels of TGF-beta1 and BMP-4 began to increase at 60 days, at which time bone ossification around the porous implants was already evident. TNF-alpha was not present in the bone next to the implants. The serum levels of cytokines IL-1beta, IL-6, and IL-10 were not increased. The serum level of TNF-alpha increased during the healing process. CONCLUSIONS: We observed that the levels of BMP-4 and TGF-beta1, which play essential roles in the osteogenesis process, increased earlier around the porous implants than around the machined implants. Similarly, the ossification process was initiated earlier at the surfaces of the porous implants than at the surfaces of the machined implants.

Follicular origin of a subset of CD5+ diffuse large B-cell lymphomas.

Most follicular lymphomas (FLs) have a phenotype consistent with the origin from CD5-, CD10+, bcl-6+ follicular center cells and can progress to diffuse large B-cell lymphoma (DLBCL). CD5 is expressed in about 10% of DLBCLs, showing prognostic value, whereas expression is rare in FL. We present 6 cases with coexisting features of CD5+ FL and CD5+ DLBCL, supporting a follicular origin for some CD5+ DLBCLs. The follicular areas showed a meshwork of CD21+ follicular dendritic cells that were lacking in the DLBCL areas. All cases showed a clonal CD19+, CD20+, CD5+, and CD10+ population in both follicular and diffuse areas. Molecularly, 4 of 6 cases demonstrated immunoglobulin heavy chain rearrangements and 1 case, a bcl-2/immunoglobulin heavy chain gene rearrangement. Somatic hypermutations were high in all 4 cases, in keeping with their germinal center origin. Four of five patients died of disease within 42 months, consistent with the proposed prognostic value of CD5 expression in DLBCL. Our data describe an aggressive variant of CD5+ FL suggesting the follicular origin of some CD5+ DLBCLs.

Oral mucosal melanoma: a series of case reports.

INTRODUCTION: Due to the rarity of oral malignant melanomas case reports are a necessary source of information. Ten new cases are reported with a minimum follow-up of 3 years. PATIENTS AND METHODS: Patients were treated during a period of 10 years. Clinical, demographic and pathologic findings were examined. RESULTS: In 6 males (60%) and 4 females with a mean age of 64.3 years the tumour locations were: hard palate-maxillary gingiva (3 cases), maxillary gingiva (2), lower gingiva (2), tongue (2), hard/soft palate-buccal mucosa (1). Pre-existing melanotic pigmentation had been present in 4 patients. Four patients were in stage I, 5 in stage II, and 1 in stage III. Surgical excision was the primary treatment in 9 cases. Five patients underwent simultaneous neck dissections. All patients received radiation and multimode adjuvant therapies. After a 3-year follow-up 3 patients are still alive (50% (2/4) of those presenting in stage I and 20% (1/5) in stage II). CONCLUSIONS: Due to the rarity of oral melanoma, individual experience is limited. The poor prognosis and the different treatments reflect this situation.

Vasculogenic potential of long term repopulating cord blood progenitors.

In the adult, involvement of bone marrow-derived circulating endothelial progenitor cells (EPCs) in tissue revascularization (vasculogenesis) and the cooperation of hematopoietic cell subsets in supporting this process have been described in different experimental animal models. However, the effective contribution of such cells in restoring organ vascularization in a clinical setting needs to be clarified. In this study, a mouse transplantation model was engrafted by human cord blood hematopoietic stem and progenitor cells to follow the behavior of donor-derived endothelial and hematopoietic cells in the presence of a localized source of an angiogenic inducer. Human endothelial markers (CD31+/CD45-, VE-cadherin+) were always detectable in the bone marrow of transplanted mice, while they were only randomly detectable in peripheral neovascularization sites. To investigate the ability of human transplanted hematopoietic stem cells to support new vessel formation in response to altered homeostatic conditions, chimeric mice were further treated by systemic injection of human mononuclear cells (MNCs). Our data indicate that MNC administration in transplanted mice enhances vasculogenesis in the newly formed vessels. Taken together these results suggest that human-derived EPCs, long-term engrafting a xenotransplantation model, have hematopoietic and endothelial developmental potential, which can be modulated by altering the physiological conditions of host microenvironment.

Constitutive expression of interleukin-18 in head and neck squamous carcinoma cells.

BACKGROUND: Interleukin (IL)-18 is a potent immunomodulatory cytokine promoting TH-1 and cytotoxic immune responses through interferon (IFN)-gamma induction. The aim of this study was to investigate the production of IL-18 by squamous cell carcinoma of the head and neck (HNSCC). METHODS: The expression of IL-18 was analyzed by reverse transcriptase-polymerase chain reaction, Western blot, and ELISA in untreated and 5-fluorouracil (5-FU)-treated HNSCC cell lines. Immunohistochemical analysis was performed on tumor specimens from 16 patients with primary invasive HNSCC. RESULTS: We have demonstrated that HNSCC cell lines express IL-18 at the mRNA, as well as the protein, level. However, the IL-18 protein was expressed intracellularly and predominantly released as an unprocessed inactive 24-kDa form. After exposure to 5-FU, the processed form of IL-18 was detected in the supernatants of both HNSCC cell lines. CONCLUSIONS: These results indicate that HNSCC cells are a potential source of IL-18 cytokine. The finding that the exposure to 5-FU can elicit its processing suggests a novel target for immunomodulatory intervention in patients with HNSCC.

Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders.

In this study we investigated telomere restriction fragment (TRF) length in a panel of mature B-cell lymphoproliferative disorders (MBCLDs) and correlated this parameter with histology and histopathogenesis in relation to the germinal center (GC). We assessed 123 MBCLD samples containing 80% or more tumor cells. TRF length was evaluated by Southern blot analysis using a chemiluminescence-based assay. GC status was assessed through screening for stable and ongoing somatic mutations within the immunoglobulin heavy-chain genes. Median TRF length was 6170 bp (range, 1896-11 200 bp) and did not correlate with patient age or sex. TRF length was greater in diffuse large cell lymphoma, Burkitt lymphoma, and follicular lymphoma (medians: 7789 bp, 9471 bp, and 7383 bp, respectively) than in mantle cell lymphoma and chronic lymphocytic leukemia (medians: 3582 bp and 4346 bp, respectively). GC-derived MBCLDs had the longest telomeres, whereas those arising from GC-inexperienced cells had the shortest (P < 10(-9)). We conclude that (1) TRF length in MBCLD is highly heterogeneous; (2) GC-derived tumors have long telomeres, suggesting that minimal telomere erosion occurs during GC-derived lymphomagenesis; and (3) the short TRF lengths of GC-inexperienced MBCLDs indicates that these neoplasms are good candidates for treatment with telomerase inhibitors, a class of molecules currently the subject of extensive preclinical evaluation.

Angiopoietin 2 induces cell cycle arrest in endothelial cells: a possible mechanism involved in advanced plaque neovascularization.

OBJECTIVE: To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques. METHODS AND RESULTS: Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (DeltaSTAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions. CONCLUSIONS: In advanced lesions, the activation of the Tie2-mediated STAT5 signaling pathway may negatively regulate vessel growth.

Onset of oral extranodal large B-cell non-Hodgkin's lymphoma in a patient with polycythemia vera: a rare presentation.

Polycythemia vera (PV) is a hematologic malignancy characterized by excessive proliferation of erythroid, myeloid and megakaryocytic elements in the bone marrow. Patients suffering from PV may subsequently be affected by other neoplasms of the haematopoietic system, but lymphomas are very rare and no cases of oral lymphoma have yet been reported. We report the case of a patient with PV in whom a primary non-Hodgkin's lymphoma (high grade malignancy on the Kiel scale) of the oral cavity subsequently developed. The case is unusual for its extranodal onset, its location in the oral cavity and the clinical presentation.

Immunohistochemical expression analysis of the human interferon-inducible gene IFI16, a member of the HIN200 family, not restricted to hematopoietic cells.

This is the first description of an extensive immunohistochemical analysis of interferon (IFN)-inducible gene IFI16 expression in normal tissues. Immunohistochemical detection of IFI16 in paraffin-embedded tissues is achieved by using a polyclonal antibody raised against its C-terminal fragment that recognizes its three closely migrating isoforms in Western blotting. The results clearly indicate that IFI16 expression is not restricted to the hematopoietic compartment. In normal adult human tissues, it is prominent in stratified squamous epithelia and particularly intense in parabasal cells in the proliferating compartments, but it gradually decreases in the more differentiated suprabasal layers. Understanding of IFI16 expression in vivo is essential for interpretation of the results obtained from in vitro studies and elucidation of its physiologic role. The constitutive expression and wider distribution of IFI16 in normal human tissues, not restricted to the hematopoietic compartment, strongly support the possibility of an important role in cell differentiation that can be further modulated by other stimuli, such as IFN.