Arthroscopic patterns of the poster-medial aspect of the knee joint: classification of the gastrocnemius-semimembranosus gateway and its relationship with Baker's cyst

Background The gastrocnemius-semimembranosus bursa may communicate with the knee joint. The arthroscopic anatomy of the posteromedial aspect varies depending on the angle of the oblique popliteal ligament, the level at which it crosses the medial gastrocnemius tendon, and its relationship with the capsular joint and synovia. The aim of this paper is to identify possible patterns, and to evaluate their characteristics and their relationship with Baker’s cyst. Methods data archived from 185 consecutive arthroscopies were evaluated; an anatomic description and classification was carried out; the percentages of association with BC and the associated pathologies were reported. Results The different anatomies were classified into six groups based on the relationship above the medial gastrocnemius tendon, the capsular joint and synovia. The prevalence of Baker’s cyst was 28.3%. The main associated intra-articular pathological condition was the contemporary presence of a meniscal tear and chondropathy. Conclusion Exploration of the posterior aspect of the knee must be performed routinely. Knowing the possible anatomy patterns of the posteromedial arthroscopic aspect of the knee joint could help to identify the cyst and its gateway, thus facilitating its treatment

Pathogenetic and Prognostic Significance of Inactivation of RASSF Proteins in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide, with limited treatment options and a dismal prognosis. Thus, there is a strong need to expand the basic and translational research on this deadly disease in order to improve the prognosis of HCC patients. Although the etiologic factors responsible for HCC development have been identified, the molecular pathogenesis of liver cancer remains poorly understood. Recent evidence has shown the frequent downregulation of Ras association domain family (RASSF) proteins both in the early and late stages of hepatocarcinogenesis. Here, we summarize the data available on the pathogenetic role of inactivation of RASSF proteins in liver cancer, the molecular mechanisms responsible for suppression of RASSF proteins in HCC, and the possible clinical implications arising from these discoveries. Altogether, the data indicate that inactivation of the RASSF1A tumor suppressor is ubiquitous in human liver cancer, while downregulation of RASSF2 and RASSF5 proteins is limited to specific HCC subsets. Also, the present findings speak in favour of therapeutic strategies aimed at reexpressing RASSF1A, RASSF2, and RASSF5 genes and/or inactivating the RASSF cellular inhibitors for the treatment of human liver cancer

Cruciate-Retaining Total Knee Arthroplasty

The debate over the relative merits of substituting or retaining the posterior cruciate ligament (PCL) in total knee arthroplasty is still ongoing. The potential advantages of PCL preservation are a more natural femoral rollback, the presence of a structure critical for the proprioception, the maintenance of a native central stabilizer of the joint, and low shear stress on the bone-cement interface of the tibial component. Numerous retrospective studies of cruciate-retaining (CR) total knee arthroplasties have demonstrated consistently good clinical results and excellent intermediate and long-term survival. The main criticisms of the surgical technique are that the distal attachment of the PCL is vulnerable to injury and that balancing the PCL can be difficult; based on our experience, surgical tricks will be described to avoid the avulsion of the ligament and they will be discussed the main points to consider when you can find a discrepancy between flexion and extension stability. Based on the current evidence, we conclude that with a standardized technique, this type of implant should be preferred even in those cases where the sacrifice of the cruciate ligament seems to be the easiest way

Comorbidity‐related quality of life in anterior cruciate ligament insufficiency: A cross‐sectional study involving 282 candidates for arthroscopic reconstruction

Background and purpose Comorbidity‐adjusted health‐related quality of life (HRQoL) in anterior cruciate ligament insufficiency (ACLI) has not been assessed to date. A cross‐sectional study was conducted to test the hypothesis that HRQoL in ACLI is comorbidity‐related and differs from the Italian norm.Methods 282 chronically ACL‐insufficient candidates for arthroscopic reconstruction with or without meniscal and/or focal chondral lesions were studied. Knee function was evaluated with IKDC form, HRQoL with SF‐36, and associated medical comorbidities with a self‐administered questionnaire allowing calculation of a comorbidity index (CI). Patients were stratified according to CI into subgroup A (CI = 0) and subgroup B (CI > 0). The SF‐36 profiles in the whole sample and in subgroups A and B were compared with the Italian norm.Results Of the 282 patients, 82 had associated comorbidity and 200 did not. Patients with comorbidity were older and had a higher degree of knee laxity than patients without comorbidity...

Notch2 controls hepatocyte-derived cholangiocarcinoma formation in mice.

Liver cancer comprises a group of malignant tumors, among which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common. ICC is especially pernicious and associated with poor clinical outcome. Studies have shown that a subset of human ICCs may originate from mature hepatocytes. However, the mechanisms driving the trans-differentiation of hepatocytes into malignant cholangiocytes remain poorly defined. We adopted lineage tracing techniques and an established murine hepatocyte-derived ICC model by hydrodynamic injection of activated forms of AKT (myr-AKT) and Yap (YapS127A) proto-oncogenes. Wild-type, Notch1 flox/flox , and Notch2 flox/flox mice were used to investigate the role of canonical Notch signaling and Notch receptors in AKT/Yap-driven ICC formation. Human ICC and HCC cell lines were transfected with siRNA against Notch2 to determine whether Notch2 regulates biliary marker expression in liver tumor cells. We found that AKT/Yap-induced ICC formation is hepatocyte derived and this process is strictly dependent on the canonical Notch signaling pathway in vivo. Deletion of Notch2 in AKT/Yap-induced tumors switched the phenotype from ICC to hepatocellular adenoma-like lesions, while inactivation of Notch1 in hepatocytes did not result in significant histomorphological changes. Finally, in vitro studies revealed that Notch2 silencing in ICC and HCC cell lines down-regulates the expression of Sox9 and EpCAM biliary markers. Notch2 is the major determinant of hepatocyte-derived ICC formation in mice

Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system

Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC

Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide, characterized by clinical aggressiveness, resistance to conventional chemotherapy, and high lethality. Consequently, there is an urgent need to better delineate the molecular pathogenesis of HCC to develop new preventive and therapeutic strategies against this deadly disease. Noticeably, emerging evidence indicates that proteins involved in lipid biosynthesis are important mediators along the development and progression of HCC in humans and rodents. Here, we provide a comprehensive overview of: (a) The pathogenetic relevance of lipogenic proteins involved in liver carcinogenesis, with a special emphasis on the master fatty acid regulator, fatty acid synthase (FASN); (b) The molecular mechanisms responsible for unrestrained activation of FASN and related fatty acid biosynthesis in HCC; (c) The findings in experimental mouse models of liver cancer and their possible clinical implications; (d) The existing potential therapies targeting FASN. A consistent body of data indicates that elevated levels of lipogenic proteins, including FASN, characterize human hepatocarcinogenesis and are predictive of poor prognosis of HCC patients. Pharmacological or genetic blockade of FASN is highly detrimental for the growth of HCC cells in both in vitro and in vivo models. In conclusion, FASN is involved in the molecular pathogenesis of HCC, where it plays a pivotal role both in tumor onset and progression. Thus, targeted inhibition of FASN and related lipogenesis could be a potentially relevant treatment for human HCC. Introduction: Human Hepatocellular Carcinom