Prognostic relevance of MMP-2 (72-kD collagenase IV) in gastric cancer

The association of MMP-2 (matrix metalloproteinase 2, 72-kD collagenase IV) with invasive and metastatic capacity of tumor cells has implicated a potential role in the prognosis for cancer patients. However, no larger study has been done to prove this hypothesis. The present study was therefore designed to investigate the prognostic impact of MMP-2 in a prospective series of 203 gastric cancer patients. MMP-2 expression was measured immunohistochemically and scored semiquantitatively (score 0-3) in carcinoma cells, and results were correlated with clinicopathological tumor parameters and parameters of the urokinase-type plasminogen activator (uPA) system. Survival analyses were done using the Kaplan-Meier method (log-rank statistics) and multivariate Cox analysis. Significant correlations were found for MMP-2 and Lauren's classification, M stage and proteases/inhibitors of the uPA system in the primary tumor. Kaplan-Meier analysis revealed an association of increasing MMP-2 expression with worse prognosis. This was especially seen in patients with a parallel high expression of uPA receptor. However, differences in survival probabilities between low and high MMP-2 levels were not significant. In a separate analysis of diffuse-type cancers, MMP-2 was significantly associated with disease-free (p = 0.0056) and overall survival (p = 0.0426). Multivariately, MMP-2 was not an independent parameter. Our results demonstrate that there is an association of immunohistochemical detection of MMP-2 with prognosis of cancer patients. For diffuse gastric cancers, it is a significant prognostic parameter, however, not of independent impact. The study further suggests that consideration of interrelated tumor-associated proteases like uPA receptor in combination with MMP-2 may improve its prognostic power

The protympanum, protiniculum and subtensor recess: an endoscopic morphological anatomy study

Objectives: An anatomical study was performed to describe the endoscopic anatomy and variations of the protympanum, including classification of the protiniculum and subtensor recess. Methods: A retrospective review was conducted of video recordings of cadaveric dissections and surgical procedures, which included visualisation of the protympanum, across 4 tertiary university referral centres over a 16-month period. A total of 97 ears were used in the analysis. Results: A quadrangular conformation of the protympanum was seen in 60 per cent of ears and a triangular conformation in 40 per cent. The protiniculum was type A (ridge) in 58 per cent, type B (bridge) in 23 per cent and type C (absent) in 19 per cent. The subtensor recess was type A (absent) in 30 per cent, type B (shallow) in 48 per cent and type C (deep) in 22 per cent. Conclusion: The protympanum is an area that has been ignored for many years because of difficulties in visualising it with an operating microscope. However, modern endoscopic equipment has changed this, providing detailed anatomical knowledge fundamental to ensuring the safety of endoscopic surgical procedures in the region

Endoscopic Middle Ear Surgery: Tips and Pearls

Program Description: Middle ear surgery can generally be performed with the aid of an operating microscope. However, under a potentially minimally invasive trans-canal approach, it is very difficult to operate on several sites using a microscope alone unless the surrounding bone is removed and retro-auricular approaches are performed. Such sites may include the epitympanum as well as the inferior and posterior parts of the mesotympanum. Although it has been more than 15 years since the introduction of operative endoscopy to middle ear surgery there is still a very limited role for the endoscope in the surgical management of middle ear disease across the globe. There are several possible reasons for that, such as the current idea of a limited and marginal role for endoscopes in middle ear surgery, a potentially long learning curve through the hassles and tribulations of adapting newer techniques and newer instrumentation, and some resistance, especially with otologists who are very comfortable with the use of microscopes. The operating microscope provides a very good quality magnified image in a straight line, however, the surgeon\u2019s field of view is limited to the narrowest segment of the ear canal when using a transcanal approach. On the other hand, endoscopes also provide a magnified vision that enables the ability to change rapidly from a close-up to a wide angle view, just by going closer or by withdrawing the instrument. Further, it provides an all-round vision to the surgeon who can rotate angled endoscopes to visualize the deep and hidden structures. In this miniseminar, we are going to discuss, with the help of very nice quality surgical movies, endoscopic anatomic dissection images and videos, virtual reality objects and also augmented reality capability the current techniques for endoscopic middle ear dissection, and surgical management of several middle ear diseases, such as tympanic membrane perforations, cholesteatomas, ossicular chain reconstruction and also stapedotomies, all performed with endoscopes discussing and commenting the equipment needed, surgical indications, also showing the potential advantages and disadvantages of the procedures, postoperative care and results and some interesting tips and pearls regarding this new way to surgically manage middle ear diseases. Educational Objectives: 1) Learn and review the endoscopic anatomy of the middle ear, discussing anatomic landmarks. 2) Identify the actual indications and limitations of this minimally invasive approach. 3) Describe and demonstrate step-wise endoscopic middle ear approaches for several diseases of this area

Endoscopic Ear Surgery: Tips and Pearls

Program Description: Endoscopic ear surgery (EES) is a current hot topic in our specialty; however, it is not entirely correct to introduce EES as \u201cnew.\u201d Although not new, it is clear that during the past few years, endoscopes have proven to be safe and effective instruments to manage ear diseases in a minimally invasive way, preserving important anatomic structures, allowing functional approaches to well-known conditions. Moreover, endoscopes have provided a better view and understanding of traditional middle ear anatomy and physiology, allowing new landmarks, novel concepts of tissue preservation, ventilation routes, and management of other conditions within the middle ear and beyond. Educational Objectives: (1) Describe the endoscopic anatomy of the middle and inner ears, discussing the concepts of related physiology. (2) Examine totally endoscopic and combined surgical approaches to middle ear conditions, discussing the possible advantages and disadvantages. (3) Present the instruments needed, system setup, surgical skills, learning curve, and also some important tips and pearls to surgeons to start doing endoscopic ear surgery

Endoscopic Middle Ear Surgery: Tips and Pearls

Program Description: We are going to discuss, with excellent quality presentations, high-definition surgical movies, endoscopic anatomic dissection images, virtual reality, and augmented reality, the current techniques of endoscopic middle ear surgery, discussing and commenting on the equipment needed, surgical indications, potential advantages and disadvantages, postoperative care, results, and some tips and pearls. Educational Objectives: 1) Learn and review the endoscopic anatomy of the middle ear, discussing the important endoscopic anatomic landmarks and showing new endoscopic anatomical findings. 2) Identify the actual indications and limitations of this minimally invasive approach. 3) Describe and demonstrate stepwise endoscopic middle ear approaches for several diseases of this area

Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma

Loss-of-function mutations in the RB1 tumour suppressor are key drivers in cancer, including osteosarcoma. RB1 loss-of-function compromises genome-maintenance and hence could yield vulnerability to therapeutics targeting such processes. Here we demonstrate selective hypersensitivity to clinically-approved inhibitors of Poly-ADP-Polymerase1,2 inhibitors (PARPi) in RB1-defective cancer cells, including an extended panel of osteosarcoma-derived lines. PARPi treatment results in extensive cell death in RB1-defective backgrounds and prolongs survival of mice carrying human RB1-defective osteosarcoma grafts. PARPi sensitivity is not associated with canonical homologous recombination defect (HRd) signatures that predict PARPi sensitivity in cancers with BRCA1,2 loss, but is accompanied by rapid activation of DNA replication checkpoint signalling, and active DNA replication is a prerequisite for sensitivity. Importantly, sensitivity in backgrounds with natural or engineered RB1 loss surpasses that seen in BRCA-mutated backgrounds where PARPi have established clinical benefit. Our work provides evidence that PARPi sensitivity extends beyond cancers identifiable by HRd and advocates PARP1,2 inhibition as a personalised strategy for RB1-mutated osteosarcoma and other cancers

Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy

Effects of methods of descending stairs forwards versus backwards on knee joint force in patients with osteoarthritis of the knee: a clinical controlled study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the kinetic characteristics of compensatory backward descending movement performed by patients with osteoarthritis of the knee.</p> <p>Methods</p> <p>Using a three-dimensional motion analysis system, we investigated lower extremity joint angles, joint moments, joint force of the support leg in forward and backward descending movements on stairs, and joint force of the leading leg at landing in 7 female patients with osteoarthritis of the knee.</p> <p>Results</p> <p>Compared with the forward descending movement, knee joint angle, joint moment and joint force of the support leg all decreased in the backward descending movement. Joint force of the leading leg at landing was also reduced in the backward descending movement. In addition, we confirmed that the center of body mass was mainly controlled by the knee and ankle joints in the forward descending movement, and by the hip joint in the backward descending movement.</p> <p>Conclusions</p> <p>Since it has been reported that knee flexion angle and extensor muscle strength are decreased in patients with osteoarthritis of the knee, we believe that backward descending movement is an effective method to use the hip joint to compensate forthese functional defects. In addition, due to the decreased knee joint force both in the leading and support legs in backward descending movement, the effectiveness of compensatory motion for pain control and knee joint protection was also suggested.</p

MEDICC2: whole-genome doubling aware copy-number phylogenies for cancer evolution

Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states