Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Preliminaries: Note on conventions Basic homotopy notions Surgery below the middle dimension Appendix: Applications Simple Poincare complexes The main theorem: Statement of results An important special case The even-dimensional case The odd-dimensional case The bounded odd-dimensional case The bounded even-dimensional case Completion of the proof Patterns of application: Manifold structures on Poincare complexes Applications to submanifolds Submanifolds: Other techniques Separating submanifolds Two-sided submanifolds One-sided submanifolds Calculations and applications: Calculations: Surgery obstruction groups Calculations: The surgery obstructions Applications: Free actions on spheres General remarks An extension of the Atiyah-Singer $G$-signature theorem Free actions of $S^1$ Fake projective spaces (real) Fake lens spaces Applications: Free uniform actions on euclidean space Fake tori Polycyclic groups Applications to 4-manifolds Postscript: Further ideas and suggestions: Recent work Function space methods Topological manifolds Poincare embeddings Homotopy and simple homotopy Further calculations Sullivan's results Reformulations of the algebra Rational surgery References Index.

Surgery on compact manifolds

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the t...

/pdf/the-surgical-infection-society-revised-guidelines-on-the-2xkh58wns3.pdf

The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection.

Intra-abdominal infections (IAIs) are common surgical emergencies and have been reported as major contributors to non-trauma deaths in the emergency departments worldwide. The cornerstones of effective treatment of IAIs are early recognition, adequate source control, and appropriate antimicrobial therapy. Prompt resuscitation of patients with ongoing sepsis is of utmost important. In hospitals worldwide, non-acceptance of, or lack of access to, accessible evidence-based practices and guidelines result in overall poorer outcome of patients suffering IAIs. The aim of this paper is to promote global standards of care in IAIs and update the 2013 WSES guidelines for management of intra-abdominal infections.

/pdf/the-management-of-intra-abdominal-infections-from-a-global-4ps525uhu4.pdf

The management of intra-abdominal infections from a global perspective: 2017 WSES guidelines for management of intra-abdominal infections

Local recurrence of colorectal cancer after 'curative' surgery is a major clinical problem. Typically, 50-70 per cent of patients presenting to a surgical clinic will undergo apparently curative surgery for disease and of these about 10-25 per cent will develop local recurrence, in either the tumour bed or bowel wall. The wide differences in local recurrence rate both between and within institutions is probably caused by variation in surgical technique. The main causes of local recurrence are inadequate excision of the primary tumour or the draining lymph nodes, and intraoperative tumour cell implantation. The most significant single factor prognostic of local recurrence is Dukes' tumour stage. Other important factors include tumour grade and fixity, level of the tumour in the rectum, blood and lymphatic vessel invasion, inadvertent perforation of the tumour during resection, and the surgeon's experience. The prognosis of patients with local recurrence is poor. Prevention of recurrence by adequate surgery and adjuvant therapy as well as its early detection offer the best prospect of improving results.

Local recurrence of colorectal cancer: The problem, mechanisms, management and adjuvant therapy

The paradigm of a therapy aimed at inhibiting the formation of blood vessels, which would consequentially deprive cells and tissues of oxygen and nutrients, was born from the concept pioneered by the late Judah Folkman that blood vessel formation is central to the progression and maintenance of diseases which involve cellular metabolism and tissue expansion, and cancer in particular. The prototype targeted angiogenesis inhibitor anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was approved in 2004 for colorectal cancer, and has since been approved for other cancers. Rheumatoid arthritis (RA) is a chronic inflammatory disease, during which inflamed tissue invades and destroys cartilage and bone. The tissue expansion, invasion, expression of cytokines and growth factors and areas of hypoxia which are a feature of RA have resulted in the hypothesis that angiogenesis inhibition may also be beneficial in RA, drawing on the success of bevacizumab. This review focuses on our current understanding of the importance of angiogenesis in RA, and on the lessons which may be learnt from the clinical experiences of angiogenesis blockade, particularly in colorectal cancer.

Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience

Imaging of tumour therapy responses by dynamic CT.

OBJECTIVE: Diltiazem is a calcium channel blocker that has shown potential to heal chronic anal fissures. We have prospectively evaluated the treatment of patients with anal fissure with diltiazem gel (SLA Pharma, UK). PATIENTS AND METHODS: All patients with chronic anal fissure from September 1999 to May 2000 were treated topically with 8 mg 2% diltiazem hydrochloride gel (equivalent to 2 cm of gel supplied by SLA Pharma) three times daily. The 23 patients (12 female), median age 45 (range 22-80) years had a 2-36 month (median 6 months) history of fissure. These were associated with a sentinel tag in 9 (39%) patients. RESULTS: The fissure healed in 11 (48%) of 23 patients, including 6 (75%) of 8 patients who previously failed to heal with GTN ointment. There were no recurrences at 3 months and no adverse effects. Of the 12 patients who did not respond to diltiazem, 4 have undergone sphincterotomy. CONCLUSION: Diltiazem gel has a healing rate similar to that observed with GTN ointment but there were no adverse effects, the recurrence rate was lower, and diltiazem was effective in 75% of patients previously treated unsuccessfully with GTN ointment.

Successful treatment of chronic anal fissure with diltiazem gel.

Colorectal cancer (CRC) is characterised by hypoxia, which activates gene transcription through hypoxia-inducible factors (HIF), as well as by expression of epidermal growth factor (EGF) and EGF receptors, targeting of which has been demonstrated to provide therapeutic benefit in CRC. Although EGF has been demonstrated to induce expression of angiogenic mediators, potential interactions in CRC between EGF-mediated signalling and the hypoxia/HIF pathway remain uncharacterised. PCR-based profiling was applied to identify angiogenic genes in Caco-2 CRC cells regulated by hypoxia, the hypoxia mimetic dimethyloxallylglycine (DMOG) and/or EGF. Western blotting was used to determine the role of HIF-1alpha, HIF-2alpha and MAPK cell signalling in mediating the angiogenic responses. We identified a total of 9 angiogenic genes, including angiopoietin-like (ANGPTL) 4, ephrin (EFNA) 3, transforming growth factor (TGF) β1 and vascular endothelial growth factor (VEGF), to be upregulated in a HIF dependent manner in Caco-2 CRC cells in response to both hypoxia and the hypoxia mimetic dimethyloxallylglycine (DMOG). Stimulation with EGF resulted in EGFR tyrosine autophosphorylation, activation of p42/p44 MAP kinases and stabilisation of HIF-1α and HIF-2α proteins. However, expression of 84 angiogenic genes remained unchanged in response to EGF alone. Crucially, addition of DMOG in combination with EGF significantly increased expression of a further 11 genes (in addition to the 9 genes upregulated in response to either DMOG alone or hypoxia alone). These additional genes included chemokines (CCL-11/eotaxin-1 and interleukin-8), collagen type IV α3 chain, integrin β3 chain, TGFα and VEGF receptor KDR. These findings suggest that although EGFR phosphorylation activates the MAP kinase signalling and promotes HIF stabilisation in CRC, this alone is not sufficient to induce angiogenic gene expression. In contrast, HIF activation downstream of hypoxia/DMOG drives expression of genes such as ANGPTL4, EFNA3, TGFβ1 and VEGF. Finally, HIF activation synergises with EGF-mediated signalling to additionally induce a unique sub-group of candidate angiogenic genes. Our data highlight the complex interrelationship between tumour hypoxia, EGF and angiogenesis in the pathogenesis of CRC.

/pdf/identification-of-the-angiogenic-gene-signature-induced-by-223iiivtoq.pdf

Identification of the angiogenic gene signature induced by EGF and hypoxia in colorectal cancer

Indoramin is an α1‐adrenoceptor antagonist and has been shown to reduce anal resting pressure. Its therapeutic potential has not been explored. The aim of this study was to determine the outcome of treatment with oral indoramin on patients with chronic anal fissure in the setting of a double‐blind randomized placebo‐controlled trial.

Double-blind randomized placebo-controlled trial of oral Indoramin to treat chronic anal fissure

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