COVID-19. Pandemic surgery guidance

Abstract – Based on high quality surgery and scientific data, scientists and surgeons are committed to protecting patients as well as healthcare staff and hereby provide this Guidance to address the special issues circumstances related to the exponential spread of the Coronavirus disease 2019 (COVID-19) during this pandemic. As a basis, the authors used the British Intercollegiate General Surgery Guidance as well as recommendations from the USA, Asia, and Italy. The aim is to take responsibility and to provide guidance for surgery during the COVID-19 crisis in a simplified way addressing the practice of surgery, healthcare staff and patient safety and care. It is the responsibility of scientists and the surgical team to specify what is needed for the protection of patients and the affiliated healthcare team. During crises, such as the COVID-19 pandemic, the responsibility and duty to provide the necessary resources such as filters, Personal Protective Equipment (PPE) consisting of gloves, fluid resistant (Type IIR) surgical face masks (FRSM), filtering face pieces, class 3 (FFP3 masks), face shields and gowns (plastic ponchos), is typically left up to the hospital administration and government. Various scientists and clinicians from disparate specialties provided a Pandemic Surgery Guidance for surgical procedures by distinct surgical disciplines such as numerous cancer surgery disciplines, cardiothoracic surgery, ENT, eye, dermatology, emergency, endocrine surgery, general surgery, gynecology, neurosurgery, orthopedics, pediatric surgery, reconstructive and plastic surgery, surgical critical care, transplantation surgery, trauma surgery and urology, performing different surgeries, as well as laparoscopy, thoracoscopy and endoscopy. Any suggestions and corrections from colleagues will be very welcome as we are all involved and locked in a rapidly evolving process on increasing COVID-19 knowledg

Imagine a world without cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Since the War on Cancer was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type. Discussion Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patients own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy. Summary Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer

Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3?

Over the past decade, significant improvements have been made in the treatment of chronic hepatitis C (CHC), especially with the introduction of combined therapy using both interferon and ribavarin. The optimal dose and duration of treatment is still a matter of debate and, importantly, the efficacy of this combined treatment varies with the viral genotype responsible for infection. In general, patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1. The introduction of a pegylated version of interferon in the past decade has produced better clinical outcomes in patients infected with viral genotype 1. However, the published literature shows no improvement in clinical outcomes in patients infected with viral genotypes 2 or 3 when they are treated with pegylated interferon as opposed to non-pegylated interferon, both given in combination with ribavarin. This is significant because the cost of a 24-wk treatment with pegylated interferon in less-developed countries is between six and 30 times greater than that of treatment with interferon. Thus, clinicians need to carefully consider the cost-versus-benefit of using pegylated interferon to treat CHC, particularly when there is no evidence for clinically measurable benefits in patients with genotypes 2 and 3 infections

Prelude and premise to the special issue: disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “

The vast majority of anticancer strategies are symptomatic but in order to achieve some tangible progress, we need to identify the cause(s) of the majority of cancers. There is a kind of zeitgeist that findings in genetics, namely somatic mutations, are reflexively viewed as being causative for carcinogenesis, although some 80% of all cancers are presently termed “sporadic” (i.e., with no proven cause). The observation that one inch of cancerous liver tissue can have more than 100 000 000 mutations and an identical mutation can result in different phenotypes, depending on the environment surrounding that mutation, makes it very unlikely that mutations by themselves are causative of most cancers. 4open debuts its Special Issue series with papers that provide strong evidence that carcinogenesis consists of a 6-step sequence (1) a pathogenic stimulus followed by (2) chronic inflammation from which develops (3) fibrosis with associated remodeling of the extracellular microenvironment, and from these changes a (4) precancerous niche (PCN), a product of fibrosis with remodeling by persistent inflammation develops which triggers the deployment of (5) a chronic stress escape strategy and when this fails to be resolved it results in (6) the normal cell to cancerous cell transition. This Special Issue contains separate papers discussing undervalued ubiquitous proteins, chronic inflammation, eicosanoids, microbiome and morbid obesity, PCN, cell transition, followed by altered signaling induced by Metformin, NF-κB signaling and crosstalk during carcinogenesis, and a brief synopsis. In essence, the available evidence, both in vitro and in vivo, lends credence to the proposition that the majority of cancers occur from a disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Microbiome and morbid obesity increase pathogenic stimulus diversity

The microbiome, the relationship between environmental factors, a high-fat diet, morbid obesity, and host response have been associated with cancer, only a small fraction of which (<10%) are genetically triggered. This nongenetic association is underpinned by a worldwide increase in morbid obesity, which is associated with both insulin resistance and chronic inflammation. The connection of the microbiome and morbid obesity is reinforced by an approximate shift of about 47% in the estimated total number of bacteria and an increase from 38,000,000,000,000 in a reference man to 56,000,000,000,000 in morbid obesity leading to a disruption of the microbial ecology within the gut. Humans contain 6,000,000,000 microbes and more than 90% of the cells of the human body are microorganisms. Changes in the microflora of the gut are associated with the polarization of ion channels by butyrate, thereby influencing cell growth. The decrease in the relative proportion of Bacteroidetes together with a change in the fermentation of carbohydrates by bacteria is observed in morbid obesity. The disruption of homeostasis of the microflora in the obese changes signaling and crosstalk of several pathways, resulting in inflammation while suppressing apoptosis. The interactions between the microbiome and morbid obesity are important to understand signaling and crosstalk in the context of the progression of the six-step sequence of carcinogenesis. This disruption of homeostasis increases remodeling of the extracellular matrix and fibrosis followed by the none-resolvable precancerous niche as the internal pathogenic stimuli continue. The chronic stress explains why under such circumstances there is a greater proclivity for normal cells to undergo the transition to cancer cells

Eicosanoids in carcinogenesis

Inflammation is the body's reaction to pathogenic (biological or chemical) stimuli and covers a burgeoning list of compounds and pathways that act in concert to maintain the health of the organism. Eicosanoids and related fatty acid derivatives can be formed from arachidonic acid and other polyenoic fatty acids via the cyclooxygenase and lipoxygenase pathways generating a variety of pro- and anti-inflammatory mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins and others. The cytochrome P450 pathway leads to the formation of hydroxy fatty acids, such as 20-hydroxyeicosatetraenoic acid, and epoxy eicosanoids. Free radical reactions induced by reactive oxygen and/or nitrogen free radical species lead to oxygenated lipids such as isoprostanes or isolevuglandins which also exhibit pro-inflammatory activities. Eicosanoids and their metabolites play fundamental endocrine, autocrine and paracrine roles in both physiological and pathological signaling in various diseases. These molecules induce various unsaturated fatty acid dependent signaling pathways that influence crosstalk, alter cell–cell interactions, and result in a wide spectrum of cellular dysfunctions including those of the tissue microenvironment. Although the complete role of eicosanoids, including that of the recently elucidated anti-inflammatory specialized pro-resolving lipid mediators (SPMs), e.g. lipoxins, resolvins, protectins and maresins, is not completely understood, the result of unremitting chronic inflammation is fostering early stages of carcinogenesis. Chronic inflammation facilitates the transition from a normal cell to a cancerous one. The disruption of homeostasis across a wide, but identifiable, swath of diverse molecular pathways creates a micromilieu which constitutes an early and necessary step in the 6-step sequence of carcinogenesis for the vast majority of cancers, termed “sporadic cancers”

Undervalued ubiquitous proteins

The role of ubiquitous proteins (UPs) and their corresponding enzymes have been underestimated in carcinogenesis as the focus of much research revolved around measuring mutations and/or other genetic epiphenomena as surrogate markers of cancer and cancer progression. Over the past three decades, the scientific community has come to realize that the concentration on microdissection of cancer cells without accounting for the neighborhood in which these cells reside, i.e., the stroma, fails to reflect the true nature of cancer biology. UPs are fundamental for cellular homeostasis and phylogenetic development as well as for the integrity of the cytoskeleton and for the stability of cells and tissues in regards to intercellular signaling, cell shape and mobility, apoptosis, wound healing, and cell polarity. Corresponding enzymes are used by microorganisms to gain entry into the host by degradation of UPs and play a role to cleave peptide bonds for killing disease-causing life forms along for the creation of the precancerous niche (PCN) during carcinogenesis, cancer invasion, and in metastasis. The language used by such proteins as well as their complementary enzymes with its influence on multiple pathways and the cross-linked extracellular matrix is incompletely understood. The role of UPs in the disruption of signaling homeostasis and resulting interference with crosstalk in carcinogenesis appears sufficiently delineated to warrant a much more refined examination of their qualitative and quantitative contribution to the development of cancer and cancer therapy

Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

The anti-hyperglycemic drug, Metformin, is effective in treating early stages of diabetes and has been associated with a 37% decrease in cancer incidence. While the precise mechanisms for the anti-cancer effects of Metformin remain to be elucidated, this review shows the multiplicity of its effects on interdicting signaling and crosstalk, anti-inflammatory effects and in restoring homeostasis, which, taken together, go beyond its well-known anti-hyperglycemic effect that serves as the basis for its use in type 2 diabetes. Metformin is much more than a one-trick pony. The recent discovery of several signaling pathways influenced by Metformin appears to have potential value in cancer therapy. Based on what we know at present, Metformin promotes beneficial effects attributed to its anti-inflammatory and anti-fibrotic effects largely demonstrated in vitro. Metformin activates or upregulates while it simultaneously inhibits or downregulates multiple signaling pathways of cell-cycle arrest and apoptosis accompanied by oxidative stress, which are in accordance with the 6-step sequence of carcinogenesis. Furthermore, in vivo studies in laboratory animals and in cancer patients are beginning to address the magnitude of the anti-cancer effects and delineate its anti-cancer effects. In this context, results from prior pancreatic and non-pancreatic cancer trials, which contained a significant proportion of the patient population treated with Metformin, will have to be reexamined in light of the observed anti-cancerous effects to gain additional insights. The detailed exploration of Metformin in the context of the “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” can provide helpful insights into the anti-proliferative mechanisms and could play a relevant role in anti-cancer therapy in the future

Chronic inflammation evoked by pathogenic stimulus during carcinogenesis

A pathogenic (biological or chemical) stimulus is the earliest information received by a cell that can result in the disruption of homeostasis with consequent development of disease. Chronic inflammation involves many cell types with numerous cytokines and signaling pathways, the release of different components by the cells, and the crosstalk provoked by such stimuli involving subclinical chronic inflammation and is mechanistically manifold. Exosomes secrete chemicals that trigger the epithelium to produce exosome-like nanoparticles promoting chronic inflammation. Small molecules, together with various cytokines, selectively target signaling pathways inducing crosstalk that suppress apoptosis. 16S rRNA gene sequencing has become routine to provide information on the composition and abundance of bacteria found in human tissues and in reservoirs. The deregulation of autophagy with chronic stimulation of inflammation is an early phenomenon in carcinogenesis. The disruption of cell–cell integrity enables transcellular CagA migration and triggers deregulation of autophagy with the net result being chronic inflammation. The complex and insidious nature of chronic inflammation can be seen both inside and outside the cell and even with intracellular nuclear fragments such as chromatin, which itself can elicit a chronic inflammatory response within the cytoplasm and affect autophagy. The ultimate result of unresolved chronic inflammation is fibrosis, a step before tissue remodeling results in the formation of a precancerous niche (PCN). Various pathogenic stimuli associated with different neoplasms result in persistent inflammation. This ongoing disruption of homeostasis in the micromilieu of cells, tissues, and organs is an essential preamble to carcinogenesis and occurs early in that process