Surgical challenges and research priorities in the era of the COVID-19 pandemic: EAES membership survey.

BACKGROUND: Healthcare systems and general surgeons are being challenged by the current pandemic. The European Association for Endoscopic Surgery (EAES) aimed to evaluate surgeons' experiences and perspectives, to identify gaps in knowledge, to record shortcomings in resources and to register research priorities. METHODS: An ad hoc web-based survey of EAES members and affiliates was developed by the EAES Research Committee. The questionnaire consisted of 69 items divided into the following sections: (Ι) demographics, (II) institutional burdens and management strategies, and (III) analysis of resource, knowledge, and evidence gaps. Descriptive statistics were summarized as frequencies, medians, ranges,, and interquartile ranges, as appropriate. RESULTS: The survey took place between March 25th and April 16th with a total of 550 surgeons from 79 countries. Eighty-one percent had to postpone elective cases or suspend their practice and 35% assumed roles not related to their primary expertise. One-fourth of respondents reported having encountered abdominal pathologies in COVID-19-positive patients, most frequently acute appendicitis (47% of respondents). The effect of protective measures in surgical or endoscopic procedures on infected patients, the effect of endoscopic surgery on infected patients, and the infectivity of positive patients undergoing laparoscopic surgery were prioritized as knowledge gaps and research priorities. CONCLUSIONS: Perspectives and priorities of EAES members in the era of the pandemic are hereto summarized. Research evidence is urgently needed to effectively respond to challenges arisen from the pandemic.

A research agenda for the European Association for Endoscopic Surgeons (EAES).

INTRODUCTION: The European Association of Endoscopic Surgeons (EAES) conducted this study aiming to identify the top research questions which are relevant to surgeons in Minimal Access Surgery (MAS). This is in order to promote and link research questions to the current clinical practice in MAS in Europe. METHODS: Using a systematic methodology, (modified Delphi), the EAES members and leadership teams were surveyed to obtain consensus on the top research priorities in MAS. The responses were categorized and redistributed to the membership to rate the level of importance of each research question. The data were reported as the weighted average score with a scale from 1 (lowest agreement) to 5 (highest agreement). RESULTS: In total, 324 of 2580 (12.5%) of the EAES members and the leaders responded to the survey and contributed to the final consensus. The ranked responses over the 80th percentile identified 39 research priorities with rating ranged from 4.22 to 3.67. The top five highest ranking research priorities in the EAES were centered on improving training in MAS, laparoscopic surgery for benign upper gastrointestinal conditions, integration of novel technology in OR, translational and basic science research in bariatric surgery and investigating the role of MAS in rectal cancer. CONCLUSION: An EAES research agenda was developed using a systematic methodology and can be used to focus MAS research. This study was commissioned by the European Association for Endoscopic Surgery (EAES).

Safety Concerns for Sclerotherapy of Telangiectases, Reticular and Varicose Veins.

BACKGROUND: Sclerotherapy has been extensively used in the treatment of valvular insufficiency of superficial veins. Although sclerotherapy seems safe, reports of serious adverse events (AE) have been published. This paper aims to review AE of sclerosing agents. METHODS: Electronical databases were searched for identifying articles on local, serious and long-term AE of sclerotherapy. RESULTS: Hyperpigmentation and matting are the most often local AE of sclerotherapy. Other local AE include superficial thrombophlevitis, pyoderma gangrenosum, pain, ulcer formation, and hypertrichosis. Local AE can be serious, that is, it can include cutaneous necrosis, intra-arterial injection with subsequent acute ischemia that can lead to amputation, and necrotizing fasciitis. Most data on systemic AE of sclerotherapy are extracted from case series and case reports. Systemic AE include neurological complications, such as ischemic stroke, transient ischemic attack, visual disturbances and cardiac toxicity, that is, myocardial infarction, Takotsubo cardiomyopathy, chest tightness, pulmonary embolism, deep vein thrombosis, septicemia, anaphylaxis. It is difficult to estimate the frequency of serious systemic AE of sclerotherapy. CONCLUSION: Physicians practicing sclerotherapy should be aware of the possible local and systemic AE of sclerotherapy, inform patients accordingly and be prepared for the appropriate management of the rare but possibly lethal serious AE.

Serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin.

Although botulinum toxin is generally considered safe, its widespread use and the constantly expanded indications raise safety issues. This study aimed to review the serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin. Serious adverse events included dysphagia, respiratory compromise, generalized muscle weakness, marked bilateral ptosis, pseudoaneurysm of the frontal branch of the temporal artery, necrotizing fasciitis, sarcoidal granuloma, Fournier gangrene, and cervical kyphosis. Death was attributed to botulism or anaphylactic shock. In conclusion, botulinum toxin may cause serious adverse events, which are more common after its therapeutic use, but can also be noticed after its cosmetic use. Thorough knowledge of the anatomy of the treated muscles and of the pharmacology of the drug is imperative to avoid serious adverse events.

Targeting DNA methylation with green tea catechins.

Aberrant epigenetic alterations in the genome such as DNA methylation play a significant role in cancer development. Green tea catechins have been reported to modulate epigenetic processes. This review aims to synthesize evidence on the modulation of DNA methylation by green tea catechins. Green tea catechins have been reported to reverse DNA methylation of tumor suppressor genes and increase transcription of these genes. Green tea catechins and especially epigallocatechin gallate modulate DNA methylation by attenuating the effect of DNA methyltransferase 1 (DNMT1). However, the exact mechanism of DNMT1 inhibition is not delineated. Suggested mechanisms include direct enzymatic inhibition, indirect enzymatic inhibition, reduced DNMT1 expression and translation. The possible effect of green tea catechins on other pathways of DNA methylation, i.e. methyl-CpG binding domain proteins, has not been investigated. Furthermore, the link between redox properties and epigenetic modulation by green tea catechins has not been defined either. Since green tea catechins are natural compounds with a rather acceptable safety profile, further research on their action as inhibitors of DNA methylation seems worthwhile.

Interaction of green tea catechins with breast cancer endocrine treatment: a systematic review.

Recent data have shown strong chemopreventive and possibly cancer chemotherapeutic effects of green tea polyphenols and EGCG against breast cancer. This systematic review aims to synthesize data on the possible interaction of green tea catechins with breast cancer endocrine treatment. Electronic databases were searched with the appropriate search terms. Experimental trials suggest a synergistic interaction of green tea catechins with tamoxifen or raloxifene in the treatment of estrogen receptor-positive and estrogen receptor-negative breast cancer through estrogen receptor-dependent and -independent mechanisms. No evidence of an interaction of green tea catechins with aromatase inhibitors or fulvestrant has been reported. As green tea catechins are natural compounds with a rather favorable safety profile, the strategy of co-administrating green tea catechins with tamoxifen seems to be a rational approach in chemoprevention, adjuvant and metastatic breast cancer treatment that needs further investigation.

Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications.

PURPOSE: Pharmacogenomics investigates interindividual genetic variability in the DNA sequence of drug targets, drug-metabolizing enzymes or disease genes, RNA expression, or protein translation of genes affecting drug response and drug safety. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications with well-documented variation in patient response in terms of efficacy and safety. This variation may in part be explained by pharmacogenomics. METHODS: In this paper I review data on the pharmacogenomics of aspirin and other NSAIDs focusing on clinical implications. RESULTS: Existing scientific evidence supports the pharmacogenomic basis of interindividual variation in treatment response to aspirin and NSAIDs, with clinical implications for antiplatelet action, cancer chemoprevention, and drug safety. However, further research efforts are needed before knowledge on the pharmacogenomics of aspirin and NSAIDs can be implemented in clinical practice. CONCLUSION: The outcome of these research efforts would be anticipated to have added value for both science and society, contributing to the enhanced efficacy and safety of these agents through patient selection.

Botulinum toxin and anal fissure: efficacy and safety systematic review.

PURPOSE: The main purpose of this study was to investigate the efficacy and safety of botulinum toxin in the treatment of anal fissure. An answer was attempted to the following research questions: (i) what is the efficacy of botulinum toxin in healing of anal fissure compared to placebo, (ii) what is the efficacy of botulinum toxin in healing of anal fissure compared to other means of chemical sphincterotomy, (iii) what is the efficacy of botulinum toxin in healing of anal fissure compared to surgical sphincterotomy, (iv) what is the short term safety of botulinum toxin injections and (v) what is the long term safety of botulinum toxin injections. METHODS: Clinical trials investigating the effect of botulinum toxin in the treatment of anal fissure met inclusion criteria. Case reports and case series were also included for the estimation of safety. Meta-analysis was not performed due to clinical heterogeneity. RESULTS: The comparator could be placebo, nitroglycerin ointment, or lateral internal sphincterotomy, with dosage ranging from 20 IU to 50 IU of botulinum toxin. Fissure healing was the most commonly reported primary endpoint but the time period from botulinum toxin injection to fissure healing ranged from 2 weeks to 4 months. Accordingly, outcome data were also heterogenous. CONCLUSIONS: Botulinum toxin injections should be considered a minimally invasive therapeutic option for the treatment of chronic anal fissure. However, well designed randomized trials are needed for the valid estimation of the efficacy and safety of botulinum toxin in this therapeutic indication.

Hemoptysis under diclofenac and antiplatelet doses of aspirin.

A previously healthy 60-year-old man receiving aspirin for primary prevention of cardiovascular disease presented with hemoptysis after 1 week of treatment for his back pain with diclofenac. He had not suffered from any bleeding episode in the past and his family history was negative for hemorrhagic disorders. He had been a heavy smoker until his thirties, but had stopped smoking since then. After extensive workup, other pulmonary and nonpulmonary causes of hemoptysis were ruled out. Thus, in this case, because of the temporal relationship between exposure to the drug and the onset of symptoms, diclofenac was considered as the most probable cause of hemoptysis either alone or as a result of its pharmacodynamic interaction with aspirin. The adverse reaction was considered probable according to the Naranjo scale. Diclofenac treatment was discontinued and occasional use of acetaminophen for the back pain was recommended. Regular use of antiplatelet doses of aspirin was also discontinued.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

The role of minimally invasive surgery in neuroendocrine pancreatic tumors.

Minimally invasive surgery has an established role in the treatment of patients with pancreatic neuroendocrine tumors (pNETs). Enucleation is an established treatment option for insulinomas. The necessity of organ sparing surgery is well established in the case of multiple pNETs. A number of studies have demonstrated the efficacy and safety of laparoscopic surgery for the treatment of pNETs. However, pNETs are rare, and large studies focusing on pNET patients are difficult to be designed unless multicenter experience is collected. Authors investigating the role of minimally invasive pancreatic surgery should be encouraged to report separately the results that involve patients presenting with pNETs. A European registry of patients with pNETs treated with minimally invasive surgery would allow further investigation of the optimal treatment of these patients. Especially in the case of syndromic pNETs, that are rare entities, co-operation and exchange of information is needed among different centers for sharing experience and transferring knowledge. Existing data come from small cohort studies, case series and case reports. Given that, pancreatic surgery is especially demanding advanced surgery with training that is not yet standardized, further research is needed for defining its role in the treatment of pancreatic neuroendocrine tumors. Regarding the role of robot-assisted surgery in the treatment of pNETS, data are quite scarce.

Robotic assisted adrenalectomy: Surgical techniques, feasibility, indications, oncological outcome and safety.

Nowadays robotic assisted adrenalectomy has become an alternative to conventional laparoscopic adrenalectomy. However, evidence on the possible advantages and drawbacks of robotic assisted adrenalectomy remains still limited. This manuscript aimed to review evidence on robotic assisted adrenalectomy in terms of surgical technique, feasibility, indications, oncological outcome and safety. Existing evidence, although limited, suggests that robotic assisted adrenalectomy is feasible and safe. However, the number of patients submitted to robotic assisted adrenalectomy is limited with the majority of them being operated for benign disease. There are only a few case reports of robotic assisted adrenalectomy performed for adrenocortical carcinoma, oncocytoma or metastasis. Partial adrenalectomy seems to be a promising application of robotic assisted adrenalectomy especially for the treatment of hereditary pheocromocytomas. Robotic assisted adrenalectomy overcoming the technical limitations of laparoscopic surgery could possibly elicit a mild surgical response instead of the well described surgical response. Surgical response affects surgical morbidity and mortality as well as oncological outcome of malignant disease. If this hypothesis is proved correct, robotic assisted adrenalectomy could be possibly indicated in the treatment of disease. In conclusion, robotic assisted adrenalectomy is feasible and safe. Further research is needed on the oncological outcome of this minimally invasive technique as well as on its effect on surgical stress response.

Pharmacogenomics and Opioid Analgesics: Clinical Implications.

Variation exists in patient response on analgesic treatment in terms of efficacy and safety. This variation may be in part explained by pharmacogenomics. This paper aimed to review data on pharmacogenomics of opioid analgesics focusing on the effect of genetic variation on the efficacy and safety of these agents. Current evidence suggests that pharmacogenomics contribute to variation in efficacy and safety of opioids. However, most data come from case control studies and case reports. In addition, a recognized drawback in the field of pharmacogenomics is the common occurrence of false positive association between polymorphisms and the investigated outcome. Prospective studies are needed to further elucidate the clinical implications of available data as well as to define the guidelines for the clinical application of pharmacogenomic data. Furthermore, basic research should focus on the identification of biologically meaningful polymorphisms enabling a hypothesis with biological plausibility driven research in the field of pharmacogenomics of analgesics. Moreover, the publication of relevant negative results should be favoured.

Aspirin and NSAIDs for breast cancer chemoprevention.

Novel treatment strategies are needed for breast cancer chemoprevention. Tamoxifen is the only drug approved for the chemoprevention of estrogen receptor-positive breast cancer. However, to date, no treatment exists for the chemoprevention of estrogen receptor-negative breast cancer. NSAID use is associated with a reduced risk of breast cancer. However, the biological mechanisms underlying the effect of NSAID on breast cancer are not well defined. NSAIDs inhibit cyclooxygenases, thus preventing the formation of prostaglandins, prostacyclin, and thromboxane. NSAIDs also exert other biological effects, including generation of reactive oxygen species and inhibition of nuclear factor-κB-mediated signals. This review synthesizes the evidence on the COX-2-independent mechanisms of action of aspirin, salicylates, and other NSAIDs on breast cancer.

Interaction of Salicylates and the Other Nonsteroidal Anti-Inflammatory Agents With Breast Cancer Endocrine Treatment: Systematic Review.

Despite advances in breast cancer treatment, mortality from breast cancer is still high. Undoubtedly, novel treatment strategies are needed for chemoprevention of high-risk women and for the treatment of receptor-negative breast cancer. An appealing strategy would be the combination of breast endocrine treatment with salicylates and the other nonsteroidal anti-inflammatory agents (NSAIDs). This systematic review aimed to synthesize evidence on the possible synergistic antitumor effect of breast cancer endocrine treatment with salicylates and the other NSAIDs. Electronic databases were searched with the appropriate search terms. Most of the identified studies investigated the possible synergistic effect of exemestane with celecoxib in different clinical settings including metastatic treatment, adjuvant treatment, ductal carcinoma in situ. The possible synergistic effect of tamoxifen with celecoxib was investigated in one experimental study and the possible synergistic effect of exemestane with aspirin was investigated in another experimental study. Synergistic effect was detected in the majority of the studies. In conclusion, existing limited evidence suggests synergistic interaction of salicylates and the other NSAIDs in the treatment of estrogen responsive breast cancer with clinical implications in the reversal of acquired resistance to breast cancer endocrine treatment and in chemoprophylaxis.

Virtual reality simulators and training in laparoscopic surgery.

Virtual reality simulators provide basic skills training without supervision in a controlled environment, free of pressure of operating on patients. Skills obtained through virtual reality simulation training can be transferred on the operating room. However, relative evidence is limited with data available only for basic surgical skills and for laparoscopic cholecystectomy. No data exist on the effect of virtual reality simulation on performance on advanced surgical procedures. Evidence suggests that performance on virtual reality simulators reliably distinguishes experienced from novice surgeons Limited available data suggest that independent approach on virtual reality simulation training is not different from proctored approach. The effect of virtual reality simulators training on acquisition of basic surgical skills does not seem to be different from the effect the physical simulators. Limited data exist on the effect of virtual reality simulation training on the acquisition of visual spatial perception and stress coping skills. Undoubtedly, virtual reality simulation training provides an alternative means of improving performance in laparoscopic surgery. However, future research efforts should focus on the effect of virtual reality simulation on performance in the context of advanced surgical procedure, on standardization of training, on the possibility of synergistic effect of virtual reality simulation training combined with mental training, on personalized training.

Etiology of familial breast cancer with undetected BRCA1 and BRCA2 mutations: clinical implications.

BACKGROUND: Familial breast cancer accounts for 20-30 % of all breast cancer cases. Mutations in the BRCA1 and BRCA2 genes account for the majority of high risk families with both early onset breast cancer and ovarian cancer. Most of the families with less than six breast cancer cases and no ovarian cancer do not carry BRCA1 or BRCA2 mutations that can be detected using routine sequencing protocols. Here, we aimed to review the etiology of familial breast cancer in cases without BRCA1 and BRCA2 mutations. RESULTS: After excluding BRCA1 and BRCA2 mutations, factors proposed to contribute to familial breast cancer include: chance clustering of apparently sporadic cases, shared lifestyle, monogenic inheritance, i.e., dominant gene mutations associated with a high risk (TP53, PTEN, STK11), dominant gene mutations associated with a relatively low risk (ATM, BRIP1, RLB2), recessive gene mutations associated with horizontal inheritance patterns (sister-sister), and polygenic inheritance where susceptibility to familial breast cancer is thought to be conferred by a large number of low risk alleles. CONCLUSIONS: Current evidence suggests that in the majority of cases with BRCA1 and BRCA2 negative familial breast cancer the etiology is due to interactions of intermediate or low risk alleles with environmental and lifestyle factors. Thus, a careful selection of patients submitted to genetic testing is needed. Clearly, further research is required to fully elucidate the etiology of non-BRCA familial breast cancer.

Targeting epigenetic mechanisms and microRNAs by aspirin and other non steroidal anti-inflammatory agents--implications for cancer treatment and chemoprevention.

BACKGROUND: Epigenetic processes and miRNAs have been recognized as new targets for anticancer drug design. However, old multi-target drugs such as aspirin may also target epigenetic processes. AIM: This review aims to provide an overview of our current knowledge on the modulation of epigenetic processes by aspirin and other non steroidal anti-inflammatory agents (NSAIDs) and their implications for cancer treatment and chemoprevention. SYNTHESIS: In vitro and in vivo studies, as well as primary patient data, suggest that aspirin and other NSAIDs reverse tumour suppressor gene hypermethylation in cancer tissues. It must be emphasized that, at this point in time, patient data are limited and DNA hypermethylation reversal has been investigated, but not tumour suppressor gene activation. In addition, evidence from experimental and patient data suggests that aspirin and NSAIDs may also reverse global DNA hypomethylation. At the histone level, both induction and inhibition of deacetylases by aspirin have been reported. Also, direct acetylation of histones by aspirin has been reported, while the natural salicylate anacardic acid has been found to inhibit histone acetyltransferase p300 both in vitro and in vivo, and to regulate gene expression through modulation of histone acetylation. Salicylates and other NSAIDs may also down-regulate miRNAs with oncogene-like functions or up-regulate miRNAs with tumour suppressor-like functions. Up till now, clinical trials have been aimed at investigating the effect of salicylates and NSAIDs on a limited number of miRNAs. CONCLUSION: So, although the existing evidence is still limited, evidence is accumulating that epigenetic targets may represent nodal targets for the anti-proliferative actions of salicylates and NSAIDs. This, in turn, may have implications for cancer chemoprevention and treatment. Undoubtedly, this notion requires further investigation, but if proved correct, it could lead to the design of less toxic agents that target epigenetic processes as part of existing or novel multi-targeted treatment modalities.