Associations of long non-coding RNAs HOTAIR, LINC00951, POLR2E and HULC polymorphisms with the risk of esophageal and esophagogastric junction cancer in a western population: a case-control study.

BACKGROUND: The incidence of single-nucleotide-polymorphisms with malignant potential in esophageal cancer tissues has only been sparsely investigated in the west. Hence, we explored the contribution of four long non-coding RNAs' polymorphisms HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016 and HULC rs7763881 in esophageal cancer susceptibility. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated for esophageal/esophagogastric junction carcinoma during 25/03/2014-25/09/2018 were processed. Demographic data, histopathological parameters, surgical and oncological outcomes were collected. DNA findings of the abovementioned population were compared with 121 healthy community controls. Both populations were of European/Greek ancestry. Sixty-seven patients underwent Ivor Lewis/McKeown esophagectomy for either squamous cell esophageal carcinoma (N = 6) or esophageal/esophagogastric junction Siewert I or II adenocarcinoma (N = 61). Twenty-eight patients were subjected to extended total gastrectomy for esophagogastric junction Siewert III adenocarcinoma. Neither LINC00951 rs11752942 nor HULC rs7763881 polymorphisms were detected more frequently in esophageal cancer patients compared with healthy community subjects. A significantly higher presence of HOTAIR rs920778 TT genotype in esophagogastric junction Siewert I/II adenocarcinoma was identified. POLR2E rs3787016 C allele and CC genotypes were overrepresented in the control group, and when found in esophageal cancer carriers were associated with earlier disease stages, as well as with minor lymph node involvement and lesser metastatic potential. CONCLUSIONS: HOTAIR rs920778 may serve as a potential therapeutic suppression target, while POLR2E rs3787016 may represent a valuable biomarker to evaluate esophageal cancer predisposition and predict treatment response and prognosis. Clinical implications of these findings need to be verified with further prospective studies with larger sample-size.

A complex modality of achalasia, diverticulum and paraesophageal hernia treated through three-dimensional left thoracoscopy.

Herein, we report a case of a patient with recurrent dysphagia after an open transabdominal hernia repair for a Type IV paraesophageal hernia performed elsewhere. Subsequent work-up and medical records' review revealed the coexistence of a large left epiphrenic diverticulum in combination with achalasia synchronous to the recently repaired paraesophageal hernia. A three-dimensional left thoracoscopic diverticulectomy with a long esophagomyotomy was conducted under endoscopic guidance intraoperatively, with no perioperative complications. At 12 months' follow-up evaluation, the patient presents well with no documented recurrence. Cumulative experience from various medical specialties regarding esophageal motility disorders and endoscopic state-of-the-art techniques, when combined with minimally invasive surgical techniques, provide an effective management of esophageal motility syndromes, overall.

Minimally Invasive Esophagectomy.

Minimally invasive esophagectomy (MIE) was introduced in the 1990s with the aim to decrease the rate of respiratory complications associated with thoracotomy, along with the benefits of reduced morbidity and a quicker return to normal activities provided by minimally invasive techniques. However, MIE is not routinely applied as a standard approach for esophageal cancer worldwide, due to the high technical complexity of this minimally invasive procedure. Therefore, the open transthoracic esophagectomy is considered to be the gold standard for resectable esophageal cancer worldwide nowadays. In this article, the current status of conventional MIE and robot-assisted minimally invasive thoraco-laparoscopic esophagectomy will be reviewed.

The role of surgical treatment in isolated organ recurrence of esophageal cancer-a systematic review of the literature.

BACKGROUND: Despite the improvements in the early detection and treatment of non-metastatic esophageal cancer, more than half of patients undergoing a curative treatment for esophageal cancer will develop recurrence within three years. The prognosis of these patients is poor. However, a wide range in overall survival has been reported, depending on the pattern of recurrence, and no optimal treatment strategy following recurrence has yet been uniformly accepted. AIM: In this article, we aimed to systematically review the literature for the role of surgical resection of metachronous distant metastasis following primary treatment of esophageal cancer. Furthermore, we discuss possible factors that could possibly predict which patients may benefit from a surgical approach. A comprehensive literature search was conducted in PubMed using combinations of keywords. RESULTS: Patients with recurrence may benefit of a multimodality treatment. Regarding the isolated recurrence of esophageal cancer in solid visceral organs, operative intervention has been proposed as a treatment that may offer a survival benefit in an individual basis. No definitive conclusions regarding the potential survival advantage offered by the surgical treatment of solitary recurrent lesions can be drawn. However, recent improvements in surgical treatment and optimization of perioperative management guarantee an acceptable operative risk, making surgical resection of solitary recurrence lesions a considerable therapeutic option. CONCLUSIONS: It can be conferred from the available studies that the surgical treatment of isolated recurrence from esophageal cancer may offer a survival benefit for properly selected patients. Prospective, multicenter studies might be useful to gain a better insight into those factors that affect selection of patients to take benefit from an operative intervention.

Carcinosarcomas of the esophagus: systematic review of a rare nosologic entity.

PURPOSE: The purpose of this study was to systematically review the literature of esophageal carcinosarcomas (ECS) and report epidemiologic and clinicopathologic data for this rare entity. We also attempted to shed light to the biologic behavior of ECSs with special reference to factors that may affect disease-free (DES) and overall survival (OS). METHODS: A systematic literature review was performed using MEDLINE, EMBASE and the Cochrane Library databases (Search date: 12 May 2017). The search strategy referred to  carcinosarcoma OR pseudosarcoma OR polypoid carcinoma OR sarcomatoid carcinoma OR spindle-cell squamous cell carcinoma OR metaplastic carcinoma OR pseudosarcomatous carcinoma AND esophagus. A total number of 103 ECS patients was identified.   Results: ECs most frequently occur in middle-aged as well as elderly men with a history of smoking or drinking. Middle and/or lower esophagus remains the most common location. Imaging plays a pivotal role in the management of ECS by delineating the anatomic extent of the tumor and thereby determining the appropriate therapeutic strategy. Nevertheless, immunohistochemistry is the gold standard for the diagnosis of carcinosarcomas, since it has been demonstrated that CEA, EMA, pancreatin, chromogranin A, CD56 and synaptophysin staining are highly specific markers for the carcinomatous components, while desmin, vimentin and smooth muscle/sarcomeric actin show affinity for the sarcomatous elements. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures, including mucosal resection and submucosal dissection have also been proposed. Alternative therapies, such as radio- and chemotherapy proved insufficient. CONCLUSION: ECS is a rare tumor. Immunohistochemistry is the gold standard for the diagnosis of this disease. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures have also been proposed while potential benefit of alternative therapies, such as radiotherapy and chemotherapy remains controversial.

Three-Stage Esophagectomy Combined with Abdominal Aortic Aneurysm Repair: First Case in the Literature.

The purpose of this report is to describe the synchronous surgical treatment of an abdominal aortic aneurysm (AAA) with concomitant esophageal cancer with a 3-stage esophagectomy, a real management challenge especially in establishing the therapeutic priorities and the ideal treatment approach. A 65-year-old male was referred for treatment in our hospital with the diagnosis of AAA. He complained of general fatigue, weight loss, and intermittent dysphagia. Contrast-enhanced computed tomography and upper endoscopy showed the AAA and a large gastroesophageal junction tumor, respectively. Considering his age and the absence of severe comorbidities, he underwent 3-stage esophagectomy combined with AAA repair. The patient had an uneventful postoperative course and was discharged on the 15th postoperative day. He was offered adjuvant chemotherapy and remains free of disease and with a patent aortic graft at 18 months of follow-up.

A functional microRNA library screen reveals miR-410 as a novel anti-apoptotic regulator of cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is characterized by late diagnosis and a poor survival rate. MicroRNAs have been involved in the pathogenesis of different cancer types, including cholangiocarcinoma. Our aim was to identify novel microRNAs regulating cholangiocarcinoma cell growth in vitro and in vivo. METHODS: A functional microRNA library screen was performed in human cholangiocarcinoma cells to identify microRNAs that regulate cholangiocarcinoma cell growth. Real-time PCR analysis evaluated miR-9 and XIAP mRNA levels in cholangiocarcinoma cells and tumors. RESULTS: The screen identified 21 microRNAs that regulated >50 % cholangiocarcinoma cell growth. MiR-410 was identified as the top suppressor of growth, while its overexpression significantly inhibited the invasion and colony formation ability of cholangiocarcinoma cells. Bioinformatics analysis revealed that microRNA-410 exerts its effects through the direct regulation of the X-linked inhibitor of apoptosis protein (XIAP). Furthermore, overexpression of miR-410 significantly reduced cholangiocarcinoma tumor growth in a xenograft mouse model through induction of apoptosis. In addition, we identified an inverse relationship between miR-410 and XIAP mRNA levels in human cholangiocarcinomas. CONCLUSIONS: Taken together, our study revealed a novel microRNA signaling pathway involved in cholangiocarcinoma and suggests that manipulation of the miR-410/XIAP pathway could have a therapeutic potential for cholangiocarcinoma.

Remote Ischemic Preconditioning May Attenuate Renal Ischemia-Reperfusion Injury in a Porcine Model of Supraceliac Aortic Cross-Clamping.

AIM: The effect of remote ischemic preconditioning (RIPC) in decreasing renal ischemia-reperfusion injury (IRI) during a suprarenal aortic cross-clamping was examined in a swine model. MATERIALS AND METHODS: Four groups of pigs were examined: (a) ischemia-reperfusion (IR) group, renal IRI produced by 30 min of supraceliac aortic cross-clamping; (b) RIPC I group, the same renal IRI following RIPC by brief occlusion of the infrarenal aorta (15 min ischemia and 15 min reperfusion); (c) RIPC II group, the same renal IRI following RIPC by brief occlusion of the infrarenal aorta (3 cycles of 5 min ischemia and 5 min reperfusion); (d) sham group. Renal function was assessed before and after IRI by examining creatinine, neutrophil gelatinase-associated lipocalin (NGAL), TNF-α, malondialdehyde (MDA), cystatin C and C-reactive protein (CRP) from renal vein blood samples at specific time intervals. RESULTS: Both RIPC groups presented significantly less impaired results compared to the IR group when considering MDA, cystatin C, CRP and creatinine. Between the two RIPC groups, RIPC II presented a better response with regard to CRP, NGAL, TNF-α, MDA and cystatin C. CONCLUSIONS: Remote IR protocols and mainly repetitive short periods of cycles of IR ameliorate the biochemical kidney effects of IRI in a model of suprarenal aortic aneurysm repair.

Genetic Impact of HOTAIR, LINC00951, POLR2E and HULC Polymorphisms in Histopathological and Laboratory Prognostic Factors in Esophageal Cancer in the West: A Case-Control Study.

Long non-coding RNAs' HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016, and HULC rs7763881 are progressively reported having a close genetic affinity with esophageal carcinogenesis in the East. Nonetheless, their correlation with variables already endorsed as significant prognostic factors in terms of staging, guiding treatment and predicting recurrence, metastasis, and survival have yet to be explored. Herein, we investigated their prognostic value by correlating them with clinicopathological and laboratory prognostic markers in esophageal cancer in the West. Formalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated on for esophageal cancer between 2014 and 2018 were compared with 121 healthy community controls. HULC was not detected differently in any of the cancer prognostic subgroups. LINC00951 was underrepresented in Ca19.9 elevated subgroup. HOTAIR was more frequent in both worse differentiation grade and positive Signet-Ring-Cell and Ca19.9 subgroups. POLR2E was identified less frequently in Adenocarcinoma, Signet-Ring-Cell, and Diffuse histologies, as well as in Perineural, Lymphovascular, and Perivascular Invasion positive, while it was overrepresented in CEA positive subgroup. These lncRNAs polymorphisms may hold great potential not only as future therapeutic agents but also as novel markers for predictive analysis of esophageal cancer risk, clinical outcome, and survival. Clinical implications of these findings need to be validated with prospective larger sample-size studies.

European clinical practice guidelines for the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer (OMEC-4).

INTRODUCTION: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD). METHODS: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD. RESULTS: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended. DISCUSSION: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment.

Definition, diagnosis and treatment of oligometastatic oesophagogastric cancer: A Delphi consensus study in Europe.

BACKGROUND: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Translating cancer genomes sequencing revolution into surgical oncology practice.

BACKGROUND: Ten years after the first complete human genome sequencing, next-generation sequencing (NGS) technology has revolutionized genomics and biomedical research. Here we discuss potential emerging and future applications of NGS platforms and how cancer genome advances may change current surgical oncology practice. MATERIALS AND METHODS: Publications in PubMed with partial or complete human and cancer genome sequencing over the last decade have been retrieved and analyzed. Recently launched international large-scale consortiums for systematic study of causal (driver) mutations underlying common complex diseases such as cancer and more recent opinion articles by leading scientists have been considered to predict the prospects of integration genomics data into surgical oncology. RESULTS: Two dozen complete human genome sequences, and three full-genome sequencing in three cancer patients have recently been published. These studies and other cancer genome systematic studies evaluating genomic rearrangements and copy-number changes consistently reveal that cancer initiation and metastasis are much more complex than we thought. This high complexity and widespread variability of cancer genes, mutations, and deregulated signaling pathways among patients with the same cancer type, tumor stage, and clinicopathologic features explains the limited effectiveness of currently used biologically targeted agents. CONCLUSIONS: Yet the impact of genomics explosion in surgical oncology is little. Nevertheless, "big" biology consortiums such as the International Cancer Genome Project and other systematic studies in the areas of genetics, genomics, and epigenetics are now providing in-depth understanding of cancer, and shape new more rational ways towards novel therapeutics for improving oncologic outcomes of millions of patients worldwide. At the beginning of the second post-genomic decade, an explosion in genomic technology has revolutionized biomedical sciences. The ability of latest DNA sequencing technology to identify, in an unprecedented level, causal mutations driving cancer initiation and metastasis raises significant expectations for improving oncologic outcomes. Which are the challenges and perspectives to translate this genomic revolution into a surgical oncology-changing era?

Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe.

BACKGROUND: Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. OBJECTIVE: To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. MATERIAL AND METHODS: European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (<50%), fair (50%-75%), or consensus (≥75%). RESULTS: A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1-2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. CONCLUSION: A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists.

Risk Models and Scores in Patients with Peripheral Artery Disease and Chronic Limb-threatening Ischemia: A Comprehensive Review.

Peripheral artery disease (PAD) affects more than 200 million patients worldwide and chronic limbthreatening ischemia (CLTI) is the most advanced stage of PAD with very high morbidity and mortality rates. Cardiovascular medicine is trending towards a more personalized approach where each individual patient will be managed according to specific risk factors, disease characteristics, expectations related to their disease and individualized assessment of potential outcomes. For this reason, a number of risk models and scores have been developed during the last few years. Our aim in this comprehensive review article is to provide an overview of selected risk models and scores for patients with PAD and CLTI. Given that some of the published scores were of low quality (minimal discriminatory ability), we included scores that were already externally validated or scores that had promising initial findings. Available scoring systems were grouped in the five following categories according to their utility: i) scores that can detect asymptomatic patients who should be screened for PAD, ii) scores for assessment of functional status and quality of life in patients with PAD, iii) scores assessing risk for amputation and other major adverse limb events among patients with CLTI, iv) scores for the optimal revascularization strategy in each patient and scores predicting successful procedural outcomes; v) scores predicting short or long-term cardiovascular and limb related outcomes after either revascularization or at least angiographic assessment. Limitations of available scoring systems include development and validation in specific populations, lack of external validation (for some of them) and also lack of synchrony with current era endovascular technology. However, with further optimization of current scores and the development of new scores, the field of PAD and CLI can be transitioned to a personalized medicine approach.

Precision Medicine in Aortic Anastomosis: A Numerical and Experimental Study of a Novel Double-Sided Needle.

BACKGROUND: Hand-sewn anastomosis is a crucial part of aortic reconstruction surgery and significantly affects its outcome. The present study presents a novel, bidirectional surgical needle aimed to improve aortic anastomosis in terms of speed and ease of use. Our objective was to assess the efficacy of the new design in comparison with the conventional needle. METHODS: A series of simulations were conducted with COMSOL software in order to perform a fatigue comparative analysis between the new and the conventional needle design. Ease of penetration into a piece of polydimethylsiloxane was evaluated. Lastly, the prototype was tested under in-vitro conditions in comparison with the conventional needle. RESULTS: Based on fatigue analysis, the new needle design improves durability, provided the two tips are equally used. The polytetrafluoroethylene coating improves penetration into the tissue by 7% to 17%, while electropolishing improves penetration up to 19%. When using the novel needle design, the average anastomotic task completion time was significantly reduced by 22% and the overall distance of hand movements was significantly reduced by 20%. CONCLUSIONS: The proposed design exhibited a shorter anastomotic time and seems promising in relation to ease of use and simplicity of the anastomotic technique it introduces.

Surgery for metachronous oligometastatic esophageal cancer: Is there enough evidence?

Esophageal cancer is the sixth most common cause of cancer-related mortality worldwide. Despite advances in diagnostic modalities and treatment options, five-year survival rates are below 20%. Esophagectomy with extended lymph node dissection is the mainstay of treatment. More than 50% of patients experience recurrence within 1-3 years postoperatively. Recurrent disease may present locoregionally at the site of anastomosis or as recurrence through lymphatic spread in lymph node basins, as hematogenic metastasis, or as a combination of these. The standard treatment of recurrence is currently predicated on systemic chemotherapy and/or radiotherapy. Recent evidence suggests that surgical treatment of metachronous oligometastatic disease may be prognostically advantageous over medical management alone. Given the considerably low response rates to chemoradiotherapy, many institutions have adopted surgical treatment strategies for oligo-recurrent disease on a case-by-case basis. The aim of this article is to review the current evidence on the role of surgical treatment for metachronous oligometastases from esophageal cancer.

Human Papilloma Virus infection and breast cancer development: Challenging theories and controversies with regard to their potential association.

Breast cancer (BC) remains the most frequently diagnosed malignancy among women worldwide. Recognized predisposing factors may be absent in the majority of affected patients, which has aroused a stronger interest in identifying risk parameters that contribute to BC pathogenesis. Human papilloma virus (HPV) infection is strongly associated with malignancies, such as cervical cancer, oropharyngeal cancer and anal cancer. Various surveys have linked HPV to the development of BC. Relevant variations in HPV identification among BC samples may be attributed to differences in study design, the populations involved and the HPV detection techniques applied, which are still controversial with conflicting opinions and results that deny the causative association between HPV infection and BC development. Furthermore, the role of HPV, a potential cause of human BC, has recently received more attention because of the possible restriction of disease progression using an HPV vaccine. The aim of this review was to evaluate both the aspects supporting and those against the theory of BC related to HPV infection. Recent literature has been also assessed in order to provide an update on the current concepts of relevant association.