Dimitrios Schizas

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

History of the infantile hepatic hemangioma: From imaging to generating a differential diagnosis.

We aim to provide an up-to-date summary of infantile hepatic hemangioma (IHH) and its misnomers and to dialectically present the differential diagnosis of these rare entities of the liver. Eligible peer-reviewed articles on hepatic infantile hemangiomas, published between 2000 and 2015, were reviewed for this study. IHH is the most common hepatic vascular tumor in children. Once a liver mass is identified in an infant, the differential diagnosis ranges from vascular malformations to benign and malignant tumors including mesenchymal hamartoma, hepatoblastoma, metastatic neuroblastoma, so careful physical examination, imaging studies, and, if indicated, tumor markers and biopsy, are of pivotal importance to ascertain the correct diagnosis. Despite the benign nature of IHHs, some of these lesions may demand medical and/or surgical intervention, especially for multiple and diffuse IHH. Complications can include hepatomegaly, hypothyroidism and cardiac failure. Therefore, a close follow-up is required until complete involution of the lesions. We propose an algorithm to guide the physicians towards the proper management of hepatic lesions.

Total robotic pancreaticoduodenectomy: a systematic review of the literature

BackgroundPancreaticoduodenectomy (PD) is a complex operation with high perioperative morbidity and mortality, even in the highest volume centers. Since the development of the robotic platform, the number of reports on robotic-assisted pancreatic surgery has been on the rise. This article reviews the current state of completely robotic PD.Materials and MethodsA systematic literature search was performed including studies published between January 2000 and July 2016 reporting PDs in which all procedural steps (dissection, resection and reconstruction) were performed robotically.ResultsThirteen studies met the inclusion criteria, including a total of 738 patients. Data regarding perioperative outcomes such as operative time, blood loss, mortality, morbidity, conversion and oncologic outcomes were analyzed. No major differences were observed in mortality, morbidity and oncologic parameters, between robotic and non-robotic approaches. However, operative time was longer in robotic PD, whereas the estimated blood loss was lower. The conversion rate to laparotomy was 6.5–7.8%.ConclusionsRobotic PD is feasible and safe in high-volume institutions, where surgeons are experienced and medical staff are appropriately trained. Randomized controlled trials are required to further investigate outcomes of robotic PD. Additionally, cost analysis and data on long-term oncologic outcomes are needed to evaluate cost-effectiveness of the robotic approach in comparison with the open technique.

Medical management of gastric cancer: a 2017 update

Gastric cancer remains a considerable health burden throughout the world. The Cancer Genome Atlas (TCGA) analysis has recently unveiled 4 genotypes of gastric cancer with data not ready to change treatment strategy yet. A multimodality approach to therapy is the cornerstone of screening, diagnosing, staging, treating and supporting patients with gastric cancer. The evidence‐based approach to localized gastric cancer (>cT1b) is to use an either preoperative or postoperative strategy to maximize the benefit of surgery. The focus of future research is to optimize chemotherapy regimens, determine the role of radiation therapy and investigate the effect of treatment timing. In metastatic gastric cancer, biologic therapies have been introduced targeting markers shown to be prognostic. The results of ongoing randomized controlled phase 3 trials using targeted and immunotherapy agents, either in combination or alone, have the potential to alter the current treatment landscape of advanced gastric cancer.

An overview of laparoscopic techniques in abdominal aortic aneurysm repair

BACKGROUND Since 1993, various laparoscopic techniques have been developed to make laparoscopic treatment of abdominal aortic aneurysms (AAAs) a possible therapeutic alternative. We aim to review all published clinical studies on laparoscopic surgery of AAAs and juxtarenal abdominal aortic aneurysms (JAAAs). METHODS A thorough search of English-language literature published between January 1966 and December 2012 was performed. Studies that reported the results of laparoscopic surgical procedures as the intended repair strategy in patients with AAAs and JAAAs were selected using specific inclusion criteria. Only case series containing more than five patients were included. Outcome measures of eligible studies were extracted, tabulated, and then analyzed cumulatively, using a purely descriptive approach. RESULTS Fourteen studies were included in the analysis encompassing 933 patients with AAAs (mean age, 68.5 years; age range, 46-88) averaging 55.8 mm in diameter and 96 patients with JAAAs (mean age, 71 years; age range, 50-81) averaging 57 mm in diameter. The mean follow-up was 15.3 months for the AAA cases and 32.8 months for the JAAA cases. Hand-assisted laparoscopy, in particular, had a low 30-day mortality rate, short cross-clamping and operative times, few perioperative and postoperative complications, high graft patency rates, and short length of both hospital and intensive care unit stay. CONCLUSIONS Laparoscopic surgical procedures are a safe, feasible, and worthwhile alternative for patients with AAAs and JAAAs. Hand-assisted laparoscopy, in particular, was associated with low morbidity and mortality and short hospital and intensive care unit stay. However, the final decision regarding the best laparoscopic treatment should be left to the surgeon because of the limits of the data.

Liver transplantation for unresectable colorectal liver metastases: A systematic review

The use of liver transplantation (LT) for liver metastases attempted in the early 1990s was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject.

Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer

The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways. Recent data also suggest that acquired-resistance to anti-EGFR MoAbs is accompanied by inhibition of EGFR internalization, ubiqutinization, degradation and prolonged downregulation. It is well established that autophagy, a self-cannibalization process, is considered to be associated with resistance to the anti-EGFR MoAbs therapy. Additionally, autophagy induced by anti-EGFR MoAbs acts as a protective response in cancer cells. Thus, inhibition of autophagy after treatment with EGFR MoAbs can result in autophagic cell death. A combination therapy comprising of anti-EGFR MoAbs and autophagy inhibitors would represent a multi-pronged approach that could be evolved into an active therapeutic strategy in mCRC patients.

Stem Cell Therapy for Congenital Heart Disease: A Systematic Review

Background: Congenital heart disease (CHD) constitutes the most prevalent and heterogeneous group of congenital anomalies. Although surgery remains the gold standard treatment modality, stem cell therapy has been gaining ground as a complimentary or alternative treatment option in certain types of CHD. The aim of this study was to present the existing published evidence and ongoing research efforts on the implementation of stem cell-based therapeutic strategies in CHD. Methods: A systematic review was conducted by searching Medline, ClinicalTrials.gov, and the Cochrane library, along with reference lists of the included studies through April 23, 2017. Results: Nineteen studies were included in this review (8 preclinical, 6 clinical, and 5 ongoing trials). Various routes of cardiac stem cell delivery have been reported, including intracoronary, intramyocardial, intravenous, and epicardial. Depending on their origin and level of differentiation at which they are harvested, stem cells may exhibit different properties. Preclinical studies have mostly focused on modeling right ventricle dysfunction or failure and pulmonary artery hypertension by using pressure or volume overload in vitro or in vivo. Only a limited number of clinical trials on patients with CHD exist, and these primarily focus on hypoplastic left heart syndrome. Cell-based tissue engineering has recently been introduced, and research currently is focusing on developing cell-seeded grafts and patches that could potentially grow in parallel with whole body growth once implanted in the heart. Conclusions: It seems that stem cell delivery to the diseased heart as an adjunct to surgical palliation may provide some benefits over surgery alone in terms of cardiac function, somatic growth, and quality of life. Despite encouraging preliminary results, stem cell therapies for patients with CHD should only be considered in the setting of well-designed clinical trials. More wet laboratory research experience is needed, and translation of promising findings to large clinical studies is warranted to clearly define the efficacy and safety profile of this alternative and potentially groundbreaking therapeutic approach.

Mullerian dysgenesis: a critical review of the literature

PurposeTo present an update of the genetic, clinical, diagnostic, and therapeutic aspects of Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome.MethodsStudies were considered eligible if they have evaluated patients with MRKH syndrome. Eligible articles were identified by a search of MEDLINE bibliographical database from 1950 to August 2016. A purely descriptive approach was adopted concerning all outcomes examined by the individual studies.ResultsMRKH syndrome is defined as congenital aplasia of the upper vagina and impairment of uterine development in normal 46XX females. Accounting for 1:4500 women, MRKH is the second most common cause of primary amenorrhea following gonadal dysgenesis. Potential association of MRKH syndrome to specific genes has been the focus of recent research. Null-association results of HOXA genes and Wnt5a, Wnt7a, and Wnt9a have been reported, while point mutations of the WNT4 gene point mutations have been associated with an MRKH-like syndrome characterized by Mullerian duct regression and hyperandrogenism. Ultrasound and Magnetic Resonance Imaging (MRI) are the main techniques to establish an accurate diagnosis of the syndrome. Several non-surgical and surgical procedures have been reported for the creation of a functional neovagina; in general, non-surgical treatment should be the first initially pursued. Along with psychological support, recent developments in assisted reproductive technologies of IVF techniques and the availability of gestational surrogacy, as well as the recent breakthrough of successful uterus transplantation, enable women with MRKH syndrome to attain their own genetic child.Conclusion(s)MRKH syndrome is a medical modality with important social, legal, and ethical projections that require a multi-disciplinary approach.

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.