Multimodal Treatment of Metastatic Rectal Cancer in a Young Patient: Case Report and Literature Review.

Metastatic colorectal cancer requires a multidisciplinary and individualized approach. Herein, we reported the case of a young woman diagnosed with metastatic rectal cancer who received an individualized multimodal treatment strategy that resulted in a remarkable survival. There were several particular aspects of this case, such as the early onset of the disease, the successful use of conversion therapy, the application of liquid biopsy to guide treatment, and the specific nature of the bone metastasis. To offer more insights for navigating such challenges in patients with metastatic colorectal cancer, we have conducted a literature review to find more data related to the particularities of this case. The incidence of early onset colorectal cancer is on the rise. Data suggests that it differs from older-onset colorectal cancer in terms of its pathological, epidemiological, anatomical, metabolic, and biological characteristics. Conversion therapy and surgical intervention provide an opportunity for cure and improve outcomes in metastatic colorectal cancer. It is important to approach each case individually, as every patient with limited liver disease should be considered as a candidate for secondary resection. Moreover, liquid biopsy has an important role in the individualized management of metastatic colorectal cancer patients, as it offers additional information for treatment decisions.

Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients.

BACKGROUND: In this study, we compared programmed death-ligand 1 (PD-L1) expression in primary tissue samples and its soluble form (sPD-L1) concentration in matched preoperative plasma samples from gastric cancer patients to understand the relationship between tissue and plasma PD-L1 expression and to determine its diagnostic and prognostic value. METHODS: PD-L1 expression in tissue was assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), and sPD-L1 concentration in plasma was quantified by ELISA. The levels of the CD274 gene, which encodes for PD-L1 protein, were examined as part of bulk tissue RNA-sequencing analyses. Additionally, we evaluated the association between sPD-L1 levels and various laboratory parameters, disease characteristics, and patient outcomes. RESULTS: GC patients had significantly higher levels of sPD-L1 in their plasma (71.69 pg/mL) compared to healthy controls (35.34 pg/mL) (p < 0.0001). Moreover, sPD-L1 levels were significantly correlated with tissue PD-L1 protein, CD274 mRNA expression, larger tumor size, advanced tumor stage, and lymph node metastasis. Elevated sPD-L1 levels (> 103.5 ng/mL) were associated with poor overall survival (HR = 2.16, 95%CI 1.15-4.08, p = 0.017). Furthermore, intratumoral neutrophil and dendritic cell levels were directly correlated with plasma sPD-L1 concentration in the GC patients. CONCLUSIONS: sPD-L1 was readily measurable in GC patients, and its level was associated with GC tissue PD-L1 expression, greater inflammatory cell infiltration, disease progression, and survival. Thus, sPD-L1 may be a useful minimally invasive diagnostic and prognostic biomarker in GC patients.

The Survival Benefit of Repetitive Ultrasound-Guided Liver Resections in the Absence of Chemotherapy for Multiple Colorectal Recurrent Liver Metastases.

We present the case of a 54-year-old female patient, diagnosed with stage IV rectal cancer, with multiple (12) synchronous liver metastases, the largest of 10 cm in diameter, bilobar distributed. The operative management consisted in simultaneous ultra-low robotic anterior resection with coloanal anastomosis (protected by ileostomy) and multiple ultrasound-guided non-anatomical liver resections (in open approach). The patient was unable to follow neoadjuvant and adjuvant chemotherapy due to the systemic side effects. The intrahepatic disease presented 2 episodes of recurrence, sanctioned by ultrasound-guided non-anatomical parenchyma sparing liver resections. In total 32 liver metastases were addressed (31 resected and 1 radiofrequency ablated). The patient presented 1 episode of lung recurrence, sanctioned by right superior lobectomy and lymphadenectomy for a singular metastasis. The patient died with disease progression both intra-, and extrahepatically after 34 months post first surgical intervention.

Molecular profile of the NF-κB signalling pathway in human colorectal cancer.

The development and progression of colorectal cancer (CRC) have been associated with inflammation processes that involve the overactivation of the NF-κB signalling pathway. The characterization of the NF-κB expression profile in CRC is an important topic since the suppression of NF-κB represents a potential therapeutic approach. In this study, we assessed the expression levels of 84 NF-κB-related genes in paired tumoral (T) and peritumoral (PT) tissues from 18 CRC patients and 18 normal colonic mucosae, and the expression levels of three miRNAs targeting the most dysregulated genes revealed by the case-control analysis. Comparing the gene expression profile of T and controls, 60 genes were dysregulated. The comparison of T and PT revealed 17 dysregulated genes in the tumoral tissues, with IL1B, CXCL8, IL1A, and CSF2 being the most upregulated. Notably, through a bioinformatics analysis, the differential gene expression of 11 out of the 17 genes was validated on a larger cohort of 308 CRC patients compared with 41 controls. Moreover, a decrease in the levels of RELA, NOD1, CASP8, BCL2L1, ELK1, and IKBKB was identified in poorly differentiated tumours compared to moderately differentiated tumours. The analysis of the three miRNAs targeting IL1B, CXCL8, IL1A, and CSF2 showed that miR-182-5p was upregulated in T compared with PT, whereas miR-10b-5p was downregulated in T compared with PT and control tissues. Our results may contribute to the design of new experimental therapeutic strategies based on endogenous molecules, such as miRNAs, to target the genetic key players of the NF- κB pathway.

Circulating Angiogenic Markers in Gastroenteropancreatic Neuroendocrine Neoplasms: A Systematic Review.

BACKGROUND: Neuroendocrine neoplasms are a heterogeneous group of tumors that raise challenges in terms of diagnosis, treatment and monitoring. Despite continuous efforts, no biomarker has showed satisfying accuracy in predicting outcome or response to treatment. METHODS: We conducted a systematic review to determine relevant circulating biomarkers for angiogenesis in neuroendocrine tumors. We searched three databases (Pubmed, Embase, Web of Science) using the keywords "neuroendocrine" and "biomarkers", plus specific biomarkers were searched by full and abbreviated name. From a total of 2448 publications, 11 articles met the eligibility criteria. RESULTS: VEGF is the most potent and the most studied angiogenic molecule, but results were highly controversial. Placental growth factor, Angiopoietin 2 and IL-8 were the most consistent markers in predicting poor outcome and aggressive disease behavior. CONCLUSIONS: There is no robust evidence so far to sustain the use of angiogenic biomarkers in routine practice, although the results show promising leads.

Collagen Family and Other Matrix Remodeling Proteins Identified by Bioinformatics Analysis as Hub Genes Involved in Gastric Cancer Progression and Prognosis.

Gastric cancer has remained in the top five cancers for over ten years, both in terms of incidence and mortality due to the shortage of biomarkers for disease follow-up and effective therapies. Aiming to fill this gap, we performed a bioinformatics assessment on our data and two additional GEO microarray profiles, followed by a deep analysis of the 40 differentially expressed genes identified. PPI network analysis and MCODE plug-in pointed out nine upregulated hub genes coding for proteins from the collagen family (COL12A1, COL5A2, and COL10A1) or involved in the assembly (BGN) or degradation of collagens (CTHRC1), and also associated with cell adhesion (THBS2 and SPP1) and extracellular matrix degradation (FAP, SULF1). Those genes were highly upregulated at the mRNA and protein level, the increase being correlated with pathological T stages. The high expression of BGN (p = 8 × 10-12), THBS2 (p = 1.2 × 10-6), CTHRC1 (p = 1.1 × 10-4), SULF1 (p = 3.8 × 10-4), COL5A1 (p = 1.3 × 10-4), COL10A1 (p = 5.7 × 10-4), COL12A1 (p = 2 × 10-3) correlated with poor overall survival and an immune infiltrate based especially on immunosuppressive M2 macrophages (p-value range 4.82 × 10-7-1.63 × 10-13). Our results emphasize that these genes could be candidate biomarkers for GC progression and prognosis and new therapeutic targets.

Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology.

Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.

Combined Positive Score for Programmed Death Ligand-1 Expression and Inflammatory Microenvironment in Gastrointestinal Stromal Tumors.

Background and Objectives: GISTs are the most frequent type of mesenchymal neoplasm of the digestive tract. The prognosis is mainly determined by tumor dimensions, mitotic rate and location, but other less well-documented factors can influence evolution and survival. The immune microenvironment and checkpoint molecule expression were proven to impact the prognosis in different types of cancer. The aim of this study was to determine PD-L1 expression in GISTs and to evaluate the level of intratumoral immune infiltration in relation to prognostic variables and survival. Materials and Methods: Sixty-five GISTs diagnosed in the same institution between 2015 and 2018 were immunohistochemically tested for PD-L1 and evaluated using CPS. Immune cells were emphasized, with CD3, CD4, CD8, CD20 and CD68 antibodies and quantified. All data were processed using statistical tools. Results: The median age was 61 years (range, 28-78) and 36 patients (55.4%) were males. The location of the tumors was predominantly gastric (46%), followed by the small bowel (17%) and colorectal (6%). In addition, 11% were EGISTs and 20% were secondary tumors (11% metastases and 9% local recurrences). PD-L1 had a variable expression in tumor and inflammatory cells, with a CPS ranging from 0 to 100. Moreover, 64.6% of cases were PD-L1 positive with no significant differences among categories of variables, such as the age and the sex of the patient, tumor location, the primary or secondary character of the tumor, dimensions, mitotic rate, the risk of disease progression and tumor cell type. Immune cells had a variable distribution throughout the tumors. CD3+ lymphocytes were the most frequent type. CD20+ cells were identified in a larger number in tumors ≤5 cm (p = 0.038). PD-L1-positive tumors had a higher number of immune cells, particularly CD3+, CD20+ and CD68+, in comparison to PD-L1-negative ones (p = 0.032, p = 0.051, p = 0.008). Epithelioid and mixed cell-type tumors had a higher number of CD68+ cells. Survival was not influenced by PD-L1 expression; instead, it was decreased in multifocal tumors (p = 0.0001) and in cases with Ki67 ≥ 50% (p = 0.008). Conclusions: PD-L1-positive expression and the presence of different immune cell types, in variable quantities, can contribute to a better understanding of the complex interactions between tumor cells and the microenvironment, with a possible therapeutic role in GISTs.

Parenchyma Sparing ALPPS - Ultrasound Guided Partition Through Segment 4 to Maximize Resectability (with video).

Background: Associating liver partition and portal vein ligation (ALPPS) has evolved as a treatment strategy for patients with liver tumors who are not amenable for upfront hepatectomy because of an insufficient future liver remnant (FLR). Aim of this study was to test the applicability of ultrasound guided parenchyma sparing surgery to ALPPS concept, by non-anatomically shifting the plane of transection in favor of FLR, resulting in a new technical variant of ALPPS, entitled parenchyma sparing ALPPS (psALPPS). Materials and Methods: Patients who could not safely undergo right trisectionectomy ALPPS because of insufficient FLR were considered eligible for psALPPS, consisting in liver partition through segment 4 using ultrasound guidance. Results: Between April 2017 and April 2021, five patients with median age of 68 years (range: 66-78), four male and one female, underwent psALPPS for colorectal liver metastases (N=2), intrahepatic cholangiocarcinoma (N=2), and hepatocellular carcinoma (N=1). Standardized FLR (sFLR) for segments 2-3 before stage 1 surgery would have been a median of 11.6%. PsALPPS could double the sFLR at stage 1 resulting in an increase of ps-sFLR from a median of 22.7% (at stage 1) to 34.0% (at stage 2) after a median interstage interval of 15 days. All patients tolerated surgery well and no major complications were recorded. Conclusions: Applying the principles of parenchyma sparing surgery to ALPPS offers the advantage to maximize FLR and simultaneously reduce ischemic injury of segment 4 compared to conventional ALPPS. In this way, psALPPS may markedly increase resectability while reducing morbidity. Video version: https://www.revistachirurgia.ro/pdfs/?EntryID=922974&art=2021-parenchyma-sparing-ALPPS-ultrasound-guided-partition.pdf

Parenchyma Sparing ALPPS Ultrasound Guided Partition Through Segment 4 to Maximize Resectability (with video).

Background: Associating liver partition and portal vein ligation (ALPPS) has evolved as a treatment strategy for patients with liver tumors who are not amenable for upfront hepatectomy because of an insufficient future liver remnant (FLR). Aim of this study was to test the applicability of ultrasound guided parenchyma sparing surgery to ALPPS concept, by non-anatomically shifting the plane of transection in favor of FLR, resulting in a new technical variant of ALPPS, entitled parenchyma sparing ALPPS (psALPPS). Materials and Methods: Patients who could not safely undergo right trisectionectomy ALPPS because of insufficient FLR were considered eligible for psALPPS, consisting in liver partition through segment 4 using ultrasound guidance. Results: Between April 2017 and April 2021, five patients with median age of 68 years (range: 66-78), four male and one female, underwent psALPPS for colorectal liver metastases (N=2), intrahepatic cholangiocarcinoma (N=2), and hepatocellular carcinoma (N=1). Standardized FLR (sFLR) for segments 2-3 before stage 1 surgery would have been a median of 11.6%. PsALPPS could double the sFLR at stage 1 resulting in an increase of ps-sFLR from a median of 22.7% (at stage 1) to 34.0% (at stage 2) after a median interstage interval of 15 days. All patients tolerated surgery well and no major complications were recorded. Conclusions: Applying the principles of parenchyma sparing surgery to ALPPS offers the advantage to maximize FLR and simultaneously reduce ischemic injury of segment 4 compared to conventional ALPPS. In this way, psALPPS may markedly increase resectability while reducing morbidity. Video: https://www.revistachirurgia.ro/pdfs/?EntryID=922974&art=2021-parenchyma-sparing-ALPPS-ultrasound-guided-partition.pdf

Is Long-Term Survival in Metastases from Neuroendocrine Neoplasms Improved by Liver Resection?

Background and Objectives: Although many of the neuroendocrine neoplasms (NEN) have a typically prolonged natural history compared with other gastrointestinal tract cancers, at least 40% of patients develop liver metastases. This study aims to identify whether liver resection improves the overall survival of patients with liver metastases from NEN. Materials and Methods: We conducted a retrospective study at "Fundeni" Clinical Institute over a time period of 15 years; we thereby identified a series of 93 patients treated for NEN with liver metastases, which we further divided into 2 groups as follows: A (45 patients) had been subjected to liver resection complemented by systemic therapies, and B (48 patients) underwent systemic therapy alone. To reduce the patient selection bias we performed at first a propensity score matching. This was followed by a bootstrapping selection with Jackknife error correction, with the purpose of getting a statistically illustrative sample. Results: The overall survival of the matched virtual cohort under study was 41 months (95% CI 37-45). Group A virtual matched patients showed a higher survival rate (52 mo., 95% CI: 45-59) than B (31 mo., 95% CI: 27-35), (p < 0.001, Log-Rank test). Upon multivariate analysis, seven independent factors were identified to have an influence on survival: location (midgut) and primary tumor grading (G3), absence of concomitant LM, number (2-4), location (unilobar), grading (G3) of LM, and 25-50% hepatic involvement at the time of the metastatic disease diagnosis. Conclusions: Hepatic resection is nowadays the main treatment providing potential cure and prolonged survival, for patients with NEN when integrated in a multimodal strategy based on systemic therapy.

Abdominoperineal Resection for Rectal Cancer: Open, Laparoscopic or Robotic Approach.

OBJECTIVES: The present study compares abdominoperineal resection (APR) performed by minimally invasive and open approach, regarding preoperative selection criteria, intraoperative and early postoperative aspects, in choosing the suitable technique performed by surgical teams with experience in both open and minimally invasive surgery (MIS). Methods: This is a retrospective study, conducted between 2008-2020. Two hundred thirty-three patients with APR performed for low rectal or anal cancer were included. The cohort was divided into two groups, depending on the surgical approach used: Minimally Invasive Surgery (laparoscopic and robotic procedures) and Open Surgery (OS). The perioperative characteristics were analyzed in order to identify the optimal approach and a possible selection criteria. Results: We identified a high percentage of patients with a history of abdominal surgery in the open group (p = .0002). Intraoperative blood loss was significantly higher in the open group (p= .02), with an increased number of simultaneous resections (p = .041). The early postoperative outcome was marked by significantly lower morbidity in the MIS group (p = .005), with mortality recorded only in the open group (3 cases), in patients that associated severe comorbidities. The hystopathological results identified a significant number of patients with stage T2 in the MIS group (p= .037). Conclusions: Minimally invasive surgery provides a major advantage to APR, by avoiding an additional incision, the specimen being extracted through the perineal wound. The success of MIS APR seems to be assured by a good preoperative selection of the patients, alongside with experienced surgical teams in both open and minimally invasive rectal resections. The lack of conversion identified in robotic APR confirm the technical superiority over laparoscopic approach.

Liver Resection for Metastases from Gastrointestinal Stromal Tumors: Does it Improve Long-Term Survival?

BACKGROUND AIMS: The emergence of tyrosine kinase inhibitors, radically altered the management of GISTs and sparked controversy regarding the role of hepatic resection for metastatic tumors. This study aims to identify whether there is improvement in the overall survival of patients with gastrointestinal liver metastases, undergoing hepatic resection in the context of multimodal treatment strategy, as to those approached only by systemic therapy. Methods: Using a retrospective database, we identified 57 patients treated at our center over a 12-year period: Group A (n=31) underwent hepatic resection alongside systemic therapies, and B (n=26) only systemic therapies. In order to obtain a more robust sample, needed for the survival analysis, we performed a propensity score matching and a bootstrapping selection with Jackknife correction for errors; thus, we created an extended sample of 1000 virtual patients. Results: The overall survival measured in all patients was 47 months (95%CI:34-60); significantly higher for group A (56 months, 95%CI:37-75) compared to group B (38 months, 95%CI:19-56), (p=0.007, Log Rank test). Multivariate analysis identified one risk factor: the presence synchronous liver metastases upon diagnosis of primary. Conclusions: Liver resection following TKI therapy is the current mainstay of treatment strategy for potential cure and prolonged survival, in appropriately selected patients evaluated in an multidisciplinary tumor board.

Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Preliminary Experience in a Single Center.

Background: The need to maximize the use of donor organs and the issue of ischemia-reperfusion injury led to the use of thermoregulated oxygenated machine perfusion that improves the function of liver graft prior to transplantation. Among these methods, the HOPE (hypothermic oxygenated perfusion) protocol shows significant benefits. The aim of the paper is to analyze the early experience in using such procedure in a high-volume liver transplantation center. Methods: Normal liver grafts with cold ischemia time â?¥6 hours, marginal grafts and discarded (beyond ECD criteria) grafts were perfused using HOPE. Our selection criteria for dual HOPE (hepatic artery and portal perfusion) were steatosis, at least 3 associated ECD criteria, and discarded grafts. The main criteria to establish graft improvement were the progressive increase of arterial and portal flows, with lactate under 3 mmol/L or, even if over this value, with a decreasing trend during perfusion. Results: Whole liver grafts harvested from 28 donors between February 2016 and June 2021 benefitted from HOPE: 9 otherwise discarded grafts were assessed and considered not fit for transplantation, while the other 19 were ECD or standard grafts that were subsequently transplanted. Dual HOPE was used in 8 out of the 19 procedures (42.1%). We obtained a significant increase of arterial and portal flow (p=0.005 and p=0.001, respectively). In recipients, significant improvement of AST, ALT, INR and lactate values were recorded (p 0.001, p 0.001, p 0.001, and p=0.05, respectively). The rate of major postoperative complications (Dindo-Clavien grade 3) after LT was 26.3%, while the rate of early graft dysfunction was 15.8%. No PRS or acute rejection was recorded. The postoperative mortality rate was 15.8%. After a median follow-up of 9.3 months (range 2-44), the late major complication rate was 15.8%, without mortality. Conclusion: Machine perfusion is nowadays part of current clinical practice. This way, marginal liver grafts (DCD, ECD-DBD) may be safely used for transplantation improving the outcome, thus effectively enhance the use of a persistent scarce pool of donors. For best results, we believe that both techniques of HOPE (mono and dual HOPE) should be used based on specific selection criteria.

Gastrointestinal stromal tumors of the colon and rectum.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms, colorectal location being met in less than 5% of cases. Knowledge about this site related particularities are limited. The aim of this study is to present our experience with colorectal GISTs between 2005 and 2018 from the clinical, morphological, and immunohistochemical perspectives, with emphasis on prognostic factors. From a total of 203 gastrointestinal stromal tumors registered, 12 were colorectal (6%). The number of colonic tumors surpassed that of the rectum (9 : 3) and on the right side were registered more cases than on the left side (6/3). 9 were primary tumors and 3 were recurrences. Men and women were represented equally and the age range was between 22 and 76. Tumor dimensions varied between 0.5 and 14 cm. Microscopically, spindle cell type was dominant. Mitotic rate was variable between 1 and 115/50HPFs. Accordingly, for primary tumors progression risks were assigned (low risk: 2 cases, intermediate risk: 3 cases and high risk: 4 cases). All GISTs were CD117 and DOG1 positive. Four of the patients died of the disease.

Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients.

BACKGROUND: The expression of microRNAs (miRNAs) is a promising prognostic and diagnostic tool in hepatocellular carcinoma (HCC). Here we performed small RNA sequencing (sRNA-seq) of tissue, serum and serum exosomes to investigate changes in miRNA expression between the different sample types and correlated the expression with clinical parameters. We also performed gene expression arrays on tumor and normal tissue. RESULTS: Paired tissue, serum and serum exosomes sequencing revealed consistent positive correlation of miR-21 between serum exosomes and tumor tissue, indicating that miR-21 could be exported from tissue to circulation via exosomes. We found that let-7 miRNAs are generally upregulated in serum exosomes compared to whole serum, indicating that these miRNAs could be preferentially loaded into exosomes. Comparing serum from HCC patients with serum from healthy individuals revealed a global increase of miRNAs in serum from HCC patients, including an almost 4-fold increase of several miRNAs, including the liver-specific miR-122. When correlating miRNA expression with clinical parameters we detected significant association between hepatitis B virus (HBV) infection and miR-122 in serum as well as several serum and tissue-miRNAs that correlated with surgery type. We found that miR-141 and miR-146 correlated with cirrhosis in tumor tissue and normal tissue, respectively. Finally, high expression of miR-21 in tumors were associated with poor survival. Focusing on gene expression we found several significant messenger RNAs (mRNAs) between tumor and normal tissue and a Gene Ontology (GO) analysis revealed that these changes were mainly related to cell cycle and metabolism. Further, we detected mRNAs that correlated with cirrhosis and HBV infection in tissue. Finally, GO analysis of predicted targets for miRNAs down-regulated in tumor found that these were enriched for functions related to collagen synthesis. CONCLUSIONS: Our combined data point to altered miRNA and mRNA expression contributing to both generally impaired lipid metabolism and increased cell proliferation and a miRNA-driven increase in collagen synthesis in HCC. Our results further indicate a correlation in miRNA expression between exosomes, serum, and tissue samples suggesting export from tumors via exosomes. This correlation could provide a basis for a more tumor-specific miRNA profile in serum.

The Role of Histopathology and Immunohistochemistry in the Diagnosis of Neuroendocrine Biliary Duct Tumor.

Neuroendocrine tumors of the biliary tract are rare entities developed form Kulchitsky cells which undergo a process of malignant transformation. However, the differential diagnostic between neuroendocrine tumors of the biliary tract and hilar cholangiocarcinoma is very difficult to be established during the preoperative workup; therefore, most patients are submitted to surgery with radical intent and the final diagnostic remains to be confirmed through histopathological and immunohistochemistry studies of the specimen of resection. We present the case of a 60 year old patient who was submitted to en bloc extended right hepatectomy (including segment IV and caudate lobe) with extra hepatic biliary tree resection and left hepatic duct preservation, left cholangiojejunostomy (Roux-En-Y technique), celiac and common hepatic arteries lymphadenectomy and segmental portal vein resection with end-to-end anastomosis for a tumor of the biliary carrefour extended to the right biliary duct and invading the portal vein. The histopathological and immunohistochemistry studies confirmed the presence of a grade 1 neuroendocrine tumor, the staining being positive for Chromogranin A, Neuron-Specific Enolase (NSE) and Ki-67 (1% nuclear positive). At 24 months follow-up the patient is free of recurrent disease.

Parietal Endometriosis: A Challenge for the General Surgeon.

Background: Parietal endometriosis (PE) is a rare pathology, which usually develops in fertile women, after surgical or gynecological procedures. Its quasi-pathognomonic symptomatology consists in catamenial pain with or without palpable mass. The diagnosis can be challenging because it may be confused with stitch granuloma, hematoma, hernia or even cancer. Patients and methods: Between January 2007 and December 2017, 10 female patients with PE were referred for diagnosis and surgery to our clinic. Results: The mean age of the patients was 35.8 years. The primary symptom was pain (9/10 patients) and a palpable mass was present in all patients. Five cases were correctly preoperatively diagnosed as PE and five were misdiagnosed as tumors (4 patients) and stitch granuloma (1 patient). Eight patients had a history of gynecological procedure (cesarean section, episiotomy) and two had no previous surgical interventions. The size of the mass varied from 1 cm to 14 cm. Resection of PE required parietal reconstruction with mesh in five patients but for the rest of the patients no mesh was needed. Conclusions: Our study confirms PE as a rare surgical entity and indicates the necessity of thorough history and physical examination, as well as imaging exams, for making the correct diagnosis in order to choose the appropriate surgical procedure.

Robotic Approach in Benign and Malignant Esophageal Tumors; A Preliminary Seven Case Series.

Esophageal surgery has been recognized as very challenging for surgeons and risky for patients. Thoracoscopic approach have proved its benefit in esophageal surgery but has some drawbacks as tremor and limited degrees of freedom, contra-intuitive movements and fulcrum effect of the surgical tools. Robotic technology has been developed with the intent to overcome these limitations of the standard laparoscopy or thoracoscopy. These benefits of robotic procedure are most advantageous when operating in remote areas difficult to reach as in esophageal surgery. AIM: The aim of this paper is to present our small experience related with robotic approach in benign and malignant esophageal tumors and critically revise the evidence available about the use of the robotic technology for the treatment of these pathology. Methods: From January 2008 to September 2016 robotic surgery interventions related with benign or malignant esophageal tumors were performed in "Dan Setlacec" Center for General Surgery and Liver Transplantation of Fundeni Clinical Institute in seven patients. This consisted of dissection of the entire esophagus as part of an abdomino-thoracic-cervical procedure for esophageal cancer in 3 patients and the extirpation of an esophageal leiomyoma in 3 cases and a foregut esophageal cyst in one case. Results: All procedures except one were completed entirely using the da Vinci robotic system. The exception was the first case - a 3 cm leiomyoma of the inferior esophagus with ulceration of the superjacent esophageal mucosa. Pathology reports revealed three esophageal leiomyoma, one foregut cyst and three squamous cell carcinomas with free of tumor resection margins. The mean number of retrieved mediastinal nodes was 24 (22 - 27). The postoperative course was uneventful in four cases, in the other three a esophageal fistula occurred in the converted leiomyoma case (closed in the 14th postoperative day), a prolonged drainage in one esophageal cancer case and a temporary right recurrent nerve palsy in an other one. One patient with esophageal cancer and all patients with benign lesions are alive with no signs of recurrence and no symptomatology. CONCLUSION: Our experience is limited and we cannot conclude for the long term benefits of robotic surgery for esophageal tumors. In our experience the early outcomes were better then using classic open approach, but similar with the cases performed by thoracoscopic approach. We have noticed significant advantages of robotic surgery in relation of lymph node retrieval, leiomyoma dissection safe from esophageal mucosa and suturing. Ergonomics for the surgeon was incomparable better then with the thoracoscopic approach.

D2 Lymphadenectomy for Gastric Adenocarcinoma: Long-term Results and the Impact of Surgeon Experience on the Survival Rates.

Background: Surgery is the main component of the multimodality treatment of gastric cancer (GC). The present study aims to comparatively assess the early and long-term outcomes after D1 and D2 lymph node dissection. Furthermore, the impact of surgeon case-load on the long-term survival after D2 gastrectomies is also explored. Methods: A number of 773 patients with curative-intent surgery for GC adenocarcinoma (1997 - 2010: 325 patients with D1 lymphadenectomy, 448 patients with D2 lymphadenectomy) were included. Results: No statistically significant differences of overall morbidity rates were observed between the D1 and D2 groups of patients (16.3%for D1 group vs. 18.8% for D2 group, p = 0.39). However, statistically significant higher rates of post operative pancreatic fistulae rates were observed in the D2 group of patients (3.2% for D1 group vs. 7.9% for D2 group, p 0.001). Interestingly, statistically significant higher rates of mortality were observed for the D1 group of patients (8.9% for D1 group vs. 2.9% for D2 group, p 0.001). The 5-year survival rate was statistically significant higher in the D2 group of patients (median overall survival time of 18 months for D1 group vs. 60 months for D2 group, p 0.001). A statistically significant correlation (p=0.005, r=0.571) was observed between the overall survival time and the number of D2 lymphadenectomies performed by each surgeon. Conclusions: D2 lymph node dissection is associated with statistically significant improved longterm survivals at the expense of higher postoperative pancreatic fistulae rates, compared to D1 surgery. However, no increased mortality rates were observed in the D2 group of patients. D2 radical gastrectomies should be performed in high-volume centers by high case-load surgeons.