PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells.

OBJECTIVE: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy. DESIGN: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance. RESULTS: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy. CONCLUSIONS: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting.

Postoperative outcomes, lymph node dissection and effects on costs among thoracotomy, video-assisted and robotic-assisted lobectomy for clinical stage I non-small cell lung cancer.

BACKGROUND: Thoracotomy, video-assisted thoracoscopic surgery (VATS) and robotic assisted thoracoscopic surgery (RATS)-lobectomy are widely accepted procedures for the surgical treatment of clinical (c)stage I non- small cell lung cancer (NSCLC). In the current literature which procedure gives more benefits is still debated. We present a comparison between these three procedures in term of advantages and postoperative outcomes. METHODS: A multicentric study about 259 lobectomies from 2013 to 2019: 128 patients underwent TL, 96 VATS and 35 RATS. Different variables were retrospectively analyzed among these three cohorts of patients with diagnosis of cStage I NSCLC. RESULTS: Rate of major complications comparable in VATS, RATS and TL; Advantages for RATS in minor complications (TL 34.4% vs. VATS 18.75% vs. RATS 8.57%. P=0.0015), postoperative days in Intensive Care Unit, days to chest tube removal, length of postoperative hospitalization (P<0.0001) and number of lymph nodes dissected (P=0.0257). Operating times are shorter in VATS than RATS (P<0.05). Pain (NRS Scale) is comparable. CONCLUSIONS: TL remains the conventional approach for stage II-IIIA(N2) NSCLC. RATS showed great advantages, but its higher operating time and costs, mostly, today don't justify its adoption as gold standard for the surgical treatment of cStage I NSCLC, instead of VATS.

Human bile microbiota: A retrospective study focusing on age and gender.

AIMS: The emerging biliary colonization of microorganisms in patients with biliary diseases may be devastating. Recent evidence suggests that age and gender may influence changes in the microbial composition of gut microbiota. To study the relationship between these parameters on bile microbiota, we retrospectively reviewed positive bile cultures following an endoscopic retrograde cholangiopancreatography (ERCP) in a QA-certified academic surgical unit of a single institution. METHODS: 449 positive bile cultures from 172 Italian patients with diseases of the biliopancreatic system hospitalized from 2006 through 2017 were investigated for aerobic, anaerobic, and fungal organisms. The patients were stratified into four age intervals (22-66, 67-74, 75-81, and 82-93 years) and followed up for five years. RESULTS: Gram-positive bacteria (GPB) was negatively associated with age only in multivariate analysis (Rpartial = -0.114, p = 0.017), with younger patients prone to harbor GPB and older patients likely to have Gram-negative bacteria (GNB). There was a definite link with the male gender using both univariate and multivariate analysis (p < 0.001). Enterococcus spp. was the most common strain identified in patients with GPB except for patients aged 67-74 years for male (95.2%) and female (80.9%) patients. Escherichia coli and Klebsiella spp. were most frequent than others in every group analyzed. Analogous results were found for bacteria Non-fermenting Gram-negative bacilli (NFGNB), such as Pseudomonas spp. and Stenotrophomonas spp. apart of the 2nd quartile. CONCLUSIONS: Our study strengthens the bond of age and gender with bile microbiota composition and suggests that further investigations may be required in targeting the aging microbiome. Other studies should also focus on Mediterranean epidemiological characteristics and antibiotic resistance surveillance system strategies.

An unusual presentation of breast tuberculosis: A case report.

Primary breast tuberculosis is an uncommon disease, especially in nonendemic areas. Its presentation could mimic a cancer or an abscess, but this entity must be considered for differential diagnosis in women coming from endemic countries.

Outpatient Treatment of Hemorrhoidal Disease: The Alternative Way to Treat Hemorrhoidal Disease in a Simple, Safe and Effective Manner.

BACKGROUND: Hemorrhoidal disease is a widespread problem in healthy working patients. The traditional surgical approaches cause a loss of several working days related to the post-- operative course that is often painful. To avoid these problems while offering a symptoms resolution in patients with low degrees hemorrhoids, the non-surgical treatments are nowadays largely proposed in proctological clinics. METHODS: We resume the recent literature on the issue to offer a practical and easy to use guide for clinicians. RESULTS: Rubber band ligation, injection sclerotherapy and infrared coagulation are cost effective, safe and effective treatments for patients with II- and III-degree hemorrhoids. Relapses are commons even if the procedures can be repeated until symptoms resolution. IV-degree hemorrhoids are not suitable of these treatments. CONCLUSION: The proctological clinics must evaluate the quality of life offered to patients and discuss with them the appropriate treatment in order to select the most appropriate one for symptoms resolution and disease cure. Less is not always the best but can be an alternative to be offered.

TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study.

BACKGROUND: TAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies. METHODS: In this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints. RESULTS: Treatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7-11.3) and the median progression-free survival was 2.1 months (95% CI 1.2-3.2), estimated using the Kaplan-Meier method. CONCLUSION: TAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

The microbiota of the bilio-pancreatic system: a cohort, STROBE-compliant study.

Background: The gut microbiota play an essential role in protecting the host against pathogenic microorganisms by modulating immunity and regulating metabolic processes. In response to environmental factors, microbes can hugely alter their metabolism. These factors can substantially impact the host and have potential pathologic implications.  Particularly pathogenic microorganisms colonizing pancreas and biliary tract tissues may be involved in chronic inflammation and cancer evolution. Purpose: To evaluate the effect of bile microbiota on survival in patients with pancreas and biliary tract disease (PBD). Patients and Methods: We investigated 152 Italian patients with cholelithiasis (CHL), cholangitis (CHA), cholangiocarcinoma (CCA), gallbladder carcinoma (GBC), pancreas head carcinoma (PHC), ampullary carcinoma (ACA), and chronic pancreatitis (CHP). Demographics, bile cultures, therapy, and survival rates were analyzed in cohorts (T1 death <6 months; T2 death <12 months; T3 death <18 months, T3S alive at 18 months). Results: The most common bacteria in T1 were E. coli , K. pneumoniae, and P. aeruginosa. In T2, the most common bacteria were E. coli and P. aeruginosa. In T3, there were no significant bacteria isolated, while in T3S the most common bacteria were like those found in T1. E. coli and K. pneumoniae were positive predictors of survival for PHC and ACA, respectively. E. coli , K. pneumoniae, and P. aeruginosa showed a high percentage of resistant bacteria to 3CGS, aminoglycosides class, and quinolone group especially at T1 and T2 in cancer patients. Conclusions: An unprecedented increase of E. coli in bile leads to a decrease in survival. We suggest that some strains isolated in bile samples may be considered within the group of risk factors in carcinogenesis and/or progression of hepato-biliary malignancy. A better understanding of bile microbiota in patients with PBD should lead to a multifaceted approach to rapidly detect and treat pathogens before patients enter the surgical setting in tandem with the implementation of the infection control policy.

Efficacy of fibrin sealant in thyroid surgery. Is drainage still necessary?

INTRODUCTION: The routinely use of drains in thyroid surgery is a traditional and well-defined method, even if there is no clear evidence of significant improvement in patients outcomes. Aim of our study is to define the feasibility, safety and cost- effectiveness of fibrin sealant in total thyroidectomy in order to overcome the use of drains. MATERIALS AND METHODS: We enrolled 262 patients (45 men and 217 women, mean age 54.7 yrs) undergone total thyroidectomy in University Hospital of Palermo (Italy), between July 2015 and October 2017. We randomized patients into group A (drain) and group B (no drain, fibrin sealant application). RESULTS: We registered statistical difference between the two groups in mean operative time, visual analogue scale of pain, post-operative stay, incidence of seromas and/or deep and superficial hematomas, re-operation and wound infection (reduced in the fibrin sealant group). No significant difference have been found in intraoperative blood loss, postoperative cough, post-operative use of analgesic and in incidence of hypoparathyroidism or recurrent palsy. CONCLUSIONS: Our study demonstrates that there is no evidence that the use of suction drains improves patients outcome and that routinely use of fibrin sealant can be advocated in thyroid surgery as an adjunct to a good surgical procedure. KEY WORDS: Complication, Drainage, Fibrin Sealant, Thyroidectomy.

Systemic schistosomiasis and large bowel perforation: An unexpected surgical urgency. Report of a case and literature review.

In the presence of suggestive clinical picture (high eosinophil count and multiple CT scan granuloma-like lesions), schistosomiasis should be taken into account in case of suspected bowel perforation even if common risk factors are not identified through anamnesis.

Dedifferentiated retroperitoneal large liposarcoma and laparoscopic treatment: Is it possible and safe? The first literature case report.

INTRODUCTION: Soft tissue sarcomas are rare neoplasms often characterized by local invasiveness and distant metastasis with poor prognosis for affected patients. Among the most frequent sarcomas we find well-differentiated and dedifferentiated liposarcomas characterized by a better survival compared to the other histological types. When it is possible the only curative treatment for these neoplasms is surgical resection. CASE REPORT: We report a case of a 62-year-old caucasian woman with CT abdominal scan that demonstrated a voluminous solid oval mass in the left perirenal space with dislocation of the kidney and in continuity with the anterior renal fascia. After a percutaneous CT-guided biopsy of the mass the histopathological diagnosis was a dedifferentiated retroperitoneal liposarcoma. We performed a laparoscopic surgical resection of the retroperitoneal mass in block with kidney and left adrenal gland. DISCUSSION: When possible, surgical resection with adequate margins represents the only curative therapeutic option for this pathology. Only a few papers are available in literature which take into consideration the possibility of laparoscopic approach for retroperitoneal masses with better vision of surgical field, reduction of post-operative pain and better cosmesis. CONCLUSION: A retroperitoneal mass represents a serious diagnostic challenge. The choice of the best surgical procedure can benefit to the patient prognosis. To our opinion laparoscopy can be a safe and successful treatment and it can represent a valid alternative to open surgery. However, we have no randomized controlled trials that compare laparoscopic versus open resection for retroperitoneal liposarcomas.

Endothelial Function, Adipokine Serum Levels, and White Matter Hyperintesities in Subjects With Diabetic Foot Syndrome.

CONTEXT: No study has analyzed the prevalence of white matter hyperintensities (WMHs) in subjects with diabetic foot syndrome (DFS) and their relationship to adipokine serum levels and indexes of endothelial and cognitive performance. OBJECTIVE: To evaluate omentin and vaspin serum levels and the prevalence of WMHs in subjects with DFS and to analyze their relationship with other endothelial, arterial stiffness, and cognitive functions. DESIGN: Case-control study enrolling 40 subjects with DFS, 40 diabetic subjects without foot complications, 40 controls with foot lesions without diabetes, and 40 patients without diabetes mellitus. MAIN OUTCOME MEASURES: Pulse wave velocity (PWV), augmentation index, reactive hyperemia index (RHI), serum vaspin and omentin levels, Fazekas score, and Mini-Mental State Examination (MMSE). RESULTS: Subjects with DFS showed higher mean PWV values when compared with diabetic controls and lower RHI values when compared with controls. They also showed a lower mean MMSE score, significantly lower omentin serum levels, and a higher prevalence of grade 2 severity of periventricular hyperintensities (PVHs). We observed a significant positive correlation between PWV and PVH and between Fazekas score and PWV among diabetic subjects, whereas among subjects with diabetic foot we observed a significant negative correlation between PVH and RHI. CONCLUSIONS: Diabetes seems to be more associated with endothelial function disturbance in comparison with patients with diabetic foot that exhibit a more strict association with microvascular brain damage as indicated by our significant finding of an association with PVHs.

Minimally Invasive Video-Assisted Thyroidectomy: Analysis of Complications From a Systematic Review.

BACKGROUND: Nowadays, minimally invasive video-assisted thyroidectomy (MIVAT) is considered a safe and effective option. However, its complication rate has not been specifically discussed yet. The aim of this systematic review was enrolling a large number of studies to estimate early and late complications (transient and definitive, uni- and bilateral laryngeal nerve palsy; transient and definitive hypocalcemia; cervical hematoma; hypertrophic or keloid scar) of MIVAT compared with conventional technique. METHODS: The review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria in PubMed and Embase. Search terms were "minimally invasive," "video-assisted," and "thyroidectomy." We enrolled randomized clinical trials, nonrandomized trials, and noncontrolled trials. RESULTS: Thirty-two articles were considered suitable. Complication rate of MIVAT was quite similar to conventional technique: only one randomized trial found a significant difference concerning overall skin complication, and a single trial highlighted hypocalcemia significantly increased in MIVAT, concerning serologic value only. No difference concerning symptomatic nor definitive hypocalcemia was found. CONCLUSIONS: We can confirm that MIVAT is a safe technique. It should be adopted in mean-high-volume surgery centers for thyroidectomy, if a strict compliance with indication was applied.

Robotic pancreatic surgery: old concerns, new perspectives.

BACKGROUND: Described for the first time in 2003, the robotic pancreatic surgery shows interesting results. The evaluation of post-operative outcomes is necessary once we describe an innovative surgical approach. METHODS: We have performed a retrospective analysis of a prospectively maintained database on robotic pancreatic surgery including malignant and benign indications for surgery. RESULTS: A total of 50 consecutive patients underwent robotic pancreatic surgery (26 pancreatico duodenectomy and 24 distal pancreatectomy) between January 2012 and July 2015 in a single centre. The overall operative time was 425 (390-620) min. In a subgroup of highly selected malignant tumours, we were able to achieve 88% of R0 resection with robotic approach. A number of lymphnodes rose significantly with growing experience (p = .025). The overall major complication rate (15%), as well as pancreatic fistula rate (16%) were acceptable. The two-year overall survival for the whole group was 65%. CONCLUSION: The robotic pancreatic surgery in a highly selected group of patients seems safe and feasible. The cost-effectiveness and long-term oncologic outcomes need further investigations.

Comparative Study of the Initial Experience in Performing Robotic and Laparoscopic Right Hepatectomy with Technical Description of the Robotic Technique.

BACKGROUND: Despite potential benefits of robotic liver surgery, it is still considered a "development in progress" technique. METHODS: The outcomes of 14 patients undergoing robotic right hepatectomy were analyzed and compared with the results of 20 laparoscopic right hepatectomies consecutively performed by the same young surgeon. RESULTS: The overall mean operative time was less in robotic arm (425 ± 139 vs. 565.18 ± 183.73, p = 0.022) and the estimated blood loss was similar (335.15 ± 139.8 vs. 423.95 ± 205.15, p = 0.17); no blood transfusion was required. Two patients in robotic group and 5 in laparoscopic group (p = 0.454) underwent conversion to open surgery; the overall morbidity was 21.4 and 15% in studied arms, respectively (p = 0.634). Pathology reports showed a mean surgical margin of 26.02 ± 3.9 in robotic arm, 28.76 ± 4.6 for laparoscopic, (p = 0.079) and we achieved a R0 resection rate of 91.66 and 85%, respectively. Reoperation and 90-days mortality rate were both null in robotic arm. One patient in laparoscopic group was reoperated due to postoperative hemorrhage. One-year overall and disease free-survival rate were 92.3 and 84.6%, respectively in robotic arm and 90 and 85% in laparoscopic arm. CONCLUSIONS: Robotic right hepatectomy is a safe and feasible technique providing promising short-term outcomes and oncological results also in the initial phase of learning curve.

Fully robotic left hepatectomy for malignant tumor: technique and initial results.

Robotic liver surgery has been considered as a unique opportunity to overcome the traditional limitations of laparoscopy; thus, it can potentially extend the indications of minimally invasive liver surgery. From April 2015 to May 2017, 35 patients underwent fully robotic left hepatectomy. The mean operative time was 315 min (200-445 min) and the mean estimated blood loss was 245 ml (125-628 ml). Pringle maneuver was required in six cases. Cancer was the indication for surgery in all patients (14 liver metastases, 18 hepatocellular carcinomas and 3 cholangiocarcinomas). There were one to four lesions in a patient and the mean lesion size was 39.2 mm (15-85 mm). The average length of hospital stay was 6.5 days (5-14 days). Perioperative morbidity rate was 17.2%. Two patients underwent conversion to open surgery. The 90-day mortality rate was nil. The mean surgical resection margin was 12 (1-22) mm, and R0-resection was reached in 33 out of 35 cases. The robotic left hepatectomy provides interesting surgical outcomes and good oncologic adequacy. It can be safely applied for the management of liver malignancies.

The abdominal wall hernia in cirrhotic patients: a historical challenge.

Background: The incidence rate of abdominal wall hernia is 20-40% in cirrhotic patients. A surgical approach was originally performed only if complication signs and symptoms occurred. Several recent studies have demonstrated the usefulness of elective surgery. During recent decades, the indications for surgical timing have changed. Methods: Cirrhotic patients with abdominal hernia who underwent surgical operation for abdominal wall hernia repair at the Policlinico "Paolo Giaccone" at Palermo University Hospital between January 2010 and September 2016 were identified in a prospective database, and the data collected were retrospectively reviewed; patients' medical and surgical records were collected from charts and surgical and intensive care unit (ICU) registries. Postoperative morbidity was determined through the Clavien-Dindo classification. Cirrhosis severity was estimated by the Child-Pugh-Turcotte (CPT) score and MELD (model of end-stage liver disease) score. Postoperative mortality was considered up to 30 days after surgery. A follow-up period of at least 1 year was used to evaluate hernia recurrence. Results: The univariate and multivariate analyses demonstrated the unique independent risk factors for the development of postsurgical morbidity (emergency surgery (OR 6.42; p 0.023), CPT class C (OR 3.72; p 0.041), American Society of Anesthesiologists (ASA) score ≥ 3 (OR 4.72; p 0.012) and MELD ≥ 20 (OR 5.64; p 0.009)) and postsurgical mortality (emergency surgery (OR 10.32; p 0.021), CPT class C (OR 5.52; p 0.014), ASA score ≥ 3 (OR 8.65; p 0.018), MELD ≥ 20 (OR 2.15; p 0.02)). Conclusions: Concerning abdominal wall hernia repair in cirrhotic patients, the worst outcome is associated with emergency surgery and with uncontrolled disease. The correct timing of the surgical operation is elective surgery after ascites drainage and albumin/electrolyte serum level and coagulation alteration correction.

Bactibilia in women affected with diseases of the biliary tract and pancreas. A STROBE guidelines-adherent cross-sectional study in Southern Italy.

PURPOSE: Bile is a hepatobiliary lipid-rich sterile solution, and its colonization by microorganisms defines the condition of bactibilia. In this study, we aimed to assess the bile microbiological flora and its potential link with comorbidity in women. METHODOLOGY: We performed a microbiologic investigation on 53 female patients with biliopancreatic diseases who granted consent, and we analysed the data using a MATLAB platform. RESULTS: We found that the most frequent disease associated with bactibilia was pancreas head carcinoma (PHC) (P=0.0015), while the least frequent disease was gall bladder carcinoma (GBC) (P=0.0002). The most common microorganisms were Pseudomonas spp. (P<0.0001) and Escherichia coli (P<0.0001). In particular Pseudomonas spp. and E. coli were negatively correlated to PHC presence and positively correlated to CCA by both univariate and multivariate analysis. CONCLUSIONS: Gram-negative bacteria have been linked to a tumour-associated inflammatory status. In the last 30 years, the analysis of mortality rate in Italy for PHC and GBC shows an increasing and a decreasing trend, respectively. Although this study targeted only 53 patients and does not reflect the frequency of diagnosis in a Southern Italian population, the decrease in GBC may raise the suggestion ofnon-adherence to a Mediterranean diet that may have become more prevalent in Southern Italy since the 1990s.

Robotic Pancreaticoduodenectomy: Technical Considerations.

Robotic surgery can help to overcome some technical limitations of laparoscopic pancreaticoduodenectomy thanks to EndoWrist instrumentations and the 3D view. Despite the potential benefits, its employment is still low and controversial. We focused on some important technical details crucial for a safe robotic pancreatectomy. After performing 52 robotic pancreatic resections that included 10 pancreatoduodenectomies, the authors describe their technique. The review of literature on robotic and laparoscopic duodenopancreatectomy is also performed in order to evaluate possible benefits of the robotic platform. We describe the step-by-step surgical procedure, analyzing all possible troubleshooting occurring in an initial center experience. The estimated blood loss as well as the length of stay was reduced by the robotic approach. We did not observe any significant increase of pancreatic fistula rate and all other postoperative complications despite our initial learning curve. Robotic pancreatoduodenectomy is a technically advanced procedure that requires important laparoscopic and robotic skills but it shows to be safe, feasible with some clear advantages in the bleeding control and in the reconstructive phase of the procedure.

Correction to: Vacuum-Assisted Wound Closure with Mesh-Mediated Fascial Traction Achieves Better Outcomes than Vacuum-Assisted Wound Closure Alone: A Comparative Study.

In the original article the credit line for the reuse of Fig. 1 from an article published in the open access journal, World Journal of Emergency Surgery is missing.