Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

Open versus laparoscopic gastrectomy for advanced gastric cancer: a propensity score matching analysis of survival in a western population-on behalf of the Italian Research Group for Gastric Cancer.

BACKGROUND: Oncologic outcomes after laparoscopic gastrectomy for advanced gastric cancer in the West have been poorly investigated. The aim of the present study was to compare survival outcomes in patients undergoing curative-intent laparoscopic and open gastrectomy for advanced gastric cancer in several centres belonging to the Italian Research Group for Gastric Cancer. METHODS: Data of patients operated between 2015 and 2018 were retrospectively analysed. Propensity Score Matching was performed to balance baseline characteristics of patients undergoing laparoscopic and open gastrectomy. The primary endpoint was 3-year overall survival. Secondary endpoints were 3-year disease-free survival and short-term outcomes. Multivariable regression analyses for survival were conducted. RESULTS: Data were retrieved from 20 centres. Of the 717 patients included, 438 patients were correctly matched, 219 per group. The 3-year overall survival was 73.6% and 68.7% in the laparoscopic and open group, respectively (p = 0.40). When compared with open gastrectomy, laparoscopic gastrectomy showed comparable 3-year disease-free survival (62.8%, vs 58.9%, p = 0.40), higher rate of return to intended oncologic treatment (56.9% vs 40.2%, p = 0.001), similar 30-day morbidity/mortality. Prognostic factors for survival were ASA Score ≥ 3, age-adjusted Charlson Comorbidity Index ≥ 5, lymph node ratio ≥ 0.15, p/ypTNM Stage III and return to intended oncologic treatment. CONCLUSIONS: Laparoscopic gastrectomy for advanced gastric cancer offers similar rates of survival when compared to open gastrectomy, with higher rates of return to intended oncologic treatment. ASA score, age-adjusted Charlson Comorbidity Index, lymph node ratio, return to intended oncologic treatment and p/ypTNM Stage, but not surgical approach, are prognostic factors for survival.

Minimally invasive Ivor Lewis oesophagectomy with trans-hiatal oesophageal transection and transabdominal specimen extraction for Siewert II oesophagogastric cancer.

The optimal surgical procedure for Siewert II oesophagogastric junction cancer is still debated. The minimally invasive Ivor Lewis technique can be considered the most adequate intervention from the oncological perspective but it is still contested owing to its technical difficulties. To allow an easier thoracoscopic stage during the procedure, we performed it with laparoscopic trans-hiatal oesophageal transection and transabdominal extraction. An 80-year-old man with stage 3 Siewert II oesophagogastric junction adenocarcinoma not suitable for neoadjuvant therapy underwent minimally invasive Ivor Lewis oesophagectomy with two-field lymphadenectomy, using a laparoscopic and thoracoscopic approach in prone position. The trans-hiatal oesophageal resection permitted easy extraction of a transabdominal specimen and frozen section examination. The prone position, together with the absence of the specimen in the operative field, allowed easier mediastinal node dissection and oesophagogastric anastomosis with better visualisation. The postoperative course was uneventful. Pathology showed a G3-pT3, N2 adenocarcinoma with 6/30 metastatic lymph nodes.

McKeown oesophagectomy and pulmonary wedge resection with a prone thoracoscopic and laparoscopic approach: a video report.

In the past few years, minimally invasive oesophagectomy has become an increasingly popular approach for oesophagectomy showing advantages in terms of fewer postoperative complications, shorter hospital stay and faster recovery. We present the case of a 60-year-old man with a lesion of the distal third of the oesophagus and solid pulmonary nodule who underwent McKeown subtotal oesophagectomy by laparoscopic and thoracoscopic approach in prone position with concomitant thoracoscopic pulmonary wedge resection. The postoperative course was smooth, and the patient was discharged on postoperative day 10. The procedure is feasible and safe, and combines better respiratory postoperative outcomes even when associated with other diagnostic or therapeutic lung procedures.

Cannabinoids Determination in Brain: A Supplemental Helpful in Postmortem Evaluation.

The scientific interest in cannabis has been documented by a wide literature, but postmortem studies and interpretations of autopsy findings are lacking or limited to few cases, few matrices analyzed or a small number of analytes. The present study describes the development and full in-house validation of a sensitive and simple method based on an optimized rapid clean-up procedure combined with a robust and highly sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS) technique, designed to simultaneous determination of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid (THC-COOH) and 11-nor-Δ9-tetrahydrocannabinol-carboxylic acid glucuronated (THC-COOH gluc.) in postmortem samples: central blood (CB), femoral blood (FB) and brain tissue (BR). The developed method was validated and applied to 24 postmortem cases involving cannabinoids. In this study, we presented a full optimization and validation of target analyses for each matrix. The procedure had proven to be reliable and accurate. This study adds new data, particularly about the cannabinoids concentrations in BR samples. Combined pattern (CB, FB, BR) can be used in the interpretation of postmortem cases, proving and strengthening the assessments made on blood data. BR matrix is a helpful supplement in the investigation of the role of cannabinoids as crucial or contributory factor in leading to death.

Immune infiltrating cells in duodenal cancers.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare yet aggressive malignancy, with increasing incidence in the last decades. Its low frequency has hampered a thorough understanding of the pathogenesis of the disease and of its biology, limiting the identification of tailored therapeutic options. A large body of evidence has clearly shown the clinical relevance of immune cells in solid tumors, correlating immune features with post-surgical prognosis. The aim of this study was to analyze the immune contexture in a cohort of duodenal adenocarcinomas surgically resected at our Institution and define its correlation with clinical variables. METHODS: Tissue slides from paraffin-embedded tumor specimens of 15 consecutive DA and 3 adenomas that underwent a pancreaticoduodenectomy in our center between 2010 to 2018 were immunohistochemically stained. The density (percentage of immune reactive area, IRA%) of immune markers CD45RO, CD8, CD20, IL-17, PD-1, CD68 was quantified by computer-assisted image analysis. Demographic, clinical, histopathological data were collected. RESULTS: In our population, median IRA % (IQR) of immune subsets was respectively CD45RO-TILs 2.19 (2.14), CD8-TIL 0.42 (0.81), CD20-TILs 0.22 (0.51), CD20-TLT 2.84 (4.64), CD68-TAM 2.19 (1.56), IL17+ cells 0.39 (0.39), PD1-TILs 0.19 (0.41). The median follow-up was 47.5 (22.4-63.3) months. At statistical analysis, the density of CD8-TILs inversely correlated with lymph node ratio (p = 0.013), number of metastatic lymph nodes (p = 0.019), and was lower in N+ adenocarcinomas compared to N0 (1.07 vs 0.29; p = 0.093), albeit not significantly. Stratifying patients for the N status, the density of CD8-TILs decreased with the increasing of the N stage (p = 0.065) and was lower in patients who experienced recurrence and died for the disease (0.276 vs 0.641; p = 0.044). Notably, also CD68-TAM distribution was different in patients who had recurrence versus patients who did not (1.028 vs 2.276; p = 0.036). CONCLUSIONS: Immune cells showed variable expression in correlation with common prognostic factors, suggesting T cell infiltration may play a protective role towards lymphatic spread of disease and nodal metastatization. Furthermore, T cell density and macrophage infiltration were associated to a lower risk of recurrence and disease related death. A multicentric approach may be indicated to allow analysis of larger cohorts of patients, potentially increasing the power of our observations.

Laparoscopic repair of a giant hiatal hernia after minimally invasive oesophagectomy.

Minimally invasive oesophagectomy has become popular, but studies showed a higher rate of postoperative hiatus hernia compared with open oesophagectomy. Our video presents the laparoscopic biosynthetic mesh repair of a symptomatic giant hiatus hernia in a 71-year-old man who had undergone minimally invasive oesophagectomy one year earlier for distal adenocarcinoma of the oesophagus. The operative time was 120 minutes. The patient started oral intake on postoperative day one and was discharged on postoperative day three. Postoperative computed tomography at six months showed no signs of recurrence. In the setting of a symptomatic hiatus hernia post-minimally invasive oesophagectomy, we suggest an initial laparoscopic approach, because of its countless advantages.

Transjejunal laparoscopic-assisted ERCP in Roux-en-Y patient: the new right path.

The incidence of biliary lithiasis after gastric surgery seems to be higher than in the general population. Endoscopic retrograde cholangiopancreatography (ERCP) allows several biliary and pancreatic pathologies to be dealt with; however, in patients with an altered anatomy of the upper and mid gastrointestinal tract, this endoscopic manoeuvre can be extremely challenging. We report a case of a 79-year-old woman with previous subtotal gastrectomy and Roux-en-Y reconstruction, admitted with a diagnosis of cholecystitis and choledocolithiasis. She was successfully treated with transjejunal laparoscopic-assisted ERCP and laparoscopic cholecystectomy, which appears to be a safe and useful procedure for choledocolithiasis treatment in patients with surgically altered anatomy.

Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria.

Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Cytomegalovirus infection in hematologic malignancy settings other than the allogeneic transplant.

Cytomegalovirus (CMV) infection in clinical settings other than the allogeneic transplant represents a poorly explored issue. Thus, we performed a comprehensive review of the medical literature about CMV infection in patients undergoing autologous hematopoietic stem cell transplant and in other nontransplant-related hematologic patients. In autologous hematopoietic stem cell transplant, a CMV reactivation is reported to occur in up to 41% of CMV seropositive patients, when a prospective monitoring of antigenemia and/or viremia by polymerase chain reaction was adopted. However, more contained frequencies, up to 12%, have been reported when the monitoring criteria were based on a clinically driven diagnostic strategy. The most relevant risk factors appear to be CD34 + selected autografts, total body irradiation, and prior treatment with Alemtuzumab, Fludarabine, or Bortezomib, respectively. Other possible risk factors (ie, prior treatment with Rituximab, T-cell lymphomas, and pretransplant HBcIgG seropositivity) are still debated. In nontransplant settings, the data are very heterogeneous; thus, CMV infection incidence and risk factors are more difficult to establish. Overall, the rate of CMV infection/reactivation ranges between 2 and 67%. High-dose steroids, advanced disease, poor performance status, and treatment with Alemtuzumab, Fludarabine, Bortezomib, and Rituximab appear as the most relevant, though putative, risk factors. Intravenous Ganciclovir represents the gold standard for first-line treatment of CMV infection in these patients. Oral Valganciclovir and Foscarnet are other possible options. Extensive prophylaxis and preemptive therapy are not generally recommended, with the exception of high-risk patients.

The impact of bariatric surgery on health outcomes, wellbeing and employment rates: analysis from a prospective cohort study.

PURPOSE: Morbid obesity is associated with several comorbidities that often impair patients' ability to obtain and keep a job and that, eventually, could hinder their fitness to work. This study aimed at determining whether the employment status of morbidly obese patients may be positively affected by bariatric surgery. METHODS: A total of 30 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from March 2014 to March 2015 were prospectively evaluated. All patients underwent a pre-operative assessment including the collection of personal and occupational data and the evaluation of musculoskeletal system. All evaluations were repeated at the end of a 24-month follow up. RESULTS: After RYGB, employment rates increased from 15/30 (50.0%) to 25/30 (83.3%, p = 0.012). Patients who were working at the end of follow-up referred lower rates of comorbidities, in particular of musculoskeletal complaints (4/25 vs. 4/5, p < 0.001), and presented significantly increased scores of energy/vitality at SF-36 assessment. CONCLUSIONS: Our study suggests that RYGB can increase employment rates, increasing tolerance to effort and reducing prevalence and severity of obesity-related symptoms and complaints.

The usefulness of sLORETA in evaluating the effect of high-dose ARA-C on brain connectivity in patients with acute myeloid leukemia: an exploratory study.

Cytosine arabinoside (Ara-C) is one of the key drugs for treating acute myeloid leukemia (AML). High intravenous doses may produce a number of central nervous system (CNS) toxicities and contribute to modifications in brain functional connectivity. sLORETA is a software used for localizing brain electrical activity and functional connectivity. The aim of this study was to apply sLORETA in the evaluation of possible effects of Ara-C on brain connectivity in patients with AML without CNS involvement. We studied eight patients with AML; four were administered standard doses of Ara-C while the other four received high doses. sLORETA was computed from computerized EEG data before treatment and after six months of treatment. Three regions of interest, corresponding to specific combinations of Brodmann areas, were defined. In the patients receiving high-dose Ara-C, a statistically significant reduction in functional connectivity was observed in the fronto-parietal network, which literature data suggest is involved in attentional processes. Our data highlight the possibility of using novel techniques to study potential CNS toxicity of cancer therapy.

Successful management of chronic disseminated candidiasis in hematologic patients treated with high-dose liposomal amphotericin B: a retrospective study of the SEIFEM registry.

PURPOSE: Chronic disseminated candidiasis (CDC) is a complication of Candida infection in immunocompromised patients, involving the liver and spleen, and rarely other organs. The aim of the study is to identify the best antifungal drug for hematologic immunocompromised patients with CDC. METHODS: In this multicentric retrospective study, the charts of 20 patients with CDC following cytotoxic agent protocols for hematological malignancies, diagnosed from 2003 to 2013, were analyzed. The response to systemic antifungal therapy within 90 days from CDC diagnosis and the possible delay in chemotherapy plan, due to the infection, were evaluated. RESULTS: Six patients were treated with high-dose (HD; 5 mg/kg/daily) liposomal amphotericin B (L-AmB), whereas three received standard-dose (SD) L-AmB (3 mg/kg/daily). Azoles were given to six patients; the remaining five were treated with echinocandins. All patients treated with HD L-AmB (6/6-100 %) achieved complete resolution of CDC; one of them had to interrupt the chemotherapy program for the infection. In the SD L-AmB group, treatment failed in the 100 % of cases and one patient had to delay chemotherapy for the infection. Of the six patients who received azoles, two achieved complete resolution of the infection, four experienced treatment failure, and only three performed chemotherapy as planned. Echinocandins treatment resulted in complete resolution of the infection in 2/5 cases, partial response in 2/5 cases, and failure in one case. In this group, 3/5 patients completed chemotherapy as planned. CONCLUSIONS: This study shows that HD L-AmB was particularly effective against CDC in hematologic patients, allowing most patients to continue cytotoxic agent program.