Nanovectors Design for Theranostic Applications in Colorectal Cancer

Colorectal cancer (CRC) is a diffused disease with limited therapeutic options, none of which are often curative. Based on the molecular markers and targets expressed by the affected tissues, numerous novel approaches have been developed to study and treat this disease. In particular, the field of nanotechnology offers an astonishingly wide array of innovative nanovectors with high versatility and adaptability for both diagnosis and therapy (the so called \u201ctheranostic platforms\u201d). However, such complexity can make the selection of a specific nanocarrier model to study a perplexing endeavour for the biomedical scientist or clinician not familiar with this field of inquiry. This review offers a comprehensive overview of this wide body of knowledge, in order to outline the essential requirements for the clinical viability evaluation of a nanovector model in CRC. In particular, the differences among the foremost designs, their specific advantages, and technological caveats will be treated, never forgetting the ultimate endpoint for these systems development: the clinical practice

Failure to rescue as a source of variation in hospital mortality after rectal surgery: The Italian experience

INTRODUCTION: Failure to rescue (FTR) patients from postoperative complications could contribute to the variability in surgical mortality seen among hospitals with different volumes. We sought to examine the impact of complications and FTR on mortality following rectal surgery. METHODS: The National Italian Hospital Discharge Dataset allowed to identify 75,280 patients who underwent rectal surgery between 2002 and 2014. Hospital volume was stratified into tertiles. Rates of major complications, FTR from complications and mortality following rectal surgery were compared. RESULTS: During the study period, both the incidence of complications (2002, 23.7% versus 2014, 21.2%), and FTR decreased overtime (2002, 6.9% versus 2014, 3.8%) (both P\u202f<\u202f0.001). The complication rate was 24.4% in low-, 21.6% in intermediate- and 20.4% in high-volume hospitals (P\u202f<\u202f0.001). Complications were less common in minimally invasive surgery (MIS) versus open cases (18.2% versus 23.2%; P\u202f<\u202f0.001). The most frequent complications included prolonged ileus or small bowel obstruction (5.3%), and anemia requiring blood transfusions (5.3%). The rate of FTR was 5.5%, 5.6% and 3.7% for low-, intermediate- and high-volume hospitals, respectively (P\u202f<\u202f0.001). FTR after MIS was 2.6% vs. 5.5% after open surgery (P\u202f<\u202f0.001). After accounting for patient and hospital characteristics, patients treated at low-volume hospitals were 23% more likely to die after a complication, compared to patients at high-volume hospitals (OR 1.23, 95%CI 1.13-1.33). CONCLUSIONS: Hospital volume is the strongest predictor of complication and FTR. The reduction in mortality in high-volume hospitals could be determined by the better ability to rescue patients. These findings support the centralization policy of rectal cancer treatment

Relationship between hospital volume and short-term outcomes: A nationwide population-based study including 75,280 rectal cancer surgical procedures

There is growing interest on the potential relationship between hospital volume (HV) and outcomes as it might justify the centralization of care for rectal cancer surgery. From the National Italian Hospital Discharge Dataset, data on 75,280 rectal cancer patients who underwent elective major surgery between 2002 and 2014 were retrieved and analyzed. HV was grouped into tertiles: low-volume performed 1-12, while high-volume hospitals performed 33+ procedures/year. The impact of HV on in-hospital mortality, abdominoperineal resection (APR), 30-day readmission, and length of stay (LOS) was assessed. Risk factors were calculated using multivariate logistic regression. The proportion of procedures performed in low-volume hospitals decreased by 6.7 percent (p<0.001). The rate of in-hospital mortality, APR and 30-day readmission was 1.3%, 16.3%, and 7.2%, respectively, and the median LOS was 13 days. The adjusted risk of in-hospital mortality (OR = 1.49, 95% CI = 1.25-1.78), APR (OR 1.10, 95%CI 1.02-1.19), 30-day readmission (OR 1.49, 95%CI 1.38-1.61), and prolonged LOS (OR 2.29, 95%CI 2.05-2.55) were greater for low-volume hospitals than for high-volume hospitals. This study shows an independent impact of HV procedures on all short-term outcome measures, justifying a policy of centralization for rectal cancer surgery, a process which is underwa

Intrinsic and Extrinsic Modulators of the Epithelial to Mesenchymal Transition: Driving the Fate of Tumor Microenvironment

The epithelial to mesenchymal transition (EMT) is an evolutionarily conserved process. In cancer, EMT can activate biochemical changes in tumor cells that enable the destruction of the cellular polarity, leading to the acquisition of invasive capabilities. EMT regulation can be triggered by intrinsic and extrinsic signaling, allowing the tumor to adapt to the microenvironment demand in the different stages of tumor progression. In concomitance, tumor cells undergoing EMT actively interact with the surrounding tumor microenvironment (TME) constituted by cell components and extracellular matrix as well as cell secretome elements. As a result, the TME is in turn modulated by the EMT process toward an aggressive behavior. The current review presents the intrinsic and extrinsic modulators of EMT and their relationship with the TME, focusing on the non-cell-derived components, such as secreted metabolites, extracellular matrix, as well as extracellular vesicles. Moreover, we explore how these modulators can be suitable targets for anticancer therapy and personalized medicine

Antiviral Property of the Fungal Metabolite 3-O-Methylfunicone in Bovine Herpesvirus 1 Infection

Bovine herpesvirus type-1 (BoHV-1) is a widespread pathogen that provokes infectious rhinotracheitis and polymicrobial infections in cattle, resulting in serious economic losses to the farm animal industry and trade restrictions. To date, non-toxic active drugs against BoHV-1 are not available. The exploitation of bioactive properties of microbial products is of great pharmaceutical interest. In fact, fungi are a promising source of novel drugs with a broad spectrum of activities and functions, including antiviral properties. Hence, the potential antiviral properties of 3-O-methylfunicone (OMF), a secondary metabolite produced by Talaromyces pinophilus, were evaluated on BoHV-1. In this study, during BoHV-1 infection in bovine cells (MDBK), the non-toxic concentration of 5 µM OMF considerably reduced signs of cell death and increased cell proliferation. Furthermore, OMF significantly decreased the virus titer as well as the cytopathic effect and strongly inhibited the expression of bICP0, the major regulatory protein in the BoHV-1 lytic cycle. These findings were accompanied by a considerable up-regulation in the expression of the aryl hydrocarbon receptor (AhR), a multifunctional transcription factor also linked to the host’s response to a herpesvirus infection. Overall, our results suggest that by involving AhR, OMF shows potential against a BoHV-1 infection

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

The impact of anastomotic leak on long-term oncological outcomes after low anterior resection for mid-low rectal cancer: extended follow-up of a randomised controlled trial

The impact of anastomotic leaks (AL) on oncological outcomes after low anterior resection for mid-low rectal cancer is still debated. The aim of this study was to evaluate overall survival (OS), disease-free survival (DFS), and local and distant recurrence in patients with AL following low anterior resection

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN)

Background Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. Methods This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo &gt; 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed &gt;= 12, and proximal and distal free resection margins length &gt;= 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. Results A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to infinity). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to infinity). Conclusions Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection

Segmental transverse colectomy. Minimally invasive versus open approach: results from a multicenter collaborative study

none65noThe role of minimally invasive surgery in the treatment of transverse colon cancer is still controversial. The aim of this study is to investigate the advantages of a totally laparoscopic technique comparing open versus laparoscopic/robotic approach. Three hundred and eighty-eight patients with transverse colon cancer, treated with a segmental colon resection, were retrospectively analyzed. Demographic data, tumor stage, operative time, intraoperative complications, number of harvested lymph nodes and recovery outcomes were recorded. Recurrences and death were also evaluated during the follow-up. No differences were found between conventional and minimally invasive surgery, both for oncological long-term outcomes (recurrence rate p = 0.28; mortality p = 0.62) and postoperative complications (overall rate p = 0.43; anemia p = 0.78; nausea p = 0.68; infections p = 0.91; bleeding p = 0.62; anastomotic leak p = 0.55; ileus p = 0.75). Nevertheless, recovery outcomes showed statistically significant differences in favor of minimally invasive surgery in terms of time to first flatus (p = 0.001), tolerance to solid diet (p = 0.017), time to first mobilization (p = 0.001) and hospital stay (p = 0.004). Compared with laparoscopic approach, robotic surgery showed significantly better results for time to first flatus (p = 0.001), to first mobilization (p = 0.005) and tolerance to solid diet (p = 0.001). Finally, anastomosis evaluation confirmed the superiority of intracorporeal approach which showed significantly better results for time to first flatus (p = 0.001), to first mobilization (p = 0.003) and tolerance to solid diet (p = 0.001); moreover, we recorded a statistical difference in favor of intracorporeal approach for infection rate (p = 0.04), bleeding (p = 0.001) and anastomotic leak (p = 0.03). Minimally invasive approach is safe and effective as the conventional open surgery, with comparable oncological results but not negligible advantages in terms of recovery outcomes. Moreover, we demonstrated that robotic approach may be considered a valid option and an intracorporeal anastomosis should always be preferred.noneMilone, Marco; Degiuli, Maurizio; Velotti, Nunzio; Manigrasso, Michele; Vertaldi, Sara; D'Ugo, Domenico; De Palma, Giovanni Domenico; Dario Bruzzese, Giuseppe Servillo, Giuseppe De Simone, Katia Di Lauro, Silvia Sofia, Marco Ettore Allaix, Mario Morino, Rossella Reddavid, Carlo Alberto Ammirati, Stefano Scabini, Gabriele Anania, Cristina Bombardini, Andrea Barberis, Roberta Longhin, Andrea Belli, Francesco Bianco, Giampaolo Formisano, Giuseppe Giuliani, Paolo Pietro Bianchi, Davide Cavaliere, Leonardo Solaini, Claudio Coco, Gianluca Rizzo, Andrea Coratti, Raffaele De Luca, Michele Simone, Alberto Di Leo, Giovanni De Manzoni, Paola De Nardi, Ugo Elmore, Riccardo Rosati, Andrea Vignali, Paolo Delrio, Ugo Pace, Daniela Rega, Antonio Di Cataldo, Giovanni Li Destri, Annibale Donini, Luigina Graziosi, Andrea Fontana, Michela Mineccia, Sergio Gentilli, Manuela Monni, Mario Guerrieri, Monica Ortenzi, Francesca Pecchini, Micaela Piccoli, Italy. Corrado Pedrazzani, Giulia Turri, Sara Pollesel, Franco Roviello, Marco Rigamonti, Michele Zuolo, Mauro Santarelli, Federica Saraceno, Pierpaolo Sileri Giuseppe Sigismondo Sica, Luigi Siragusa Salvatore Pucciarelli, Matteo ZuinMilone, Marco; Degiuli, Maurizio; Velotti, Nunzio; Manigrasso, Michele; Vertaldi, Sara; D'Ugo, Domenico; De Palma, Giovanni Domenico; Dario Bruzzese, Giuseppe Servillo, Giuseppe De Simone, Katia Di Lauro, Silvia Sofia, Marco Ettore Allaix, Mario Morino, Rossella Reddavid, Carlo Alberto Ammirati, Stefano Scabini, Gabriele Anania, Cristina Bombardini, Andrea Barberis, Roberta Longhin, Andrea Belli, Francesco Bianco, Giampaolo Formisano, Giuseppe Giuliani, Paolo Pietro Bianchi, Davide Cavaliere, Leonardo Solaini, Claudio Coco, Gianluca Rizzo, Andrea Coratti, Raffaele De Luca, Michele Simone, Alberto Di Leo, Giovanni De Manzoni, Paola De Nardi, Ugo Elmore, Riccardo Rosati, Andrea Vignali, Paolo Delrio, Ugo Pace, Daniela Rega, Antonio Di Cataldo, Giovanni Li Destri, Annibale Donini, Luigina Graziosi, Andrea Fontana, Michela Mineccia, Sergio Gentilli, Manuela Monni, Mario Guerrieri, Monica Ortenzi, Francesca Pecchini, Micaela Piccoli, Italy. Corrado Pedrazzani, Giulia Turri, Sara Pollesel, Franco Roviello, Marco Rigamonti, Michele Zuolo, Mauro Santarelli, Federica Saraceno, Pierpaolo Sileri Giuseppe Sigismondo Sica, Luigi Siragusa Salvatore Pucciarelli, Matteo Zui