Inhibition of C5aR1 as a promising approach to treat taxane-induced neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several antitumor agents resulting in progressive and often irreversible damage of peripheral nerves. In addition to their known anticancer effects, taxanes, including paclitaxel, can also induce peripheral neuropathy by activating microglia and astrocytes, which release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1ß), and chemokine (C-C motif) ligand 2 (CCL-2). All these events contribute to the maintenance of neuropathic or inflammatory response. Complement component 5a (C5a)/C5a receptor 1 (C5aR1) signaling was very recently shown to play a crucial role in paclitaxel-induced peripheral neuropathy. Our recent findings highlighted that taxanes have the previously unreported property of binding and activating C5aR1, and that C5aR1 inhibition by DF3966A is effective in preventing paclitaxel-induced peripheral neuropathy (PIPN) in animal models. Here, we investigated if C5aR1 inhibition maintains efficacy in reducing PIPN in a therapeutic setting. Furthermore, we characterized the role of C5aR1 activation by paclitaxel and the CIPN-associated activation of nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. Our results clearly show that administration of the C5aR1 inhibitor strongly reduced cold and mechanical allodynia in mice when given both during the onset of PIPN and when neuropathy is well established. C5aR1 activation by paclitaxel was found to be a key event in the induction of inflammatory factors in spinal cord, such as TNF-α, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP). In addition, C5aR1 inhibition significantly mitigated paclitaxel-induced inflammation and inflammasome activation by reducing IL-1ß and NLRP3 expression at both sciatic and dorsal root ganglia level, confirming the involvement of inflammasome in PIPN. Moreover, paclitaxel-induced upregulation of C5aR1 was significantly reduced by DF3966A treatment in central nervous system. Lastly, the antinociceptive effect of C5aR1 inhibition was confirmed in an in vitro model of sensory neurons in which we focused on receptor channels usually activated upon neuropathy. In conclusion, C5aR1 inhibition is proposed as a therapeutic option with the potential to exert long-term protective effect on PIPN-associated neuropathic pain and inflammation.

Postoperative Dysnatremia in Pediatric Patients Undergoing Palatoplasty.

OBJECTIVE: Identifying predisposing factors to dysnatremia to improve perioperative care after cleft surgery. DESIGN: Retrospective case series. Patient data were obtained through the electronic medical records of the hospital. SETTING: Tertiary care university hospital. PATIENTS: The inclusion criterion was the measurement of an abnormal natremia value, defined as Na >150 or <130 mmol/l after a cleft lip or cleft palate repair procedure. The exclusion criterion was natremia between 131 and 149 mmol/l. RESULTS: Natremia measurements were available for 215 patients born between 1995 and 2018. Five patients presented with postoperative dysnatremia. Several predisposing factors to dysnatremia have been identified: drugs, infection, administration of intravenous fluids, and postoperative syndrome of inappropriate antidiuretic hormone secretion. Although the hospital environment contributes to dysnatremia development, the fact that only patients undergoing cleft palate repair develop natremia anomalies suggests that this surgery may be itself a risk factor. CONCLUSION: Children undergoing palatoplasty may be at higher risk to develop postoperative dysnatremia. Early recognition of symptoms and risk factors, postoperative monitoring, and prompt treatment of dysnatremia diminish the risk of neurological complications.

Discovery and characterization of heterogeneous and multipotent fibroblast populations isolated from excised cleft lip tissue.

BACKGROUND: Regularly discarded lip tissue obtained from corrective surgeries to close the cleft lip represents an easily accessible and rich source for the isolation of primary fibroblasts. Primary fibroblasts have been described to show compelling similarities to mesenchymal stem cells (MSCs). Hence, cleft lip and palate (CLP) lip-derived fibroblasts could be thought as an intriguing cell source for personalized regenerative therapies in CLP-affected patients. METHODS: Initially, we thoroughly characterized the fibroblastic nature of the lip-derived mesenchymal outgrowths by molecular and functional assays. Next, we compared their phenotype and genotype to that of bone marrow-mesenchymal stem cells (BM-MSCs) and of human lung-derived fibroblasts WI38, by assessing their morphology, surface marker expression, trilineage differentiation potential, colony-forming (CFU) capacity, and immunomodulation property. Finally, to better decipher the heterogeneity of our CLP cultures, we performed a single cell clonal analysis and tested expanded clones for surface marker expression, as well as osteogenic and CFU potential. RESULTS: We identified intriguingly similar phenotypic and genotypic properties between CLP lip fibroblasts and BM-MSCs, which makes them distinct from WI38. Furthermore, our own data in combination with the complex anatomy of the lip tissue indicated heterogeneity in our CLP cultures. Using a clonal analysis, we discovered single cell-derived clones with increased levels of the MSC markers CD106 and CD146 and clones with variabilities in their commitment to differentiate into bone-forming cells and in their potential to form single cell-derived colonies. However, we were not able to gain clones possessing superior MSC-like capacities when compared to the heterogeneous parental CLP population. Additionally, all clones could still generate contractile forces and retained robust levels of the fibroblast specific marker FSP1, which was not detectable in BM-MSCs. CONCLUSIONS: Our results suggest that we isolate heterogeneous populations of fibroblasts from discarded CLP lip tissue, which show a prominently multipotent character in their entirety avoiding the need for elaborate subpopulation selections in vitro. These findings suggest that CLP lip fibroblasts might be a novel potential cell source for personalized regenerative medicine of clinical benefit for CLP patients.

How the COVID-19 pandemic has affected the colorectal cancer screening in Italy: A minireview.

The coronavirus disease 2019 (COVID-19) pandemic has caused detrimental effects on many aspects of healthcare practice. Screening programs for the commonest malignancies, namely colorectal cancer (CRC), breast cancer and cervical cancer have been discontinued or interrupted since the beginning of restriction measures aimed to limit transmission of the new coronavirus infection. Robust evidence exists in favour of the role of screening campaigns in reducing mortality from CRC. In fact, the majority of pre-malignant lesions of the colon and rectum can be diagnosed with colonoscopy and treated by endoscopic or surgical resection. Besides, colonoscopy screening allows the diagnosis of CRCs in their pre-clinical stage. Italy was one of the first European countries where a high level of COVID-19 infections and deaths was observed, and one of the first where lockdowns and strict measures were adopted to reduce the risk of COVID-19 diffusion among the population. A systematic review of the literature was performed, including the PubMed, Scopus, Web of Sciences, and Reference Citation Analysis databases, with the aim of critically evaluating the impact of the COVID-19 pandemic on CRC screening in Italy. We found that reduction of CRC screening activity surpassed 50% in most endoscopic units, with almost 600000 fewer CRC screening exams conducted in the first 5 mo of 2020 vs the same period of 2019. While the consequences of the discontinuation of endoscopy screening for the prognosis and mortality of CRC will be evident in the next few years, recent data confirm that CRC is currently treated at a more advanced stage than in the pre-COVID-19 era. Since delays in CRC prevention and early diagnosis may translate to increased CRC-specific mortality, world healthcare systems should adopt strategies to maintain the regularity of CRC screening during subsequent peaks of the COVID-19 pandemic, or future events that might hamper screening programs.

Use of a Spinal-Caudal Epidural Technique for Abdominal Surgery in a Newborn With Noonan Syndrome and Severe Hypertrophic Cardiomyopathy.

Features of Noonan syndrome include a distinctive facial appearance, short stature, a broad or webbed neck, congenital heart disease, bleeding problems, skeletal malformations, and developmental delay. Although pulmonary stenosis is most commonly reported, up to 20% of patients have hypertrophic cardiomyopathy (HCM). We report the use of a combined spinal-caudal epidural anesthesia technique during urologic surgery (pyeloplasty) in an 8-week-old infant with Noonan syndrome and HCM. A spinal-caudal epidural technique provides favorable hemodynamic conditions, avoids the need for airway instrumentation, and may serve as an alternative to general anesthesia in these high risk patients.

Jejunal adenocarcinoma after biliopancreatic diversion. Report of a case.

The effects of bariatric surgery on the development of gastrointestinal cancers remain ill defined. We present a case of jejunal adenocarcinoma developing 19 years after biliopancreatic diversion (BPD) procedure according to Scopinaro's technique. The patient developed a marked distension of the biliopancreatic limb caused by a jejunal mass, evolving towards the so called "duodenal blowout". Emergency jejunal resection of the biliopancreatic limb, with creation of a new end-to-side jejunal-ileal anastomosis was necessary. The histological examination resulted in a moderately-differentiated ulcerated adenocarcinoma, with reactive lymph nodes and tumor-free resection margins. Tumors of the gastrointestinal system can arise following malabsorptive operations for morbid obesity, and they may be difficult to diagnose, since the symptoms are often attributed to the anatomical-functional changes resulting from this type of surgery. The case reported herein suggests that there is a need for surveillance in patients complaining of digestive symptoms after malabsorptive bariatric surgery.

Current management of incidental gallbladder cancer: A review.

Early-stage gallbladder cancer (GBC) is mostly discovered incidentally by the pathologist after cholecystectomy for a presumed benign disease. It is the most common malignancy of the biliary tract with a variable incidence rate all over the World. The majority of patients with GBC remain asymptomatic for a long time and diagnosis is usually late when the disease is at an advanced stage. Radical surgery consisting in resection of the gallbladder liver bed and regional lymph nodes seems to be the best treatment option for incidental GBC. However, recurrence rates after salvage surgery are still high and the addition of neoadjuvant/adjuvant chemotherapy may improve outcomes. The aim of the present review is to evaluate current literature for advances in management of incidental GBC, with particular focus on staging techniques and surgical options.

Adipose-Derived Stem Cell Features and MCF-7.

Human adipose tissue-derived stem cells (hADSCs) are highly suitable for regeneration therapies being easily collected and propagated in vitro. The effects of different external factors and culturing conditions are able to affect hADSC proliferation, senescence, differentiation, and migration, even at the molecular level. In the present paper, we exposed hADSCs to an exhausted medium from the breast cancer cell line (MCF-7) to evaluate whether the soluble factors released by these cells may be able to induce changes in stem cell behavior. In particular, we investigated the expression of stemness-related genes (OCT4; Sox 2; Nanog), the cell-cycle regulators p21 (WAF1/CIP1) p53, epigenetic markers (DNMT1 and Sirt1), and autophagy-related proteins. From our results, we can infer that the exhausted medium from MCF-7 is able to influence the hADSCs behavior increasing the expression of stemness-related genes, cell proliferation, and autophagy. Polyamines detectable in MCF-7 exhausted medium could be related to the higher proliferation capability observed in hADSCs, suggesting direct crosstalk between these molecules and the observed changes in stem cell potency.

Vascular resection for locally advanced pancreatic ductal adenocarcinoma: analysis of long-term outcomes from a single-centre series.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis. Radical surgery is the best option for cure and, nowadays, it is performed by many surgeons also in cases of vascular infiltration. Whether this aggressive approach to a locally advanced PDAC produces a survival benefit is under debate. Most data in the literature come from retrospective comparative studies; therefore, it is still unclear if such an extensive surgery for an advanced cancer is justified. METHODS: A retrospective review of patients with PDAC treated at our institution over a 12-year period was performed. Data concerning patients' characteristics, operative details, postoperative course, and long-term survival were retrieved from prospective databases and analysed. Factors associated with poor survival were assessed via Cox regression analysis. RESULTS: A total of 173 patients with PDAC were included in the analysis, 41 subjects underwent pancreatectomy with vascular resection for locally advanced disease, and in 132 patients, only a pancreatic resection was undertaken. Demographics, major comorbidities, and tumour characteristics were similar between the two groups. Length of surgery (P=0.0006), intraoperative blood transfusions (P<0.0001), and overall complications (P<0.0001) were significantly higher in the vascular resection group. Length of hospital stay (P=0.684) and 90-day mortality (P=0.575) were comparable between groups. Overall median survival (P= 0.717) and survival rates at 1, 3, and 5 years (P=0.964, P=0.500, and P=0.445, respectively) did not differ significantly between groups. Age ≥70 years and postoperative complications were independent predictors of lower survival. CONCLUSIONS: Our study confirms that pancreatectomy with vascular resection for a locally advanced PDAC is a complex operation associated with a significant longer operating time that may increase morbidity; however, in selected patients, R0 margins can be obtained with an acceptable long-term survival rate. Older patients are less likely to benefit from surgery.

Laparoscopic versus Open Transverse-Incision Approach for Right Hemicolectomy: A Systematic Review and Meta-Analysis.

Background and Objectives: There is general agreement on the benefits of laparoscopy for treatment of rectal and left colon cancers, whereas findings regarding the comparison of laparoscopic and open right colonic resections are discordant. The aim of this systematic review and meta-analysis was to assess the outcomes and advantages of laparoscopic versus transverse-incision open surgery for management of right colon cancer. Materials and Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Comparative studies evaluating the results of laparoscopic and transverse-incision open right hemicolectomies were analyzed. The measured outcomes were mean operative time, time to feeding, duration of hospital stay, and number of lymph nodes harvested. Results: A total of 5 studies including 318 patients met the inclusion criteria. Meta-analysis revealed no differences in time to resume oral feeding, hospital stay, and number of lymph nodes harvested in between groups, but mean length of surgery was significantly longer in the laparoscopic group. Conclusion: These data confirm that the preferred approach to right hemicolectomy is yet unclear. Laparoscopy has a longer operative time than transverse-incision open surgery, and no significant short-term benefits were observed for the studied parameters. Well-designed randomized control trials (RCTs) might help to identify the differences between these two techniques for the surgical treatment of right colon cancer.

Perianal mucinous adenocarcinoma with dysplastic polyps of the colon: A case report.

INTRODUCTION: Perianal mucinous adenocarcinoma is rarely encountered in the setting of anal neoplasms. The rarity of the disease and the paucity of publications on this topic are responsible for a lack of diagnostic and therapeutic guidelines. PRESENTATION OF CASE: An 80-year-old man with mucinous adenocarcinoma of the anal canal associated with dysplastic polyps of the colon was treated by multiple endoscopic polypectomies and abdomino-perineal resection of the rectum. We discuss the management of this rare case from the diagnosis up to one-year follow-up. DISCUSSION: Perianal mucinous adenocarcinoma is a very rare entity frequently combined with chronic fistulas. Inflammatory symptoms may mislead its diagnosis, which is often delayed. The unique association between perianal mucinous adenocarcinoma and dysplastic polyps of the colon, that we have reported, may suggest a secondary etiology. High clinical suspicion is important for early and correct diagnosis, which should be based on endoanal ultrasound and/or magnetic resonance imaging followed by deep tissue biopsies. CONCLUSION: We stress the importance of accumulating such cases in the literature. The understanding of the etiopathogenic mechanisms may lead to the development of novel diagnostic and therapeutic protocols.

In situ reconstruction with autologous graft in the treatment of secondary aortoenteric fistulas: A retrospective case series.

Infections caused by secondary aortoenteric fistulas (SAEF) may be extremely complex and threaten patient's life. We report our surgical approach to SAEF consisting in removal of the infected graft and in situ reconstruction using an autologous venous graft. Seven consecutive patients with SAEF treated with graft removal and in situ reconstruction using an autologous venous graft from 2008 to 2017 were reviewed. Six of seven patients (86%) survived 30-day. In one case a graft thrombosis and acute lower limb ischemia occurred requiring re-operations. All patients received injective antibiotic therapy for 20 days, followed by oral therapy for 3 months. There were no major complications at long-term follow-up. Our results suggest that superficial femoral vein reconstruction of the abdominal aorta for SAEF is effective with an acceptable in-hospital mortality and low rate of major complications. We stress the importance of the deep femoral veins to create the graft because the large saphenous vein is often affected by significant intimal hyperplasia that can cause steno-occlusive complications.

Laparoscopic versus open transverse-incision right hemicolectomy: a retrospective comparison study.

BACKGROUND: The optimal surgical approach to right colon cancer is still under debate. The aim of the present study was to compare the short- and long-term outcomes of laparoscopic and transverse-incision open approaches to right hemicolectomy for colon cancer. METHODS: Data on 99 adult patients with right-side colon cancer undergoing either laparoscopic or open transverse-incision right hemicolectomy at two different university hospitals, between January 2013 and December 2016, were retrospectively reviewed. Data concerning patients' characteristics, operative details and post-operative recovery were retrieved from prospective databases and analysed. RESULTS: Forty-nine subjects were operated on laparoscopically, while 50 through an open transverse incision. Operating time was significantly longer in the laparoscopic group compared with the open group (182 versus 105 min; P < 0.01). Patients treated laparoscopically had a shorter time to first bowel movement, while time to resume a normal diet and post-operative length of hospital stay were comparable in between groups. The median number of lymph nodes harvested was higher in the laparoscopic group (25.6 versus 18.6; P < 0.01), but no significant difference in overall survival between groups was detected. At long-term follow-up, the incidence of incisional hernia was higher in the laparoscopic group as compared to the open group (24.5% versus 0%; P = 0.0002). CONCLUSION: Our results show that laparoscopic right hemicolectomy when compared to the transverse-incision open procedure may guarantee the same oncological radicality, but short-term functional benefits are still unclear. Randomized control studies are warranted to better clarify the comparison of these two approaches for right-sided colon cancers.

Multiple arteriovenous malformations caused by RASA1 gene mutation presenting during pregnancy - a case report and review of the literature.

Pregnancy can influence the development and progression of congenital arteriovenous malformations (AVM) and thus lead to life-threatening complications for the mother and fetus like high output cardiac failure and premature delivery. The simultaneous presence of a capillary malformation and AVM strongly suggests a RASA1 related disorder. Keywords: Arteriovenous malformations, capillary malformation-arteriovenous malformation, capillaries/abnormalities, port-wine stain, pregnancy, RASA1 protein.

Inflammatory cell indexes as preoperative predictors of hospital stay in open elective thoracic surgery.

BACKGROUND: Shorter and safer hospital stay (HS) is a desired outcome for patients undergoing thoracic surgery. The aim of the present study was to evaluate the predictive capacity of a series of pre-defined inflammatory cell indexes based on preoperative complete blood counts, towards length of HS in open elective thoracic surgery. METHODS: We retrospectively studied 157 consecutive patients undergoing open elective thoracic surgery. Preoperative neutrophil to lymphocyte, platelet to lymphocyte and lymphocyte to monocyte ratios were calculated, and the red cell distribution width and mean platelet volume were registered. In addition, the systemic inflammation response index (SIRI) and a further derivative index, the aggregate inflammation systemic index (AISI) were calculated. RESULTS: Statistically significant and positive correlations were observed between HS and SIRI, and between HS and AISI. In multiple logistic regression analysis, after dividing the patients in groups with normal and prolonged HS and adjusting for several confounders, only AISI was independently associated with HS. CONCLUSIONS: Our results suggest that simple, inexpensive and widely available inflammatory cell indexes like SIRI and, particularly AISI, can be useful for the early identification of patients at risk of prolonged HS in open elective thoracic surgery.

miR-194-5p/BCLAF1 deregulation in AML tumorigenesis.

This corrects the article DOI: 10.1038/leu.2017.64.

Cost and morbidity analysis of chest port insertion in adults: Outpatient clinic versus operating room placement.

BACKGROUND: Totally implantable venous access devices (TIVADs) represent a convenient way for the administration of medications or nutrients. Traditionally, chest ports have been positioned by surgeons in the operating room, however there has been a transition over the years to port insertion by interventional radiologists in the radiology suite. The optimal method for chest port placement is still under debate. MATERIALS AND METHODS: Data on all adult patients undergoing isolated chest port placement at our institution in a 12-year period were retrospectively reviewed. The aim of this cohort study was to compare cost and morbidity for chest port insertion in two different settings: outpatient clinic and operating room. RESULTS: Between 2003 and 2015 a total of 527 chest ports were placed in adult patients. Of them, 262 procedures were performed in the operating room and 265 procedures were undertaken in the outpatient clinic. Patient characteristics were similar and there was no significant difference in early (<30 days, p = 0.54) and late complications (30-120 days, p = 0.53). The average charge for placement of a chest port was 1270 Euros in the operating room versus 620 Euros in the outpatient clinic. CONCLUSION: Our results suggest that chest ports can be safely placed in most patients under local anesthesia in the office setting without fluoroscopy or ultrasound guidance. Future randomized controlled studies may evaluate if surgeons or interventional radiologists should routinely perform these procedures in a dedicated office setting and reserve more sophisticated facilities only for patients at high risk of technical failure.