Initial failures of anti-tau antibodies in Alzheimer’s disease are reminiscent of the amyloid-βstory

Tau is an important protein of the central nervous system formed by 352-441 amino acids and encoded by the MAPT(microtubule-associated protein tau)gene on chromosome 17 which generates 6 isoforms.Tau is located in axons,dendrites,nucleus,cell membrane,and synapses of neurons.The protein is also expressed to a lesser extent in astrocytes and oligodendrocytes,although its role in these cells has been little investigated.The protein is also present in the interstitial fluid and can cross into the cerebrospinal fluid(CSF)and reach the systemic circulation.

Robot-assisted adrenalectomy:Step-by-step technique and surgical outcomes at a high-volume robotic center

Objective In the last years,robotic surgery was introduced in several different settings with good perioperative results.However,its role in the management of adrenal masses is still debated.In order to provide a contribution to this field,we described our step-by-step technique for robotic adrenalectomy(RA)and related modifications according to the type of adrenal mass treated.Methods We retrospectively analyzed 27 consecutive patients who underwent RA at Onze-Lieve-Vrouw hospital(Aalst,Belgium)between January 2009 and October 2022.Demographic,intra-and post-operative,and pathological data were retrieved from our prospectively maintained institutional database.Continuous variables are summarized as median and interquartile range(IQR).Categorical variables are reported as frequencies(percentages).Results Twenty-seven patients underwent RA were included in the study.Median age,body mass index,and Charlson's comorbidity index were 61(IQR:49-71)years,26(IQR:24-29)kg/m^(2),and 2(IQR:0-3),respectively,and 16(59.3%)patients were male.Median tumor size at computed tomography scan was 6.0(IQR:3.5-8.0)cm.Median operative time and blood loss were 105(IQR:82-120)min and 175(IQR:94-250)mL,respectively.No intraoperative complications were recorded.Overall postoperative complications rate was 11.1%,with a postoperative transfusion rate of 3.7%.A total of 10(37.0%)patients harbored malignant adrenal masses.Among them,3(11.1%)had adrenocortical carcinoma,6(22.2%)secondary metastasis,and 1(3.7%)malignant pheochromocytoma on final pathological exam.Only 1(10.0%)patient had positive surgical margins.Conclusion We described our step-by-step technique for RA,which can be safely performed even in case of high challenging settings as malignant tumors,pheochromocytoma,and large masses.The standardization of perioperative protocol should be encouraged to maximize the outcomes of this complex surgical procedure.

Gastric cancer in 2022:Is there still a role for endoscopic ultrasound?

Gastric cancer(GC)represents the fourth leading cause of cancer death worldwide and many factors can influence its development(diet,geographic area,genetic,Helicobacter pylori or Epstein-Barr virus infections).High quality endoscopy represents the modality of choice for GC diagnosis.The correct morphologic classification during a high-resolution endoscopy is fundamental for oncologic diagnosis,staging and therapeutic decisions.Since its initial introduction in clinical practice the endoscopic ultrasound(EUS)has been considered a valuable tool for tumor(T-)and lymph nodes(N-)staging also in GC,in order to establish the best therapeutic strategy for the patient(e.g.,upfront surgery vs neoadjuvant treatments).EUS tools as elastography,Doppler and contrast administration can improve diagnosis mainly in case of malignant lymph node evaluation.EUS has a marginal role in disease staging but has a fundamental role in case of a pre-endoscopic resection management and in the new era of endoscopic mucosal resection or submucosal dissection as minimally invasive surgery.Diagnosis and locoregional staging of GC with EUS are a method of inarguable value for the assessment of gastric wall involvement and presence of infiltrated paragastric lymph nodes.EUS can also have a role in disease restaging in those patients who have undergone neoadjuvant treatment.EUS can also have a role in the advanced phases of the disease,in facilitating palliative,minimallyinvasive treatments,such as gastroenterostomy or biliary drainages.This review intends to discuss the modern role of EUS in GC topic.

Peri-operative score for elderly patients with resectable hepatocellular carcinoma

BACKGROUND Liver resection is the mainstay for a curative treatment for patients with resectable hepatocellular carcinoma(HCC),also in elderly population.Despite this,the evaluation of patient condition,liver function and extent of disease remains a demanding process with the aim to reduce postoperative morbidity and mortality.AIM To identify new perioperative risk factors that could be associated with higher 90-and 180-d mortality in elderly patients eligible for liver resection for HCC considering traditional perioperative risk scores and to develop a risk score.METHODS A multicentric,retrospective study was performed by reviewing the medical records of patients aged 70 years or older who electively underwent liver resection for HCC;several independent variables correlated with death from all causes at 90 and 180 d were studied.The coefficients of Cox regression proportional-hazards model for sixmonth mortality were rounded to the nearest integer to assign risk factors'weights and derive the scoring algorithm.RESULTS Multivariate analysis found variables(American Society of Anesthesiology score,high rate of comorbidities,Mayo end stage liver disease score and size of biggest lesion)that had independent correlations with increased 90-and 180-d mortality.A clinical risk score was developed with survival profiles.CONCLUSION This score can aid in stratifying this population in order to assess who can benefit from surgical treatment in terms of postoperative mortality.

How reliable is current imaging in restaging rectal cancer after neoadjuvant therapy?

In patients with advanced rectal cancer,neoadjuvant chemo radiotherapy provides tumor downstaging and downsizing and complete pathological response in up to 30%of cases.After proctectomy complete pathological response is associated with low rates of local recurrence and excellent long term survival.Several authors claim a less invasive surgery or a non operative policy in patients with partial or clinical complete response respectively,however to identify patients with true complete pathological response before surgical resection remains a challenge.Current imaging techniques have been reported to be highly accurate in the primary staging of rectal cancer,however neoadjuvant therapy course produces deep modifications on cancer tissue and on surrounding structures such as overgrowth fibrosis,deep stroma alteration,wall thickness,muscle disarrangement,tumor necrosis,calcification,and inflammatory infiltration.As a result,the same imaging techniques,when used for restaging,are far less accurate.Local tumor extent may be overestimated or underestimated.The diagnostic accuracy of clinical examination,rectal ultrasound,computed tomography,magnetic resonance imaging,and positron emission tomography using 18F-fluoro-2’-deoxy-Dglucose ranges between 25%and 75%being less than 60%in most studies,both for rectal wall invasion and for lymph nodes involvement.In particular the ability to predict complete pathological response,in order to tailor the surgical approach,remains low.Due to the radio-induced tissue modifications,combined with imaging technical aspects,low rate accuracy is achieved,making modern imaging techniques still unreliable in restaging rectal cancer after chemo-radiotherapy.

Apparent diffusion coefficient by diffusion-weighted magnetic resonance imaging as a sole biomarker for staging and prognosis of gastric cancer

Objective： To investigate the role of apparent diffusion coefficient （ADC） from diffusion-weighted magnetic resonance imaging （DW-MRI） when applied to the 7th TNM classification in the staging and prognosis of gastric cancer （GC）. Methods： Between October 2009 and May 2014, a total of 89 patients with non-metastatic, biopsy proven GC underwent 1.5T DW-MRI, and then treated with radical surgery. Tumor ADC was measured retrospectively and compared with final histology following the 7th TNM staging （local invasion, nodal involvement and according to the different groups -- stage Ⅰ, Ⅱ and Ⅲ）. Kaplan-Meier curves were also generated. The follow-up period is updated to May 2016. Results： Median follow-up period was 33 months and 45/89 （51%） deaths from GC were observed. ADC was significantly different both for local invasion and nodal involvement （P〈0.001）. Considering final histology as the reference standard, a preoperative ADC cut-offof 1.80×10-3 mm^2/s could distinguish between stages I and Ⅱ and an ADC value of ≤1.36-10-3 mm^2/s was associated with stage Ⅲ（P〈0.001）. Kaplan-Meier curves demonstrated that the survival rates for the three prognostic groups were significantly different according to final histology and ADC cut-offs （P〈0.001）. Conclusions： ADC is different according to local invasion, nodal involvement and the 7th TNM stage groups for GC, representing a potential, additional prognostic biomarker. The addition of DW-MRI could aid in the staging and risk stratification of GC.

Endoscopic ultrasound and magnetic resonance imaging for re-staging rectal cancer after radiotherapy

AIM:To compare the sensitivity and specificity of two imaging techniques,endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI),in patients with rectal cancer after neoadjuvant chemoradiation therapy. And we compared EUS and MRI data with histological fi ndings from surgical specimens. METHODS:Thirty-nine consecutive patients (51.3% Male; mean age:68.2 ± 8.9 years) with histologically confirmed distal rectal cancer were examined for staging. All patients underwent EUS and MRI imaging before and after neoadjuvant chemoradiation therapy. RESULTS:After neoadjuvant chemoradiation,EUS and MRI correctly classified 46% (18/39) and 44% (17/39) of patients,respectively,in line with their histological T stage (P > 0.05). These proportions were higher for both techniques when nodal involvement was considered:69% (27/39) and 62% (24/39). When patients were sorted into T and N subgroups,the diagnostic accuracy of EUS was better than MRI for patients withT0-T2 (44% vs 33%,P > 0.05) and N0 disease (87% vs 52%,P = 0.013). However,MRI was more accurate than EUS in T and N staging for patients with more advanced disease after radiotherapy,though these differences did not reach statistical significance. CONCLUSION:EUS and MRI are accurate imaging techniques for staging rectal cancer. However,after neoadjuvant RT-CT,the role of both methods in the assessment of residual rectal tumors remains uncertain.

Human bocavirus: Current knowledge and future challenges

Human bocavirus(HBoV) is a parvovirus isolated about a decade ago and found worldwide in both respiratory samples, mainly from early life and children of 6-24 mo of age with acute respiratory infection, and in stool samples, from patients with gastroenteritis. Since then, other viruses related to the first HBoV isolate(HBoV 1), namely HBoV 2, HBoV 3 and HBoV 4, have been detected principally in human faeces. HBo Vs are small nonenveloped single-stranded DNA viruses of about 5300 nucleotides, consisting of three open reading frames encoding the first two the non-structural protein 1(NS1) and nuclear phosphoprotein(NP1) and the third the viral capsid proteins 1 and 2(VP1 and VP2). HBoV pathogenicity remains to be fully clarified mainly due to the lack of animal models for the difficulties in replicating the virus in in vitro cell cultures, and the fact that HBo V infection is frequently accompanied by at least another viral and/or bacterial respiratory and/or gastroenteric pathogen infection. Current diagnostic methods to support HBoV detection include polymerase chain reaction, real-time PCR, enzymelinked immunosorbent assay and enzyme immunoassay using recombinant VP2 or virus-like particle capsid proteins, although sequence-independent amplification techniques combined with next-generation sequencing platforms promise rapid and simultaneous detection of the pathogens in the future. This review presents the current knowledge on HBoV genotypes with emphasis on taxonomy, phylogenetic relationship and genomic analysis, biology, epidemiology, pathogenesis and diagnostic methods. The emerging discussion on HBoV s as true pathogen or innocent bystander is also emphasized.

Oropharyngeal acid reflux and motility abnormalities of the proximal esophagus

AIM To investigate the relationship between pathological oropharyngeal(OP) acid exposure and esophageal motility in patients with extra-esophageal syndromes.METHODS In this prospective study we enrolled consecutive outpatients with extra-esophageal symptoms suspected to be related to gastroesophageal reflux disease(GERD). We enrolled only patients with a reflux symptom index(RSI) score-higher than 13 and with previous lung, allergy and ear, nose and throat evaluations excluding other specific diagnoses. All patients underwent 24-h OP pH-metry with the Dx probe and esophageal highresolution manometry(HRM). Patients were divided into two groups on the basis of a normal or pathological p H-metric finding(Ryan Score) and all manometric characteristics of the two groups were compared.RESULTS We examined 135 patients with chronic extra-esophageal syndromes. Fifty-one were considered eligible for the study. Of these, 42 decided to participate in the protocol. Patients were divided into two groups on the basis of normal or pathological OP acid exposure. All the HRM parameters were compared for the two groups. Significant differences were found in the median upper esophageal sphincter resting pressure(median 71 mmH g vs 126 mmH g, P = 0.004) and the median proximal contractile integral(median 215.5 cm·mmH g·s vs 313.5 cm·mmH g·s, P = 0.039), both being lower in the group with pathological OP acid exposure, and the number of contractions with small or large breaks, which were more frequent in the same group. This group also had a larger number of peristaltic contractions with breaks in the 20 mm Hg isobaric contour(38.7% vs 15.38%, P < 0.0001).CONCLUSION In patients with suspected GERD-related extraesophageal syndromes pathological OP acid exposure was associated with weaker proximal esophageal motility.

Transoral incisionless fundoplication for gastro-esophageal reflux disease: Techniques and outcomes

Gastro-esophageal reflux disease(GERD)is a verycommon disorder that results primarily from the loss of an effective antireflux barrier,which forms a mechanical obstacle to the retrograde movement of gastric content.GERD can be currently treated by medical therapy,surgical or endoscopic transoral intervention.Medical therapy is the most common approach,though concerns have been increasingly raised in recent years about the potential side effects of continuous longterm medication,drug intolerance or unresponsiveness,and the need for high dosages for long periods to treat symptoms or prevent recurrences.Surgery too may in some cases have consequences such as longlasting dysphagia,flatulence,inability to belch or vomit,diarrhea,or functional dyspepsia related to delayed gastric emptying.In the last few years,transoral incisionless fundoplication(TIF)has proved an effective and promising therapeutic option as an alternative to medical and surgical therapy.This review describes the steps of the TIF technique,using the Esophy X&#174;device and the MUSETM system.Complications and their management are described in detail,and the recent literature regarding the outcomes is reviewed.TIF reconfigures the tissue to obtain a full-thickness gastroesophageal valve from inside the stomach,by serosato-serosa plications which include the muscle layers.To date the procedure has achieved lasting improvement of GERD symptoms(up to six years),cessation or reduction of proton pump inhibitor medication in about 75%of patients,and improvement of functional findings,measured by either p H or impedance monitoring.

Multidisciplinary treatment of rectal cancer in 2014: Where are we going?

In the present review we discuss the recent developments and future directions in the multimodal treatment of locally advanced rectal cancer, with respect to staging and re-staging modalities, to the current role of neoadjuvant chemo-radiation and to the conservative and more limited surgical approaches based on tumour response after neoadjuvant combined therapy. When initial tumor staging is considered a high accuracy has been reported for T pre-treatment staging, while preoperative lymph node mapping is still suboptimal. With respect to tumour re-staging, all the current available modalities still present a limited accuracy, in particular in defining a complete response. The role of short vs long-course radiotherapy regimens as well as the optimal time of surgery are still unclear and under investigation by means of ongoing randomized trials. Observational management or local excision following tumour complete response are promising alternatives to total mesorectal excision, but need further evaluation, and their use outside of a clinical trial is not recommended.The preoperative selection of patients who will benefit from neoadjuvant radiotherapy or not, as well as the proper identification of a clinical complete tumour response after combined treatment modalities,will influence the future directions in the treatment of locally advanced rectal cancer.

Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas

the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin.Consequently,preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular,histological and pathophysiological features.Intraepithelial neoplasms are reported in biliary tract,as biliary intraepithelial neoplasm(BilIN),and in pancreas,as pancreatic intraepithelial neoplasm(PanIN).Both can evolve to invasive carcinomas,respectively cholangiocarcinoma(CCA)and pancreatic ductal adenocarcinoma(PDAC).Intraductal papillary neoplasms arise in biliary tract and pancreas.Intraductal papillary neoplasm of the biliary tract(IPNB)share common histologic and phenotypic features such as pancreatobiliary,gastric,intestinal and oncocytic types,and biological behavior with the pancreatic counterpart,the intraductal papillary mucinous neoplasm of the pancreas(IPMN).All these neoplastic lesions exhibit similar immunohistochemical phenotypes,suggesting a common carcinogenic process.Indeed,CCA and PDAC display similar clinic-pathological features as growth pattern,poor response to conventional chemotherapy and radiotherapy and,as a consequence,an unfavorable prognosis.The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.

Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology

Neuroendocrine carcinomas(NEC) of the pancreas are defined by a mitotic count > 20 mitoses/10 high power fields and/or Ki67 index > 20%, and included all the tumors previously classified as poorly differentiated endocrine carcinomas. These latter are aggressive malignancies with a high propensity for distant metastases and poor prognosis, and they can be further divided into small- and large-cell subtypes. However in the NEC category are included also neuroendocrine tumors with a well differentiated morphology but ki67 index > 20%. This category is associated with better prognosis and does not significantly respond to cisplatin-based chemotherapy, which represents the gold standard therapeutic approach for poorly differentiated NEC. In this review, the differences between well differentiated and poorly differentiated NEC are discussed considering both pathology, imaging features, treatment and prognostic implications. Diagnostic and therapeutic flowcharts are proposed. The need for a revision of current classification system is stressed being well differentiated NEC a more indolent disease compared to poorly differentiated tumors.

Adjuvant treatment in biliary tract cancer: To treat or not to treat?

Biliary tract cancer is a rare malignant tumor. There is limited knowledge about biology and natural history of this disease and considerable uncertainty remains regarding its optimal diagnostic and therapeutic man- agement. The role of adjuvant therapy is object of debate and controversy. Although resection is identified as the most effective and the only potentially curative treatment, there is no consensus on the impact of ad- juvant chemotherapy and/or radiotherapy on the high incidence of disease recurrence and on survival. This is mainly due to the rarity of this disease and the consequent difficulty in performing randomized trials. The only two prospectively controlled trials concluded that adjuvant chemotherapy did not improve survival. Most of the retrospective trials, which had limited sample size and included heterogeneous patients population and non-standardized therapies, suggested a marginal benefit of chemoradiotherapy in reducing locoregional recurrence and an uncertain impact on survival. Welldesigned multi-institutional randomized trials are necessary to clarify the role of adjuvant therapy. Two ongoing phase Ⅲ trials may provide relevant information.

TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype

AIM To evaluate the impact of the Glu167Lys(E167K) transmembrane 6 superfamily member 2(TM6SF2) variant on the biochemical and morphologic expression of liver lesions in human immunodeficiency virus(HIV)/hepatitis C virus(HCV) co-infected patients.METHODS The study comprised 167 consecutive patients with HIV/HCV coinfection and biopsy-proven chronic hepatitis. A pathologist graded liver fibrosis and necroinflammation using the Ishak scoring system, and steatosis using Kleiner's scoring system. Patients were genotyped for TM6SF2 E167K(rs58542926) by real-time Polymerase chain reaction. The 167 patients, 35 therapy-naive and 132 receiving ART, were prevalently males(73.6%), the median age was 40.7 years and the immunological condition good(median CD4+ cells/mm3 = 505.5).RESULTS The 17 patients with the TM6SF2 E167 K variant, compared with the 150 with TM6SF2-E/E, showed higher AST(P = 0.02) and alanine aminotransferase(P = 0.02) and higher fibrosis score(3.1 ± 2.0 vs 2.3 ± 1.5, P = 0.05). In a multivariate analysis, TM6SF2 E167 K was independently associated with severe fibrosis. The same analysis showed that HCV-genotype 3, present in 42.2% of patients was an independent predictor of severe steatosis. The association of TM6SF2 E167 K with severe steatosis, absent for the whole group of 167 patients, was re-evaluated separately for HCVgenotype 3 and non-3 patients: No factor was independently associated with severe steatosis in the HCV-genotype-3 subgroup, whereas an independent association was observed between severe steatosis and TM6SF2 E167 K in non-3 HCV genotypes. No association between the TM6SF2 E167 K variant and severe liver necroinflammation was observed.CONCLUSION In HIV/HCV coinfection the TM6SF2 E167 K variant is an independent predictor of severe fibrosis, but appears to be independently associated with severe steatosis only for patients with a non-3 HCV genotype.

Enhanced recovery pathways in pancreatic surgery: State of the art

Pancreatic surgery is being offered to an increasing number of patients every year. Although postoperative outcomes have significantly improved in the last decades, even in high-volume centers patients still experience significant postoperative morbidity and full recovery after surgery takes longer than we think. In recent years, enhanced recovery pathways incorporating a large number of evidence-based perioperative interventions have proved to be beneficial i n t e r m s o f i m p rove d p o s t o p e ra t i ve o u t c o m e s, and accelerated patient recovery in the context of gastrointestinal, genitourinary and orthopedic surgery. The role of these pathways for pancreatic surgery is still unclear as high-quality randomized controlled trials are lacking. To date, non-randomized studies have shown that care pathways for pancreaticoduodenectomy and distal pancreatectomy are safe with no difference in postoperative morbidity, leading to early discharge and no increase in hospital readmissions. Hospital costs are reduced due to better organization of care and resource utilization. However, further research is needed to clarify the effect of enhanced recovery pathways on patient recovery and post-discharge outcomes following pancreatic resection. Future studies should be prospective and follow recent recommendations for the design and reporting of enhanced recovery pathways.

Neoadjuvant treatment for resectable pancreatic cancer: Time for phase Ⅲ testing?

This paper discusses the rationale for phaseⅢtesting of neoadjuvant therapy in patients affected by resectable pancreatic adenocarcinoma.The therapeutic management of patients affected by resectable pancreatic cancer is particularly troublesome due to the aggressiveness of the disease and to the limited efficacy and sometimes unfavourable risk-benefit ratio of the available therapeutic tools.Conflicting data on the role of adjuvant chemoradiation have been reported,while adjuvant single-agent chemotherapy significantly improved overall survival(OS)when compared to surgery alone. However,the OS figures for adjuvant chemotherapy remain disappointing.In effect,pancreatic cancer exhibits a prominent tendency to recur after a brief median time interval from surgery and extra-pancreatic dissemination represents the predominant pattern of disease failure.Neoadjuvant treatment has a strong rationale in this disease but limited information on the efficacy of this approach is available from single arm trials with low levels of evidence.Thus,in spite of two decades of investigation there is currently no evidence to support the routine use of pre-surgical therapy in clinical practice. To foster knowledge on the optimal management of this disease,and to produce evidence-based treatment guidelines,there is no alternative to well designed randomized trials.Systemic chemotherapy is a candidate for testing because it is supported by a more robust rationale than chemoradiation.Combination chemotherapy regimens with elevated activity in advanced disease warrant investigation.Caution would suggest the running of an exploratory phaseⅡrandomized trial before embarking on a large phase Ⅲ study.

Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis

AIM:To assess the rate of relapses of acute pancreatitis(AP),recurrent AP(RAP)and the evolution of endosonographic signs of chronic pancreatitis(CP)in patients with pancreas divisum(PDiv)and RAP.METHODS:Over a five-year period,patients with PDiv and RAP prospectively enrolled were divided into two groups:(1)those with relapses of AP in the year before enrollment were assigned to have endoscopic therapy(recent RAP group);and(2)those free of recurrences were conservatively managed,unless they relapsed during follow-up(previous RAP group).All patients in both groups entered a follow-up protocol that includedclinical and biochemical evaluation,pancreatic endoscopic ultrasonography(EUS)every year and after every recurrence of AP,at the same time as endoscopic retrograde cholangiopancreatography(ERCP).RESULTS:Twenty-two were treated by ERCP and 14were conservatively managed during a mean follow-up of 4.5±1.2 years.In the recent RAP group in whom dorsal duct drainage was achieved,AP still recurred in11(57.9%)after the first ERCP,in 6 after the second ERCP(31.6%)and in 5 after the third ERCP(26.3%).Overall,endotherapy was successful 73.7%.There were no cases of recurrences in the previous RAP group.EUS signs of CP developed in 57.9%of treated and 64.3%of untreated patients.EUS signs of CP occurred in 42.8%of patients whose ERCPs were successful and in all those in whom it was unsuccessful(P=0.04).There were no significant differences in the rate of AP recurrences after endotherapy and in the prevalence of EUS signs suggesting CP when comparing patients with dilated and non-dilated dorsal pancreatic ducts within each group.CONCLUSION:Patients with PDiv and recent episodes of AP can benefit from endoscopic therapy.Effective endotherapy may reduce the risk of developing EUS signs of CP at a rate similar to that seen in patients of previous RAP group,managed conservatively.However,in a subset of patients,endotherapy,although successful,did not prevent the evolution of endosonographic signs of CP.

A novel expressed prostatic secretion(EPS)-urine metabolomic signature for the diagnosis of clinically significant prostate cancer

Objective:Significant efforts are currently being made to identify novel biomarkers for the diagnosis and risk stratification of prostate cancer(PCa).Metabolomics can be a very useful approach in biomarker discovery because metabolites are an important read-out of the disease when characterized in biological samples.We aimed to determine a metabolomic signature which can accurately distinguish men with clinically significant PCa from those affected by benign prostatic hyperplasia(BPH).Methods:We first performed untargeted metabolomics using ultrahigh-performance liquid chromatography tandem mass spectrometry on expressed prostatic secretion urine(EPS-urine)from 25 patients affected by BPH and 25 men with clinically significant PCa(defined as Gleason score≥3+4).Diagnosis was histologically confirmed after surgical treatment.The EPS-urine metabolomic approach was then applied to a larger,prospective cohort of 92 consecutive patients undergoing multiparametric magnetic resonance imaging for clinical suspicion of PCa prior to biopsy.Results:We established a novel metabolomic signature capable of accurately distinguishing PCa from benign tissue.A metabolomic signature was associated with clinically significant PCa in all subgroups of the Prostate Imaging Reporting and Data System(PI-RADS)classification(100%and 89.13%of accuracy when the PI-RADS was in range of 1–2 and 4–5,respectively,and 87.50%in the more critical cases when the PI-RADS was 3).Conclusions:A combination of metabolites and clinical variables can effectively help in identifying PCa patients that might be overlooked by current imaging technologies.Metabolites from EPS-urine should help in defining the diagnostic pathway of PCa,thus improving PCa detection and decreasing the number of unnecessary prostate biopsies.

Colorectal cancer screening from 45 years of age: Thesis, antithesis and synthesis

Colorectal cancer incidence and mortality in patients younger than 50 years are increasing, but screening before the age of 50 is not offered in Europe. Advancedstage diagnosis and mortality from colorectal cancer before 50 years of age are increasing. This is not a detection-bias effect;it is a real issue affecting the entire population. Three independent computational models indicate that screening from 45 years of age would yield a better balance of benefits and risks than the current start at 50 years of age. Experimental data support these predictions in a sex- and race-independent manner. Earlier screening is seemingly affordable, with minimal impediments to providing younger adults with colonoscopy. Indeed, the American Cancer Society has already started to recommend screening from 45 years of age in the United States. Implementing early screening is a societal and public health problem. The three independent computational models that suggested earlier screening were criticized for assuming perfect compliance. Guidelines and recommendations should be derived from well-collected and reproducible data, and not from mathematical predictions. In the era of personalized medicine, screening decisions might not be based solely on age, and sophisticated prediction software may better guide screening. Moreover, early screening might divert resources away from older individuals with greater biological risks. Finally, it is still unknown whether early colorectal cancer is part of a continuum of disease or a biologically distinct disease and, as such, it might not benefit from screening at all. The increase in early-onset colorectal cancer incidence and mortality demonstrates an obligation to take actions. Earlier screening would save lives, and starting at the age of 45 years may be a robust screening option.