Colorectal and interval cancers of the Colorectal Cancer Screening Program in the Basque Country (Spain)

AIM To assess proportions, related conditions and survival of interval cancer(IC).METHODS The programme has a linkage with different clinical databases and cancer registers to allow suitable evaluation. This evaluation involves the detection of ICs after a negative faecal inmunochemical test(FIT), interval cancer FIT(IC-FIT) prior to a subsequent invitation, and the detection of ICs after a positive FIT and confirmatory diagnosis without colorectal cancer(CRC) detected and before the following recommended c o l o n o s c o p y, I C-c o l o n o s c o p y. W e c o n d u c t e d a retrospective observational study analyzing from January 2009 to December 2015 1193602 invited people onto the Programme(participation rate of 68.6%).RESULTS Two thousand five hundred and eighteen cancers were diagnosed through the programme, 18 cases of IC-colonoscopy were found before the recommended follow-up(43542 colonoscopies performed) and 186 IC-FIT were identified before the following invitation of the 769200 negative FITs. There was no statistically significant relation between the predictor variables of ICs with sex, age and deprivation index, but there was relation between location and stage. Additionally, it was observed that there was less risk when the location was distal rather than proximal(OR = 0.28, 95%CI: 0.20-0.40, P < 0.0001), with no statistical significance when the location was in the rectum as opposed to proximal. When comparing the screen-detected cancers(SCs) with ICs, significant differences in survival were found(P < 0.001); being the 5-years survival for SCs 91.6% and IC-FIT 77.8%.CONCLUSION These findings in a Population Based CRC Screening Programme indicate the need of population-based studies that continue analyzing related factors to improve their detection and reducing harm.

Suitability and limitations of mesenchymal stem cells to elucidate human bone illness

Functional impairment of mesenchymal stem cells(MSCs),osteoblast progenitor cells,has been proposed to be a pathological mechanism contributing to bone disorders,such as osteoporosis(the most common bone disease)and other rare inherited skeletal dysplasias.Pathological bone loss can be caused not only by an enhanced bone resorption activity but also by hampered osteogenic differentiation of MSCs.The majority of the current treatment options counteract bone loss,and therefore bone fragility by blocking bone resorption.These socalled antiresorptive treatments,in spite of being effective at reducing fracture risk,cannot be administered for extended periods due to security concerns.Therefore,there is a real need to develop osteoanabolic therapies to promote bone formation.Human MSCs emerge as a suitable tool to study the etiology of bone disorders at the cellular level as well as to be used for cell therapy purposes for bone diseases.This review will focus on the most relevant findings using human MSCs as an in vitro cell model to unravel pathological bone mechanisms and the application and outcomes of human MSCs in cell therapy clinical trials for bone disease.

Genetics of adult attachment:An updated review of the literature

Attachment style,which has been theorized to be rooted in childhood bonding experiences,influences adult cognitive,emotional and interpersonal functioning.Despite its relationship with early experiences,research indicates that the continuity of attachment style across childhood and adulthood is only partial,being a malleable tendency that is shaped throughout development,with an increasing influence of genetics,as it occurs in other cognitive and behavioral phenotypes.Genetic research indicates that up to 45% of the variability in anxious and 39% in avoidant adult attachment style could be explained by genetic causes,but the precise mechanisms remain unclear.A narrative review is conducted analyzing the existing literature regarding the implication of candidate genes related to oxytocin,dopaminergic pathways,serotonergic pathways and brainderived neurotrophic factor in adult attachment,with both vulnerability and differential susceptibility approaches,yielding mixed results.We highlight the lack of genome-wide studies and the scarcity of epigenetic investigation.Based on the existing data,we conclude that the genetics of adult attachment is an area that requires further research to clarify its etiological role and that it should be preferably approached as an interaction between nature and nurture.

Are all prostate cancer patients "fit" for salvage radiotherapy?

The indication for salvage radiotherapy(RT)(SRT)in patients with biochemically-recurrent prostate cancer after surgery is based on prostate-specific antigen(PSA)levels at the time of biochemical recurrence.Although there are clear criteria(pT3-pT4 disease and/or positive margins)for the use of adjuvant radiotherapy,no specific clinical or tumour-related criteria have yet been defined for SRT.In retrospective series,5-year biochemical progression-free survival(PFS)ranges from 35%-85%,depending on the PSA level at the start of RT.Two phase 3 trials have compared SRT with and without androgen deprivation therapy(ADT),finding that combined treatment(SRT+ADT)improves both PFS and overall survival.Similar to adjuvant RT,the indication for ADT is based on tumour-related factors such as PSA levels,tumour stage,and surgical margins.The number of patients referred to radiation oncology departments for SRT continues to rise.In the present article,we define the clinical,therapeutic,and tumour-related factors that we believe should be evaluated before prescribing SRT.In addition,we propose a decision algorithm to determine whether the patient is fit for SRT.This algorithm will help to identify patients in whom radiotherapy is likely to improve survival without significantly worsening quality of life.

Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease

Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation

BACKGROUND Tacrolimus trough levels(TTL)during the first weeks after liver transplantation(LT)have been related with long-term renal function and hepatocellular carcinoma recurrence.Nevertheless,the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied.Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy.Patients were classified into 2 groups according to their mean TTL within the first month after transplantation:≤10(n=98)and>10 ng/mL(n=57).Multivariate analyses were performed to assess risk factors for patient mortality.RESULTS Mean levels within the first month post-transplant were 7.4±1.7 and 12.6±2.2 ng/mL in the≤10 and>10 groups,respectively.Donor age was higher in the high TTL group 62.9±16.8 years vs 45.7±17.5 years(P=0.002)whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7%vs 15.8%(P=0.02).Recipient features were generally similar across groups.After a median follow-up of 52.8 mo(range 2.8-81.1),no significant differences were observed in:Mean estimated glomerular filtration rate(P=0.69),hepatocellular carcinoma recurrence(P=0.44),de novo tumors(P=0.77),new-onset diabetes(P=0.13),or biopsy-proven acute rejection rate(12.2%and 8.8%,respectively;P=0.50).Eighteen patients died during the follow-up and were evenly distributed across groups(P=0.83).Five-year patient survival was 90.5%and 84.9%,respectively(P=0.44),while 5-year graft survival was 88.2%and 80.8%,respectively(P=0.42).Early TTL was not an independent factor for patient mortality in multivariate analyses.CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.

Endovascular treatment for early hepatic artery occlusion after liver transplantation: Angioplasty or stent

To the Editor:We read with great interest the recent article by Zhu et al.[1].In the study,the authors analyzed the outcomes of 26 patients diagnosed with hepatic artery occlusion(HAO)and treated with an endovascular approach(EVT)within the first 30 days after ortho-topic liver transplantation(LT).The median interval from LT to EVT was 7 days,most patients were treated with angioplasty and only two(7.7%)needed stent placement.The authors should be congrat-ulated as they achieved a 100%of success rate with an 80.8%of 1-year survival rate.

Genetic variables of the glutamatergic system associated with treatment-resistant depression:A review of the literature

Depression is a common,recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide.Up to 15%-40%of cases do not respond to diverse pharmacological treatments and,thus,can be defined as treatment-resistant depression(TRD).The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment.Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD.Specifically,the N-methyl-D-aspartic acid receptor(NMDAR)andα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR),which are targeted by ketamine and esketamine,are proposed as promising pathways.A literature search was performed to identify studies on the genetics of the glutamatergic system in depression,focused on variables related to NMDARs and AMPARs.Our review highlights GRIN2B,which encodes the NR2B subunit of NMDAR,as a candidate gene in the pathogenesis of TRD.In addition,several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation.These genes encoding glutamatergic receptors could,therefore,be candidate genes for understanding the etiopathogenesis of TRD,as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.

Environmental pollution with psychiatric drugs

Among all contaminants of emerging interest,drugs are the ones that give rise to the greatest concern.Any of the multiple stages of the drug's life cycle(production,consumption and waste management)is a possible entry point to the different environmental matrices.Psychiatric drugs have received special attention because of two reasons.First,their use is increasing.Second,many of them act on phylogenetically highly conserved neuroendocrine systems,so they have the potential to affect many non-target organisms.Currently,wastewater is considered the most important source of drugs to the environment.Furthermore,the currently available wastewater treatment plants are not specifically prepared to remove drugs,so they reach practically all environmental matrices,even tap water.As drugs are designed to produce pharmacological effects at low concentrations,they are capable of producing ecotoxicological effects on microorganisms,flora and fauna,even on human health.It has also been observed that certain antidepressants and antipsychotics can bioaccumulate along the food chain.Drug pollution is a complicated and diffuse problem characterized by scientific uncertainties,a large number of stakeholders with different values and interests,and enormous complexity.Possible solutions consist on acting at source,using medicines more rationally,eco-prescribing or prescribing greener drugs,designing pharmaceuticals that are more readily biodegraded,educating both health professionals and citizens,and improving coordination and collaboration between environmental and healthcare sciences.Besides,end of pipe measures like improving or developing new purification systems(biological,physical,chemical,combination)that eliminate these residues efficiently and at a sustainable cost should be a priority.Here,we describe and discuss the main aspects of drug pollution,highlighting the specific issues of psychiatric drugs.

m6A levels and expression of its modification genes show significant differences in breast cancer molecular subtypes

N6-methyladenosine(m6A)is the most abundant modification in eukaryotic messenger RNA.1 This modification is dynamic,reversible,and mediated by proteins characterized as methyltransferases and demethylases.Recent investigations have found that aberrant expression of methyltransferases and demethylases results in m6A dysregulation and,in consequence,affects the biological functions in which this modification is involved.Indeed,m6A dysregulation affects the development and maintenance of various diseases,including cancer.2 For this reason,we explored the potential role that m6A modification has in invasive breast cancer of no special type(IBC-NST)and its molecular subtypes luminal A,luminal B HER2-,luminal B HER2+,HER2+,and triple-negative breast cancer(TNBC)whose degree of global m6A methylation has not yet been studied.

DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation andmetabolic remodeling

Dear Editor,Of all human tumors,pheochromocytomas and paragangliomas(PPGLs)have the highest heritability rate.Over 15%of PPGLs harbor mutations in genes encoding tricarboxylic acid(TCA)cycle-related enzymes that cause oncometabolite accumulation and drive tumorigenesis via metabolic adaptation to hypoxia and global hypermethylation[1].The dihydrolipoamide S-succinyltransferase(DLST)gene was recently described as a new PPGL susceptibility gene[2].

Robotic versus laparoscopic liver resection for huge (≥10 cm) liver tumors: an international multicenter propensity-score matched cohort study of 799 cases

Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours≥10 cm.Methods:This was a retrospective review of 971 patients who underwent LLR and RLR for huge(≥10 cm)tumors at 42 international centers between 2002-2020.Results:One hundred RLR and 699 LLR which met study criteria were included.The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching(PSM)(73 vs.219).Before PSM,LLR was associated with significantly increased frequency of previous abdominal surgery,malignant pathology,liver cirrhosis and increased median blood.After PSM,RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time(242 vs.290 min,P=0.286),transfusion rate rate(19.2%vs.16.9%,P=0.652),median blood loss(200 vs.300 mL,P=0.694),open conversion rate(8.2%vs.11.0%,P=0.519),morbidity(28.8%vs.21.9%,P=0.221),major morbidity(4.1%vs.9.6%,P=0.152),mortality and postoperative length of stay(6 vs.6 days,P=0.435).Conclusions:RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes.There was no significant difference in perioperative outcomes after RLR or LLR.

CD300a inhibits CD16-mediated NK cell effector functions in HIV-1-infected patients

Natural killer(NK)cell-mediated antibody-dependent cellular cytotoxicity(ADCC)through CD16 plays a critical role in antihuman immunodeficiency virus(HIV)responses.1–3 CD300a is a surface receptor highly expressed on NK cells that has the capacity to inhibit NK cell-mediated cytotoxicity in healthy donors.4 The CD300a molecule has been related to several viral infections and is able to diminish the NK cell killing of pseudorabies-infected cells through interactions with its ligands phosphatidylserine and phosphatidylethanolamine.5 In addition,CD300a expression on B and CD4+T lymphocytes is altered during HIV-1 infection,and combined antiretroviral therapy(cART)does not restore nonpathological expression levels.5,6 However,the expression and function of CD300a on NK cells during HIV-1 infection is still unknown.We have determined the surface expression of CD300a on different NK cell subsets and the capacity of this receptor to inhibit CD16-induced NK cell effector functions in healthy and HIV-1 infected individuals.

Minimally invasive liver resection for huge(≥10cm)tumors:an international multicenter matched cohort study with regression discontinuity analyses

Background:The application and feasibility of minimally invasive liver resection(MILR)for huge liver tumours(≥10 cm)has not been well documented.Methods:Retrospective analysis of data on 6,617 patients who had MILR for liver tumours were gathered from 21 international centers between 2009-2019.Huge tumors and large tumors were defined as tumors with a size≥10.0 cm and 3.0-9.9 cm based on histology,respectively.1:1 coarsened exact-matching(CEM)and 1:2 Mahalanobis distance-matching(MDM)was performed according to clinically-selected variables.Regression discontinuity analyses were performed as an additional line of sensitivity analysis to estimate local treatment effects at the 10-cm tumor size cutoff.Results:Of 2,890 patients with tumours≥3 cm,there were 205 huge tumors.After 1:1 CEM,174 huge tumors were matched to 174 large tumors;and after 1:2 MDM,190 huge tumours were matched to 380 large tumours.There was significantly and consistently increased intraoperative blood loss,frequency in the application of Pringle maneuver,major morbidity and postoperative stay in the huge tumour group compared to the large tumour group after both 1:1 CEM and 1:2 MDM.These findings were reinforced in RD analyses.Intraoperative blood transfusion rate and open conversion rate were significantly higher in the huge tumor group after only 1:2 MDM but not 1:1 CEM.Conclusions:MILR for huge tumours can be safely performed in expert centers It is an operation with substantial complexity and high technical requirement,with worse perioperative outcomes compared to MILR for large tumors,therefore judicious patient selection is pivotal.