Practical review for diagnosis and clinical management of perihilar cholangiocarcinoma

Cholangiocarcinoma(CCC)is the most aggressive malignant tumor of the biliary tract.Perihilar CCC(pCCC)is the most common CCC and is burdened by a complicated diagnostic iter and its anatomical location makes surgical approach burden by poor results.Besides its clinical presentation,a multimodal diagnostic approach should be carried on by a tertiary specialized center to avoid missdiagnosis.Preoperative staging must consider the extent of liver resection to avoid post-surgical hepatic failure.During staging iter,magnetic resonance can obtain satisfactory cholangiographic images,while invasive techniques should be used if bile duct samples are needed.Consistently,to improve diagnostic potential,bile duct drainage is not necessary in jaundice,while it is indicated in refractory cholangitis or when liver hypertrophy is needed.Once resecability criteria are identified,the extent of liver resection is secondary to the longitudinal spread of CCC.While in the past type IV pCCC was not considered resectable,some authors reported good results after their treatment.Conversely,in selected unresectable cases,liver transplantation could be a valuable option.Adjuvant chemotherapy is the standard of care for resected patients,while neoadjuvant approach has growing evidences.If curative resection is not achieved,radiotherapy can be added to chemotherapy.This multistep curative iter must be carried on in specialized centers.Hence,the aim of this review is to highlight the main steps and pitfalls of the diagnostic and therapeutic approach to pCCC with a peculiar attention to type IV pCCC.

Heart Rate Variability, Standard of Measurement, Physiological Interpretation and Clinical Use in Mountain Marathon Runners during Sleep and after Acclimatization at 3480 m

Fluctuations in autonomic cardiovascular regulation during exposure to high altitude may increase the risk of heart attack during waking and sleep. This study compared heart rate variability (HVR) and its components during sleep at low altitude and after 30 - 41 hours of acclimatization at high altitude (3480 m) in five mountain marathon runners controlled for diet, drugs, light-dark cycle and jet lag. In comparison to sea level, RR-intervals during sleep at high altitude decreased significantly (P 0.001). The significant increase in sympathetic autonomic cardiovascular modulation at high altitude protects against excessive oxygen deprivation during sleep. Increases in R-R intervals can require longer periods of acclimatization at3480 m to mitigate the effects of altitude/hypoxia on sympathetic tone, thus reducing cardiovascular distress at rest during waking and sleep and probably before during and after athletic performance at altitude.

Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer

BACKGROUND Leukocytes,such as T cells and macrophages,play an important role in tumorigenesis.CC chemokine ligand(CCL)4,which is produced by lymphocytes and macrophages,has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes.AIM To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer(CRC)and evaluate their prognostic significance.METHODS Luminex technology was used to determine CCL4 Levels in CRC tissue(n=98),compared with paired normal tissue,and in plasma from patients with CRC(n=103),compared with healthy controls(n=97).Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery,Ryhov County Hospital,Jönköping,Sweden.Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue(n=101).Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls.RESULTS The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue(90%,P<0.001 and 45%,P<0.05,respectively).CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease.Low CCL4 protein expression levels in CRC tissue were associated with a 30%lower cancer-specific survival rate in patients(P<0.01).The level of plasma CCL4 was 11%higher in CRC patients than in healthy controls(P<0.05)and was positively correlated(r=0.56,P<0.01)with the CCL4 protein level in CRC tissue.The analysis of CCL4 gene polymorphism rs10491121 showed a difference(P<0.05)between localized disease and disseminated disease in the right colon,with a dominance of allele A in localized disease.Moreover,the rate of the A allele was higher among CRC patients with mucinous cancer than among those with nonmucinous cancer.CONCLUSION The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121,particularly in the right colon,are associated with clinical outcome in CRC patients.

Phylogeny of Murray Valley encephalitis virus in Australia and Papua New Guinea

Objective:To study the genetic diversity of Murray Valley encephalitis virus(MVEV) in Australia and Papua New Guinea.Methods:MVEV envelope gene sequences were aligned using Clustal X and manual editing was performed with Bioedit.ModelTest v.3.7 was used to select the simplest evolutionary model that adequately fitted the sequence data.Maximum likelihood analysis was performed using PhyML.The phylogenetic signal of the dataset wa.s investigated by the likelihood mapping analysis.The Bayesian phylogenetic tree was built using BEAST.Results:The phylogenetic trees showed two main clades.The clade Ⅰincluding eight strains isolated from West Australia.The clade Ⅱ was characterized by at least four epidemic entries,three of which localized in Northern West Australia and one in Papua New Guinea.The estimated mean evolutionary rate value of the MVEV envelope gene wa.s0.407 × 10^(-3) substitution/site/year(95%HPD:0.623 × 10~4-0.780× 10^(-3)).Population dynamics defines a relative constant population until the year 2000.when a reduction occurred,probably due to a bottleneck.Conclusions:This study has been useful in supporting the probable connection between climate changes and viral evolution also by the vector point of view:multidisciplinary monitoring studies are important to prevent new viral epidemics inside and outside new endemic areas.

Liver-side of inflammatory bowel diseases:Hepatobiliary and druginduced disorders

Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases(IBD),both in Crohn’s disease and ulcerative colitis(UC),and therefore represent a diagnostic challenge.Immunemediated conditions include primary sclerosing cholangitis(PSC)as the main form,variant forms of PSC(namely small-duct PSC,PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis)and granulomatous hepatitis.PSC is by far the most common,presenting in up to 8%of IBD patients,more frequently in UC.Several genetic foci have been identified,but environmental factors are preponderant on disease pathogenesis.The course of the two diseases is typically independent.PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies.Risk of cholangiocarcinoma is significantly increased in PSC,as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis.No disease-modifying drugs are approved to date.Thus,PSC management is directed against symptoms and complications and includes medical therapies for pruritus,endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease.Other nonimmune-mediated hepatobiliary disorders are gallstone disease,whose incidence is higher in IBD and reported in up to one third of IBD patients,non-alcoholic fatty liver disease,pyogenic liver abscess and portal vein thrombosis.Druginduced liver injury(DILI)is an important issue in IBD,since most IBD therapies may cause liver toxicity;however,the incidence of serious adverse events is low.Thiopurines and methotrexate are the most associated with DILI,while the risk related to anti-tumor necrosis factor-αand anti-integrins is low.Data on hepatotoxicity of newer drugs approved for IBD,like anti-interleukin 12/23 and tofacitinib,are still scarce,but the evidence from other rheumatic diseases is reassuring.Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD,and adequate screening and vaccination is warranted.On the other hand,hepatitis C reactivation does not seem to be a real risk,and hepatitis C antiviral treatment does not influence IBD natural history.The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis,but it is of paramount importance to make a quick and accurate diagnosis,as it may influence the therapeutic management.

Roles of cell fusion, hybridization and polyploid cell formation in cancer metastasis

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation,repair and regeneration.Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations.Factors that stimulate cell fusion are inflammation and hypoxia.Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes,e.g.,reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition.There is now considerable in vitro,in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis.Of the many changes in cancer cells after hybridizing with leucocytes,it is notable that hybrids acquire resistance to chemo-and radiation therapy.One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization.Regardless of the mechanism of polyploid cell formation,it happens in response to genotoxic stresses and enhances a cancer cell’s ability to survive.Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis.In addition,we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors.

Effects of diabetes type 2 and metformin treatment in Swedish patients with colorectal cancer

The association between type 2 diabetes mellitus(DM)and colorectal cancer(CRC)has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients.The association between DM and the survival of patients with CRC is controversial.Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM.In our cohort,we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin.On the other hand,we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients.The dominance of the T bearing genotypes in patients with DM was statistically significant(P=0.038),with an odds ratio of 1.66(95%confidence interval:1.03-2.69).

Assessment of psychological predictors of weight loss:How and what for?

Obesity is a multifactorial disease and the prominent factors playing a role in its pathogenesis are biological, environmental and psychological. There is a growing interest in understanding psychological functioning of obese subjects and the influence of psychological factors on treatment outcome. The aim of the present narrative review is to critically analyze the current literature, in order to point out the most common psychological constructs studied in obesity and to give an overview of the main existing tools investigating psychological features which have been considered significant for the prediction of success in weight loss and maintenance programs in obese patients. In this framework, the most common psychological constructs studied are: self-motivation, self-efficacy, locus of control, health related quality of life, self-esteem, self-control, concerns about body image, outcome expectations, and personality traits. These features have been explored through a wide variety of psychometric instruments. However, as an overall, studies evaluating the association between psychological features and treatment outcome failed to give consistent results. A possible explanation may consist on the fact that many tools widely used to explore psychological features were not specifically designed for obese patients and none of them was comprehensive of all possible psychological features involved. The identification of well-defined subgroups of patients and the validation of more reliable and comprehensive tools, specifically designed for obese subjects, should be forecasted in order to reach a better knowledge of psychological functioning of obese individuals and to improve the outcome of weight loss programs.

Magnetotactic bacteria from the human gut microbiome associated with orientation and navigation regions of the brain

Magnetotactic bacteria(MTB),ubiquitous in soil and fresh and saltwater sources have been identified in the microbiome of humans and many animals.MTB endogenously produce magnetic nanocrystals enabling them to orient and navigate along geomagnetic fields.Similar magnetite deposits have been found throughout the tissues of the human brain,including brain regions associated with orientation such as the cerebellum and hippocampus,the origins of which remain unknown.Speculation over the role and source of MTB in humans,as well as any association with the brain,remain unanswered.We performed a metagenomic analysis of the gut microbiome of 34 healthy females as well as grey matter volume analysis in magnetite-rich brain regions associated with orientation and navigation with the goal of identifying specific MTB that could be associated with brain structure in orientation and navigation regions.We identified seven MTB in the human gut microbiome:Magnetococcus marinus,Magnetospira sp.QH-2,Magnetospirillum magneticum,Magnetospirillum sp.ME-1,Magnetospirillum sp.XM-1,Magnetospirillum gryphiswaldense,and Desulfovibrio magneticus.Our preliminary results show significant negative associations between multiple MTB with bilateral flocculonodular lobes of the cerebellum and hippocampus(adjusted for total intracranial volume,uncorrected P<0.05).These findings indicate that MTB in the gut are associated with grey matter volume in magnetite-rich brain regions related to orientation and navigation.These preliminary findings support MTB as a potential biogenic source for brain magnetite in humans.Further studies will be necessary to validate and elucidate the relationship between these bacteria,magnetite concentrations,and brain function.

Prognostic role of intestinal ultrasound in Crohn’s disease

The majority of patients affected by Crohn’s disease(CD)develop a chronic condition with persistent inflammation and relapses that may cause progressive and irreversible damage to the bowel,resulting in stricturing or penetrating complications in around 50%of patients during the natural history of the disease.Surgery is frequently needed to treat complicated disease when pharmacological therapy failes,with a high risk of repeated operations in time.Intestinal ultrasound(IUS),a non-invasive,cost-effective,radiation free and reproducible method for the diagnosis and follow-up of CD,in expert hands,allow a precise assessment of all the disease manifestations:Bowel characteristics,retrodilation,wrapping fat,fistulas and abscesses.Moreover,IUS is able to assess bowel wall thickness,bowel wall stratification(echo-pattern),vascularization and elasticity,as well as mesenteric hypertrophy,lymph-nodes and mesenteric blood flow.Its role in the disease evaluation and behaviour description is well assessed in literature,but less is known about the potential space of IUS as predictor of prognostic factors suggesting response to a medical treatment or postoperative recurrence.The availability of a low cost exam as IUS,able to recognize which patients are more likely to respond to a specific therapy and which patients are at high risk of surgery or complications,could be a very useful instrument in the hands of IBD physician.The aim of this review is to present current evidence about the prognostic role that IUS can show in predicting response to treatment,disease progression,risk of surgery and risk of post-surgical recurrence in CD.

Etiology matters:genetic and acquired prion diseases engage different mechanisms at a presymptomatic stage

One of the most enigmatic problems in biomedical research surrounds the phenomenon that neurodegenerative diseases target specific cell types and brain regions.This is difficult to explain because the proteins that cause them are widely expressed,often highest in resistant regions.This mystery is further complicated by the fact that some disease-causing proteins are associated with multiple diseases.

Mitochondrial dysfunctions in neurodegenerative diseases:role in disease pathogenesis,strategies for analysis and therapeutic prospects

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes,the mitochondria are required for multiple pivotal processes that include the production of biological energy,the biosynthesis of reactive oxygen species,the control of calcium homeostasis,and the triggering of cell death.The disruption of anyone of these processes has been shown to impact strongly the function of all cells,but especially of neurons.In this review,we discuss the role of the mitochondria impairment in the development of the neurodegenerative diseases Amyotrophic Lateral Sclerosis,Parkinson's disease and Alzheimer's disease.We highlight how mitochondria disruption revolves around the processes that underlie the mitochondria's life cycle:fusion,fission,production of reactive oxygen species and energy failure.Both genetic and sporadic forms of neurodegenerative diseases are unavoidably accompanied with and often caused by the dysfunction in one or more of the key mitochondrial processes.Therefore,in order to get in depth insights into their health status in neurodegenerative diseases,we need to focus into innovative strategies aimed at characterizing the various mitochondrial processes.Current techniques include Mitostress,Mitotracker,transmission electron microscopy,oxidative stress assays along with expression measurement of the proteins that maintain the mitochondrial health.We will also discuss a panel of approaches aimed at mitigating the mitochondrial dysfunction.These include canonical drugs,natural compounds,supplements,lifestyle interventions and innovative approaches as mitochondria transplantation and gene therapy.In conclusion,because mitochondria are fundamental organelles necessary for virtually all the cell functions and are severely impaired in neurodegenerative diseases,it is critical to develop novel methods to measure the mitochondrial state,and novel therapeutic strategies aimed at improving their health.

Chikungunya virus,epidemiology,clinics and phylogenesis:A review

Chikungunva virus is a mosquito-transmitted alphavirus that causes chikungunva fever,a febrile illness associated with severe arthralgia and rash.Chikungunva virus is transmitted by culicine mosquitoes:Chikungunya virus replicates in the skin,disseminates to liver,muscle,joints.lymphoid tissue and brain,presumably through the blood.Phylogenetic studies showed that the Indian Ocean and the Indian subcontinent epidemics were caused by two different introductions of distinct strains of East/Central/South African genotype of CHIKV.The paraphyletic grouping of African CHIK viruses supports the historical evidence that the virus was introduced into Asia from Africa.Phylogenetic analysis divided Chikungunva virus isolates into three distinct genotypes based on geographical origins:the first,the West Africa genotype,consisted of isolates from Senegal and Nigeria;the second contained strains from East/Central/South African genotype,while the third contained solely Asian.The most recent common ancestor for the recent epidemic,which ravaged Indian Ocean islands and Indian subcontinent in 2004- 2007.was found to date in 2002.Asian lineage dated about 1952 and exhibits similar spread patterns of the recent Indian Ocean outbreak lineage,with successive epidemics detected along an eastward path.Asian group splitted into two clades:an Indian lineage and a south east lineage.Outbreaks of Chikungunya virus fever in Asia have not been associated necessarily with outbreaks in Africa.Phylogenetic tools can reconstruct geographic spread of Chikungunva virus during the epidemics wave.The good management of patients with acute Chikungunva virus infection is essential for public health in susceptible areas with current Aedes spp activity.

Development of an HPLC–UV assay method for the simultaneous quantification of nine antiretroviral agents in the plasma of HIV-infected patients

A new method using high-performance liquid chromatography coupled with ultra violet detection(HPLC–UV)was developed and validated for the simultaneous quantification of atazanavir,dolutegravir,darunavir,efavirenz,etravirine lopinavir,raltegravir,rilpivirine and tipranavir in human plasma.For the first time we reported here the development and validation of an HPLC–UV assay to quantify the frequently administered 9antiretroviral compounds including dolutegravir and rilpivirine.A simple solid phase extraction procedure was applied to 500 μL aliquots of plasma.The chromatographic separation of the drugs and internal standard(quinoxaline) was achieved with a gradient of acetonitrile and sodium acetate buffer on a C_(18) reverse-phase analytical column with a 25 min analytical run time.Calibration curves were optimised according to the therapeutic range of drug concentrations in patients,and the coefficient of determination(r^2) was higher than0.99 for all analytes.Mean intraday and interday precisions(RSD) for all compounds were less than 15.0%,and the mean accuracy(% deviation from nominal concentration) was also found to be less than 15.0%.Extraction recovery range was between 80% and 120% for all drugs analysed.The solid phase extraction and HPLC–UV method enable a specific,sensitive,and reliable simultaneous determination of nine antiretroviral agents in plasma.Good extraction efficiency and low limit of HPLC–UV quantification make this method suitable for use in clinical trials and therapeutic drug monitoring.

Enigmatic origin of hepatitis B virus:An ancient travelling companion or a recent encounter?

Hepatitis B virus(HBV)is the leading cause of liver disease and infects an estimated 240 million people worldwide.It is characterised by a high degree of genetic heterogeneity because of the use of a reverse transcriptase during viral replication.The ten genotypes(A-J)that have been described so far further segregate into a number of subgenotypes which have distinct ethno-geographic distribution.Genotypes A and D are ubiquitous and the most prevalent genotypes in Europe(mainly represented by subgenotypes D1-3 and A2);genotypes B and C are restricted to eastern Asia and Oceania;genotype E to central and western Africa;and genotypes H and F(classified into 4 subgenotypes)to Latin America and Alaska.This review summarises the data obtained by studying the global phylodynamics and phylogeography of HBV genotypes,particularly those concerning the origin and dispersion histories of genotypes A,D,E and F and their subgenotypes.The lack of any consensus concerning the HBV substitution rate and the conflicting data obtained using different calibration approaches make the time of origin and divergence of the various genotypes and subgenotypes largely uncertain.It is hypothesised that HBV evolutionary rates are time dependent,and that the changes depend on the main transmission routes of the genotypes and the dynamics of the infected populations.

How to perform gastrointestinal ultrasound: anatomy and normal findings

Gastrointestinal ultrasound is a practical, safe, cheap and reproducible diagnostic tool in inflammatorybowel disease gaining global prominence amongst clinicians. Understanding the embryological processes of the intestinal tract assists in the interpretation of abnormal sonographic findings. In general terms, the examination principally comprises interrogation of the colon, mesentery and small intestine using both lowfrequency and high-frequency probes. Interpretation of findings on GIUS includes assessment of bowel wall thickness, symmetry of this thickness, evidence of transmural changes, assessment of vascularity using Doppler imaging and assessment of other specific features including lymph nodes, mesentery and luminal motility. In addition to B-mode imaging, transperineal ultrasonography, elastography and contrast-enhanced ultrasonography are useful adjuncts. This supplement expands upon these features in more depth.

Glucose intolerance and diabetes mellitus in ulcerative colitis: Pathogenetic and therapeutic implications

Diabetes mellitus is one of the most frequent co-morbidities of ulcerative colitis patients.The epidemiological association of these diseases suggested a genetic sharing and has challenged gene identification.Diabetes co-morbidity in ulcerative colitis has also relevant clinical and therapeutic implications,with potential clinical impact on the follow up and outcome of patients.These diseases share specific complications,such as neuropathy,hepatic steatosis,osteoporosis and venous thrombosis.It is still unknown whether the coexistence of these diseases may increase their occurrence.Diabetes and hyperglycaemia represent relevant risk factors for postoperative complications and pouch failure in ulcerative colitis.Medical treatment of ulcerative colitis in patients with diabetes mellitus may be particularly challenging.Corticosteroids are the treatment of choice of active ulcerative colitis.Their use may be associated with the onset of glucose intolerance and diabetes,with difficult control of glucose levels andwith complications in diabetic patients.Epidemiologic and genetic evidences about diabetes co-morbidity in ulcerative colitis patients and shared complications and treatment of patients with these diseases have been discussed in the present review.

Intestinal metastasis from breast cancer:Presentation,treatment and survival from a systematic literature review

BACKGROUND Intestinal metastases from breast cancer(BC)arerare;available data depend mainly on case reports and case series.AIM To conduct a review of the literature regarding presentation,diagnosis,treatment and survival of patients with intestinal metastasis from BC.METHODS We identified all articles that described patients with intestinal metastasis(from duodenum to anum)from BC using MEDLINE(1975 to 2020)and EMBASE(1975 to 2020)electronic databases.RESULTS We found 96 cases of intestinal metastasis of BC.Metastasization involved large bowel(cecum,colon,sigmoid,rectum)(51%),small bowel(duodenum,jejunum,ileum)(49%),and anum(<1%).Median age of patients was 61-years.The most frequent histology was infiltrating lobular carcinoma followed by infiltrating ductal carcinoma.In more than half of patients,the diagnosis was made after the diagnosis of BC(median:7.2 years)and in many cases of emergency,for bowel obstruction,bleeding or perforation.Diagnosis was achieved through endoscopy,radiological examination or both.In most of the cases,patients underwent surgery with or without systemic therapies.Survival of patients included in this review was available in less than 50%of patients and showed an overall median of 12 mo since diagnosis of the intestinal metastasis.CONCLUSION Although,intestinal metastases of BC are considered a rare condition,clinicians should consider the possibility of intestinal involvement in case of abdominal symptoms even in acute setting and many years after the diagnosis of BC,especially in patients with a histology of lobular carcinoma.

Blood Chemistry, Acid-Base, Electrolyte, Blood Lactate Metabolism and Sleep at 3480 m in Mountain Marathon Runners

Altered blood chemistry, acid-base and electrolyte are suggested determinants of sleep disturbance, with frequent arousal at high altitude even in well and long-trained altitude marathon runners. In this sample of experienced altitude marathon runners with maximal aerobic power at sea level of 61.4 ± 2.7 ml/kg-1·min-1 we found that pO2 and percent of oxygen saturation (%SO2) were lower at2050 mand3480 mthan at sea level;pO2 was higher after 38 - 41 hours than after 30 - 31 hours of acclimatization at3480 m(P 2 decreased (P 2 and (P 2 at a sleeping altitude of3480 mwas lower (P Simple regression analysis disclosed a significant correlation between the changes in TST and the percent of REM sleep and the changes in %SpaO2 recorded during sleep (P 2 at higher altitude and the percent of W and of TST (P 2, tCO2 and [HCO3-] correlated negatively and significantly with the percent of REM sleep changes at high altitude (P 2 and pH and correlated negatively with the changes in %SO2, pCO2, tCO2, and [HCO3-] (P ++] and [BE] and negatively with the changes in buffered bases [BB] and [BEeffective] (P 2 and significantly and negatively with the changes in [K+] (P 2, tCO2, [HCO3-] and [K+]

Real-world evaluation of upfront docetaxel in metastatic castrationsensitive prostate cancer

BACKGROUND The majority of patients with newly diagnosed metastatic prostate cancer(PC)initially respond to androgen deprivation therapy(ADT)and are classified as metastatic castration-sensitive PC(mCSPC).Following months to years of ADT,the disease tends to become resistant to ADT.Recent randomized phase-III trials demonstrated a survival benefit with the addition of upfront docetaxel to ADT in mCSPC.Following its implementation in routine care,this combined treatment strategy requires more detailed evaluation in a real-world setting.AIM To assess the real-world outcome and safety of upfront docetaxel treatment in mCSPC.METHODS A multicenter retrospective cohort study in the Southeast Health Care Region of Sweden was performed.This region includes approximately 1.1 million citizens and the oncology departments of Linköping,Jönköping,and Kalmar.All patients given upfront docetaxel for mCSPC from July 2015 until December 2017 were included.The primary endpoint was progression-free survival(PFS)at 12 mo,and the secondary endpoints were PFS at 24 mo,overall survival(OS),treatment intensity,adverse events,and unplanned hospitalizations.Exploratory analyses on potential prognostic parameters were performed.RESULTS Ninety-four patients were eligible and formed the study cohort.PFS at 12 and 24 mo was 75%(95%CI:66–84)and 58%(46–70),respectively.OS at 12 and 24 mo was 93%(87–99)and 86%(76–96).A total of 91%of patients(n=86)were given docetaxel according to the standard protocol of 75 mg/m2 every 3 wk(6 cycles),while 9%(n=8)received a modified protocol of 50 mg/m2 every 2 wk(9 cycles).The average overall dose intensity for those commencing standard treatment was 91%.Univariate Cox regression analyses show that baseline PSA>180 vs<180 and the presence of distant metastases vs locoregional lymph node metastases were only negative prognostic factors(HR 2.86,95%CI:1.39–5.87,P=0.0041 and 3.36,95%CI:1.03–10.96,P=0.045).Following multivariate analysis,statistical significance remained for PSA(2.51,95%CI:1.21–5.19,P=0.013)but not for metastatic status(2.60,95%CI:0.78–8.65,P=0.12).Febrile neutropenia was recorded in 21%(n=20)of patients,and 26%(n=24)had at least one episode of unplanned hospitalization under and up to 30 d after the treatment course.CONCLUSION Results from this study support the implementation of upfront docetaxel plus ADT as part of the standard of care treatment strategy in mCSPC.