Precision medicine in sepsis and septic shock:From omics to clinical tools

Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes.As it is associated with an increased risk of death,patients with this condition are candidates for receipt of a very well-structured and protocolized treatment.All patients should receive the fundamental pillars of sepsis management,which are infection control,initial resuscitation,and multiorgan support.However,specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms.Herein,we will review the framework for identifying subpopulations of patients with sepsis,septic shock,and multiorgan dysfunction who may benefit from specific therapies.Some of these approaches are still in the early stages of research,while others are already in routine use in clinical practice,but together will help in the effective generation and safe implementation of precision medicine in sepsis.

GOECP/SEOR clinical recommendations for lung cancer radiotherapy during the COVID-19 pandemic

The coronavirus disease 2019 crisis has had a major and highly complex impact on the clinical practice of radiation oncology worldwide.Spain is one of the countries hardest hit by the virus,with devastating consequences.There is an urgent need to share experiences and offer guidance on decision-making with regard to the indications and standards for radiation therapy in the treatment of lung cancer.In the present article,the Oncological Group for the Study of Lung Cancer of the Spanish Society of Radiation Oncology reviews the literature and establishes a series of consensus-based recommendations for the treatment of patients with lung cancer in different clinical scenarios during the present pandemic.

Analysis of tumor-draining vein secretome: A direct access to tumor-derived extracellular vesicles in surgical lung cancer patients

Tumor-secreted extracellular vesicles(EVs)participate in the metastasis process through different mechanisms,including the preparation of the pre-metastatic niche to grant circulating tumor cells(CTCs)implantation and growth.The study of the metastasis process through the analysis of CTCs and tumor-derived EVs is difficult because of the dilution grade of these elements in peripheral blood.In early-stage lung cancer patients,the tumor-secreted products are even more diluted.An attractive strategy in surgical lung cancer patients is to purify them from a pulmonary tumor-draining vein where they are enriched.The information obtained from the analysis of EVs and CTCs purified from this source could give more accurate information about tumor biology and could be an important source of biomarkers to identify patients at high risk of relapse after curative surgery.

Biomaterial engineering strategies for modeling the Bruch's membrane in age-related macular degeneration

Age-related macular degeneration,a multifactorial inflammatory degenerative retinal disease,ranks as the leading cause of blindness in the elderly.Strikingly,there is a scarcity of curative therapies,especially for the atrophic advanced form of age-related macular degeneration,likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier,the prime to rget tissue of age-related macular degeneration.Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier,integrated by the dynamic interaction of the retinal pigment epithelium,the Bruch's membrane,and the underlying choriocapillaris.The Bruch's membrane provides structu ral and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier,and therefo re adequate Bruch's membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrie r.In the last years,advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch's membrane from a variety of materials.This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healt hy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch's membrane biomimetic systems.Then,we discuss novel materials and techniques to fabricate Bruch's membrane-like scaffolds for age-related macular degeneration in vitro modeling,discussing their advantages and challenges with a special focus on the potential of Bruch's membrane-like mimics based on decellularized tissue.

Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease

Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis.These molecules are well tolerated with scarce secondary effects.Very few cases of possible hepatotoxicity due to these substances have been described.The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease.A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology(mean age 59 years,56.9%women)attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results.Twenty-three patients(15.2%)recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire.Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment;one of the cases simultaneously presented a skin rash attributed to the drug.Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate.The clinical spectrum is variable,and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity.The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

Invasive strategy in elderly patients with acute coronary syndrome in 2018: close to the truth?

Elderly population constitutes an increasingly larger proportion of patients admitted for acute coronary syndromes(ACS).The optimal management of ACS in these patients is still a challenge due to their clinical peculiarities and the paucity of specific data,and they have been traditionally managed more conservatively mainly based on subjective criteria.In ST^segment elevation acute myocardial infarction urgent reperfusion is the standard of care and there is no upper age limit.In non-ST segment elevation acute myocardial infarction evidence is controversial,incomplete and mainly focused on chronological age.While a strict conservative strategy should be avoided,routine invasive strategy may reduce the occurrence of myocardial infarction and need for revascularization at follow-up with no established benefit in terms of mortality.Clinical characteristics associated with aging,such as comorbidities and frailty,further discriminate patient's risk beyond age.Evidence is scarce,but it suggests that these features may modulate the benefit of invasive strategy in this population.Ongoing trials should clarify the optimal management of ACS based on these parameters.

Cost-effectiveness of enhanced liver fibrosis test to assess liver fibrosis in chronic hepatitis C virus and alcoholic liver disease patients

AIM To assess liver fibrosis(LF) in hepatitis C virus(HCV) and alcoholic liver disease(ALD), estimate health outcomes and costs of new noninvasive testing strategies METHODS A Markov model was developed to simulate LF progression in HCV and ALD for a cohort of 40-yearold men with abnormal levels of transaminases. Three different testing alternatives were studied: a single liver biopsy; annual Enhanced liver fibrosis(ELF?) followed by liver stiffness measurement(LSM) imaging as a confirmation test if the ELF test is positive; and annual ELF test without LSM. The analysis was performed from the perspective of a university hospital in Spain.Clinical data were obtained from published literature. Costs were sourced from administrative databases of the hospital. Deterministic and probabilistic sensitivity analyses were performed.RESULTS In HCV patients, annual sequential ELF test/LSM and annual ELF test alone prevented respectively 12.9 and 13.3 liver fibrosis-related deaths per 100 persons tested, compared to biopsy. The incremental costeffectiveness ratios(ICERs) were respectively €13400 and €11500 per quality-adjusted life year(QALY). In ALD, fibrosis-related deaths decreased by 11.7 and 22.1 per 100 persons tested respectively with sequential ELF test/LSM and annual ELF test alone. ICERs were €280 and €190 per QALY, respectively.CONCLUSION The use of the ELF test with or without a confirmation LSM are cost-effective options compared to a single liver biopsy for testing liver fibrosis in HCV and ALD patients in Spain.

Pseudomelanosis duodeni associated with chronic renal failure

Pseudomelanosis duodeni (PD) is a rare dark speckled appearance of the duodenum associated with gastrointestinal bleeding,hypertension,chronic heart failure,chronic renal failure and consumption of different drugs.We report four cases of PD associated with chronic renal failure admitted to the gastroenterology outpatient unit due to epigastric pain,nausea,melena and progressive reduction of hemoglobin index.Gastroduodenal endoscopy revealed erosions in the esophagus and stomach,with no active bleeding at the moment.In addition,the duodenal mucosa presented marked signs of melanosis;later confirmed by histopathological study.Even though PD is usually regarded as a benign condition,its pathogenesis and clinical significance is yet to be defined.

Medical management of connector pin thrombosis with the Amplatzer cardiac plug left atrial closure device

Transcatheter closure of the left atrial appendage with the Amplatzer cardiac plug device and double antiplatelet treatment for 3 mo has become an alternative treatment for patients with atrial fibrillation at high embolism risk and contraindications for chronic oral anticoagulation.The inadequate implantation of the left atrial appendage closure device and the discontinuation of double antiplatelet therapy are well-known as factors related to device thrombosis.Nevertheless,device thrombosis after adequate implantation requiring surgical treatment or restarting chronic oral anticoagulation has been reported and can reach 15% of patients.The connector pin thrombosis of the Amplatzer cardiac plug,despite a good adherence to antiplatelet treatment,has been recently described as a potential mechanism for device thrombosis.Our clinical case reports the management of this condition for the first time,showing that the early detection of thrombotic complications by transesophageal echocardiography permits solving this serious complication with medical treatment only.

Gastrotomy closure with a new tissue anchoring device:A porcine survival study

AIM: To evaluate the feasibility, reproducibility and efficacy of a new tissue anchoring device in a porcine survival model. METHODS: Gastrotomies were performed using a needle-knife and balloon dilator in 10 female Yorkshire pigs weighing 30-35 kg. Gastric closure was attempted using a new tissue anchoring device. The tightness of the closure was confirmed by means of air insufflation and the ability to maintain gastric distension with stability in peritoneal pressure measured with a Veress needle. All animals were monitored daily for signs of peritonitis and sepsis over 14 d. During necropsy, the peritoneal cavity and the gastric access site were examined.RESULTS: Transgastric access, closure and 14 d survival was achieved in all pigs. The mean closure time was 18.1 ± 19.2 min and a mean of 2.1 ± 1 devices were used. Supplementary clips were necessary in 2 cases. The closure time was progressively reduced (24.8 ± 13.9 min in the first 5 pigs vs 11.4 ± 5.9 min in the last 5, P = NS). At necropsy, the gastric access site was correctly closed in all cases with all brace-bars present. One device was misplaced in the mesocolon. Minimal adhesions were observed in 3 pigs and signs of mild peritonitis and adhesions in one. CONCLUSIONS: The use of this new tissue anchoring device in porcine stomachs is feasible, reproducible and effective and requires a short learning curve.

Pathological response to neoadjuvant therapy with chemotherapy vs chemoradiotherapy in stage III NSCLC-contribution of IASLC recommendations

BACKGROUND Neoadjuvant treatment(NT)with chemotherapy(Ch)is a standard option for resectable stage III(N2)NSCLC.Several studies have suggested benefits with the addition of radiotherapy(RT)to NT Ch.The International Association for the Study of Lung Cancer(IASLC)published recommendations for the pathological response(PHR)of NSCLC resection specimens after NT.AIM To contribute to the IASLC recommendations showing our results of PHR to NT Ch vs NT chemoradiotherapy(ChRT).METHODS We analyzed 67 consecutive patients with resectable stage III NSCLC with positive mediastinal nodes treated with surgery after NT Ch or NT ChRT between 2013 and 2020.After NT,all patients were evaluated for radiological response(RR)according to Response Evaluation Criteria in Solid Tumours criteria and evaluated for surgery by a specialized group of thoracic surgeons.All histological samples were examined by the same two pathologists.PHR was evaluated by the percentage of viable cells in the tumor and the resected lymph nodes.RESULTS Forty patients underwent NT ChRT and 27 NT Ch.Fifty-six(83.6%)patients underwent surgery(35 ChRT and 21 Ch).The median time from ChRT to surgery was 6 wk(3-19)and 8 wk(3-21)for Ch patients.We observed significant differences in RR,with disease progression in 2.5%and 14.8%of patients with ChRT and Ch,respectively,and partial response in 62.5%ChRT vs 29.6%Ch(P=0.025).In PHR we observed≤10%viable cells in the tumor in 19(54.4%)and 2 cases(9.5%),and in the resected lymph nodes(RLN)30(85.7%)and 7(33.3%)in ChRT and Ch,respectively(P=0.001).Downstaging was greater in the ChRT compared to the Ch group(80%vs 33.3%;P=0.002).In the univariate analysis,NT ChRT had a significant impact on partial RR[odds ratio(OR)12.5;95%confidence interval(CI):1.21-128.61;P=0.034],a decreased risk of persistence of cancer cells in the tumor and RLN and an 87.5%increased probability for achieving downstaging(OR 8;95%CI:2.34-27.32;P=0.001).CONCLUSION We found significant benefits in RR and PHR by adding RT to Ch as NT.A longer follow-up is necessary to assess the impact on clinical outcomes.

Medical consultation in ulcerative colitis:Key elements for improvement

Ulcerative colitis(UC)is a chronic inflammatory disease with a high impact.In order to improve patient outcomes,the clinician-patient relationship in daily practice is critical.Clinical guidelines provide a framework for UC diagnosis and treatment.However,standard procedures and the medical content focused upon medical consultations in UC patients has not yet been defined.Moreover,UC is a complex disease,given that patient characteristics and patient needs have been proven to vary during clinical consultation since establishing the diagnosis and upon the course of the disease.In this article,we have discussed the key elements and specific objectives to consider in medical consultation,such as diagnosis,first visits,follow-up visits,active disease patients,patients on topical therapies,new treatment initiation,refractory patients,extra-intestinal manifestations,as well as challenging situations.The key elements have been mentioned to comprise effective communication techniques,motivational interviewing(MI),as well as information and educational aspects,or organizational issues.The key elements to be implemented in daily practice were reported to comprise several general principles like duly prepared consultations,in addition to honesty and empathy with patients,as well as effective communication techniques,MI,information and educational points,or organizational issues.The role of other healthcare professionals such as specialized nurses,psychologists,or the use of checklists was also discussed and commented on.

Infiltrative xanthogranulomatous cholecystitis mimicking aggressive gallbladder carcinoma: A diagnostic and therapeutic dilemma

Xanthogranulomatous cholecystitis(XGC) is an uncommon variant of chronic cholecystitis. The perioperative findings in aggressive cases may be indistinguishable from those of gallbladder or biliary tract carcinomas. Three patients presented mass lesions that infiltrated the hepatic hilum,provoked biliary dilatation and jaundice,and were indicative of malignancy. Surgical excision was performed following oncological principles and included extirpation of the gallbladder,extrahepatic bile duct,and hilar lymph nodes,as well as partial hepatectomy. Postoperative morbidity was minimal. Surgical pathology demonstrated XGC and absence of malignancy in all three cases. All three patients are alive and well after years of follow-up. XGC may have such an aggressive presentation that carcinoma may only be ruled out on surgical pathology. In such cases,the best option may be radical resection following oncological principles performed by expert surgeons,in order that postoperative complications may be minimized if not avoided altogether.

Management of biliary complications after orthotopic liver transplantation:The role of endoscopy

Biliary complications are signifi cant causes of morbidity and mortality after orthotopic liver transplantation (OLT). The estimated incidence of biliary complications after OLT ranges between 10%-25%,however,these numbers continue to decline due to improvement in surgical techniques. The most common biliary complications are strictures (both anastomotic and non-anastomotic) and bile leaks. Most of these problems can be appropriately managed with endoscopic retrograde colangiography (ERC). Other complications such as bile duct stones,bile casts,sphincter of Oddi dysfunction,and hemobilia,are less frequent and also can be managed with ERC. This article will review the risk factors,diagnosis,and endoscopic management of the most common biliary complications after OLT.

Different profile of cytokine synthesis according to the severity of acute pancreatitis

AIM: To evaluate the cellular synthetic ability of cytokines involved in pro- and anti-inflammatory reactions in patients with AP.METHODS: Sixty-seven patients with AP (16 severe,51 mild) and 10 controls were included in the study.Cultures of whole blood were performed in samples obtained within the first 72 h from the onset of pain.Serum levels of interleukins (IL) 6, 8, 10, and TNF-α were measured at baseline and in the supernatant of cultures with (functional reserve) or without stimulation with phytohemaglutinin.RESULTS: Basal levels of cytokines were significantly higher in patients with severe AP. A significant increase of all pro-inflammatory cytokines vs basal levels was observed in the supernatant after 24 h of whole blood cultures in patients, but not in controls. In contrast, IL-10 increased significantly in the supernatant of cultures only in patients with mild AP. Cells showed a statistically significant functional reserve for all IL in patients with mild, but only for pro-inflammatory cytokines in patients with severe AP.CONCLUSION: A marked activation of immune system may be observed in patients with AP, being balanced between pro- and anti-inflammatory cytokines in patients with mild but not severe AP. A reduced functional reserve for the synthesis of IL-10 may be observed in patients with severe AP, which might lead to a worst prognosis.

Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions

Milan criteria are currently the benchmark related to liver transplantation(LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria(yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of "Metroticket" and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

Inflammatory bowel disease (IBD) includes two entities, Crohn’s disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient’s quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn’s disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn’s disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn’s disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn’s disease patients (AZTEC study).

Effect of transjugular intrahepatic portosystemic shunt on pulmonary gas exchange in patients with portal hypertension and hepatopulmonary syndrome

AIM: To assess the impact of transjugular intrahepatic portosystemic shunt (TIPS) on pulmonary gas exchange and to evaluate the use of TIPS for the treatment of hepatopulmonary syndrome (HPS).METHODS: Seven patients, three of them with advanced HPS, in whom detailed pulmonary function tests were performed before and after TIPS placementat the University of Alabama Hospital and at the Hospital Clinic, Barcelona, were considered.RESULTS: TIPS patency was confirmed by hemodynamic evaluation. No changes in arterial blood gases were observed in the overall subset of patients. Transient arterial oxygenation improvement was observed in only one HPS patient, early after TIPS, but this was not sustained 4 mo later.CONCLUSION: TIPS neither improved nor worsened pulmonary gas exchange in patients with portal hypertension. This data does not support the use of TIPS as a specific treatment for HPS. However, it does reinforce the view that TIPS can be safely performed for the treatment of other complications of portal hypertension in patients with HPS.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation

AIM:To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy.METHODS:Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy.Laparoscopic surgery was planned after 5-8 wk.Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol.Patients with ypT1-2N0 or ypT3-4 or N+were offered 5-fluorouracil-based adjuvant treatment on an individual basis.An external cohort was used as a reference for the findings.RESULTS:One hundred and seventy six patients were treated with induction chemoradiotherapy and 170underwent total mesorectal excision.Cancer staging of ypT0N0 was achieved in 26/170(15.3%)patients.After a median follow-up of 58.3 mo,patients withypT0N0 had five-year disease-free and overall survival rates of 96%(95%CI:77-99)and 100%,respectively.We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation.The inherent good prognosis of these patients will have implications for clinical trial design and care of patients.CONCLUSION:Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

Sustained low diffusing capacity in hepatopulmonary syndrome after liver transplantation

AIM: To study the presence of sustained low diffusing capacity (DLCO) after liver transplantation (LT) in patients with hepatopulmonary syndrome (HPS).METHODS: Six patients with mild-to-severe HPS and 24 without HPS who underwent LT were prospectively followed before and after LT at mid-term (median, 15 mo). HPS patients were also assessed at long-tem (median, 86 mo).RESULTS: Before LT, HPS patients showed lower PaO2 (71 ± 8 mmHg), higher AaPO2 (43 ± 10 mmHg) and lower DLCO (54% ± 9% predicted), due to a combination of moderate-to-severe ventilation-perfusion (VA/Q) imbalance, mild shunt and diffusion limitation, than non-HPS patients (94 ± 4 mmHg and 19 ± 3 mmHg, and 85% ± 3% predicted, respectively) (P < 0.05 each). Seven non-HPS patients had also reduced DLCO (70% ± 4% predicted).At mid- and long-term after LT, compared to pre-LT, HPS patients normalized PaO2 (91 ± 3 mmHg and 87 ± 5 mmHg), AaPO2 (14 ± 3 mmHg and 23 ± 5 mmHg) and all VA/Q descriptors (P < 0.05 each) without changes in DLCO (53% ± 8% and 56% ± 7% predicted, respectively). Post-LT DLCO in non-HPS patients with pre-LT low DLCO was unchanged (75% ± 6% predicted).CONCLUSION: While complete VA/Q resolution in HPS indicates a reversible functional disturbance, sustained low DLCO after LT also present in some non-HPS patients, points to persistence of sub-clinical liver-induced pulmonary vascular changes.