Hepatocyte transplantation program:Lessons learned andfuture strategies

This review aims to share the lessons we learned over time during the setting of the hepatocyte transplantation(HT) program at the Hepatic Cell Therapy Unit at Hospital La Fe in Valencia. New sources of liver tissue for hepatocyte isolation have been explored. The hepatocyte isolation and cryopreservation procedures have been optimized and quality criteria for assessment of functionality of hepatocyte preparations and suitability for HT have been established. The results indicate that:(1) Only highly viable and functional hepatocytes allow to recover those functions lacking in the native liver;(2) Organs with steatosis(≥ 40%) and from elderly donors are declined since low hepatocyte yields, viability and cell survival after cryopreservation, are obtained;(3) Neonatal hepatocytes are cryopreserved without significant loss of viability or function representing high-quality cells to improve human HT;(4) Cryopreservation has the advantage of providing hepatocytes constantly available and of allowing the quality evaluation and suitability for transplantation; and(5) Our results from 5 adults with acute liver failure and 4 from children with inborn metabolic diseases, indicate that HT could be a veryuseful and safe cell therapy, as long as viable and metabolically functional human hepatocytes are used.

Late complications of pancreas transplant

To summarize the long-term complications after pancreas transplantation that affect graft function,a literature search was carried out on the long-term complications of pancreatic transplantation,namely,complications from postoperative 3rd mo onwards,in terms of loss of graft function,late infection and vascular complications as pseudoaneurysms.The most relevant reviews and studies were selected to obtain the current evidence on these topics.The definition of graft failure varies among different studies,so it is difficult to evaluate,a standardized definition is of utmost importance to know the magnitude of the problem in all worldwide series.Chronic rejection is the main cause of long-term graft failure,occurring in 10%of patients.From the 3rd mo of transplantation onwards,the main risk factor for late infections is immunosuppression,and patients have opportunistic infections like:Cytomegalovirus,hepatitis B and C viruses,Epstein-Barr virus and varicella-zoster virus;opportunistic bacteria,reactivation of latent infections as tuberculosis or fungal infections.Complete preoperative studies and serological tests should be made in all recipients to avoid these infections,adding perioperative prophylactic treatments when indicated.Pseudoaneurysm are uncommon,but one of the main causes of late bleeding,which can be fatal.The treatment should be performed with radiological endovascular approaches or open surgery in case of failure.Despite all therapeutic options for the complications mentioned above,transplantectomy is a necessary option in approximately 50%of relaparotomies,especially in lifethreatening complications.Late complications in pancreatic transplantation threatens long-term graft function.An exhaustive follow-up as well as a correct immunosuppression protocol are necessary for prevention.

Percutaneous Ultrasound-Guided Radiofrequency Thermal Ablation for Treatment of Uterine Fibroids

Purpose: To assess the safety, efficacy and effectiveness of percutaneous radiofrequency (RF) thermal ablation to reduce symptoms of uterine fibroids. Materials and Methods: 17 premenopausal women with symptomatic uterine fibroids despite conventional medical treatment were included. The assessment of symptoms and characteristics of fibroids by vaginal ultrasound, magnetic resonance imaging (MRI) and contrast enhanced ultrasound (CEUS) was performed before starting treatment and 6 months after the procedure. Successful treatment was clinically considered if patients reported a reduction in symptoms 6 months after RF myolysis. Successful treatment was also considered if the necrosis of the fibroid was greater than 50%, 6 months after treatment. Results: The baseline score on visual analogue scale (VAS) for dysmenorrhea and intermenstrual pain was 5.76 ± 3.31 and 3.0 ± 3.4, respectively. According to a score of 0 - 3, baseline bleeding during menstruation was 2.29 ± 0.92. Six months after RF myolysis, the VAS for dysmenorrhea was 2.75 ± 3.32 (p = 0.004), whereas for intermenstrual pain it was 1.38 ± 2.56 (p = 0.02). Menstrual bleeding was reduced to 1.13 ± 0.89 (p = 0.005). Clinical success of the treatment was evident in 11 (64.7%) of the 17 patients with a 95% CI [38.6%, 84.7%]. Fourteen patients underwent MRI monitoring 6 months post-myolysis. Compared to baseline fibroid volume, ultrasound and MRI volume were 57.38% and 79.66% six months after surgery, respectively. A total of 13 patients (92.86%) had radiological success from the treatment (95% CI [64.2%, 99.6%]). Conclusion: Since percutaneous RF myolysis reduces volume and symptoms of uterine fibroids, it may be considered as a valid treatment for symptomatic fibroids.

Predictive factors for survival and score application in liver retransplantation for hepatitis C recurrence

AIM: To identify risk factors associated with survival in patients retransplanted for hepatitis C virus(HCV) recurrence and to apply a survival score to this population.METHODS: We retrospectively identified 108 patients retransplanted for HCV recurrence in eight European liver transplantation centers(seven in France, one in Spain). Data collection comprised clinical and laboratory variables, including virological and antiviral treatment data. We then analyzed the factors associated with survival in this population. A recently published score that predicts survival in retransplantation in patients with hepatitis C was applied. Because there are currently no uniform recommendations regarding selection of the best candidates for retransplantation in this setting, we also described the clinical characteristics of 164 patients not retransplanted, with F3, F4, or fibrosing cholestatic hepatitis(FCH) post-first graft presenting with hepatic decompensation. RESULTS: Overall retransplantation patient survival rates were 55%, 47%, and 43% at 3, 5, and 10 years, respectively. Patients who were retransplanted for advanced cirrhosis had survival rates of 59%, 52%, and 49% at 3, 5, and 10 years, while those retransplanted for FCH had survival rates of 34%, 29%, and 11%, respectively. Under multivariate analysis, and adjusting for the center effect and the occurrence of FCH, factors associated with better survival after retransplantation were: negative HCV viremia before retransplantation, antiviral therapy after retransplantation, non-genotype 1, a Model for End-stage Liver Disease(MELD) score < 25 when replaced on the waiting list, and a retransplantation donor age < 60 years. Although the numbers were small, in the context of the new antivirals era, we showed that outcomes in patientswho underwent retransplantation with undetectable HCV viremia did not depend on donor age and MELD score. The Andrés score was applied to 102 patients for whom all score variables were available, producing a mean score of 43.4(SD = 6.6). Survival rates after the date of the first decompensation post-first liver transplantation(LT1) in the liver retransplantation(re LT) group(94 patients decompensated) at 3, 5, and 10 years were 62%, 59%, and 51%, respectively, among 78 retransplanted individuals with advanced cirrhosis, and 42%, 32%, and 16% among 16 retransplanted individuals with FCH. In the non-re LT group with hepatic decompensation, survival rates were 27%, 18%, and 9% at 3, 5, and 10 years, respectively(P < 0.0001). Compared with non-retransplanted patients, retransplanted patients were younger at LT1(mean age 48 ± 8 years compared to 53 ± 9 years in the no re LT group, P < 0.0001), less likely to have human immunodeficiency virus(HIV) co-infection(4% vs 14% among no re LT patients, P = 0.005), more likely to have received corticosteroid bolus therapy after LT1(25% in re LT vs 12% in the no re LT group, P = 0.01), and more likely to have presented with sustained virological response(SVR) after the first transplantation(20% in the re LT group vs 7% in the no re LT group, P = 0.028).CONCLUSION: Antiviral therapy before and after retransplantation had a substantial impact on survival in the context of retransplantation for HCV recurrence, and with the new direct-acting antivirals now available, outcomes should be even better in the future.

Efficacy of Isotonic Seawater Solution on Inflammation of the Ocular Surface in Matrix Metalloproteinase MMP-9-Positive Dry Eye Disease Patients

Purpose: Prospective study to evaluate the anti-inflammatory efficacy of isotonic seawater solution on metalloproteinase 9 (MMP-9) levels in the tears of patients with dry eye disease (DED). Methods: A total of 50 patients were included, with the following dry eye criteria in both eyes: InflammaDry? test initially positive, ocular surface disease index (OSDI) score ≥ 12 and <33, tear film breakup time (TBUT) ≤ 10 seconds, Shirmer I test result ≤ 10 mm/5 minutes, corneal staining ≥ 1. Additionally, all the patients selected corresponded to a dry eye type 2 - 3 severity degree - mild and moderate - Dry Eye Workshop Study (DEWS) classification. The InflammaDry test is used to measure levels of MMP9 at the beginning and the end of the study. All patients were treated exclusively with isotonic seawater solution 5 times a day for 3 weeks. Results: The InflammaDry test was positive in 100% of the patients (n = 50) and in 100% (n = 100) of the eyes before treatment. In 14 (28%) patients the test became negative in both eyes, and in 15 (30%) it was negative in one of the eyes. In 43% (n = 43) of the positive eyes, MMP-9 became undetectable in the tear fluid following treatment with isotonic seawater. This change was statistically significant (p < 0.001). Conclusions: The washes with ophthalmic isotonic seawater solution have a significant impact on inflammation of the ocular surface in dry eye disease, with an ability to make MMP-9 levels negative in 43% of cases.

Rapid Recurrence of Unilateral Endometrioma in a Teenager with a Noncommunicating Rudimentary Horn and Unicornuate Uterus

A 17-year-old nulligravida woman presented to the emergency department complaining of a six months’ history of severe dysmenorrhea. The patient underwent a laparoscopic excision of a right ovarian endometrioma in another hospital one year ago, 24 months after menarche at 14 years of age. Transvaginal ultrasonography, magnetic resonance imaging, hysteroscopy as well as laparo- scopy revealed a unicornuate uterus with a noncommunicating right rudimentary horn, a dilated right fallopian tube and a novel 40 mm right ovarian endometrioma. An excision of the right fallopian tube, the rudimentary horn and the endometrioma was performed. Since endometriosis may be originated by retrograde menstruation, an obstructive müllerian malformation should be ruled out at the diagnosis of endometriosis, particularly in adolescents. It may lead clinicians to provide an initial definitive treatment for avoidingrapid recurrent endometriosis.

Management of Crohn’s disease in smokers:Is an alternative approach necessary?

Inflammatory bowel disease(IBD) is a chronic condition with a pathogenic background that involves both genetic and environmental factors.Although important progress has been made regarding the former in the last decade,scarce knowledge is available for the latter.In this sense,smoking remains the most important environmental factor in IBD.Active smoking increases the risk of developing Crohn's disease(CD).Moreover,CD patients who start or continue smoking after disease diagnosis are at risk for poorer outcomes such as higher therapeutic requirements and disease-related complications,as compared to those patients who quit smoking or who never smoked.However,the harmful effect of active smoking is not uniform in all patients or in all clinical scenarios.Interventions designed to facilitate smoking cessation may impact the course of the disease.In this article,the available evidence of the deleterious effects of smoking on CD is reviewed in detail,and alternative therapeutic approaches to CD in smokers are proposed.

Review of the treatment of liver hydatid cysts

A review was carried out in Medline,LILACS and the Cochrane Library.Our database search strategy included the following terms: "hydatid cyst","liver","management","meta-analysis" and "randomized controlled trial".No language limits were used in the literature search.The latest electronic search date was the 7th of January 2014.Inclusion and exclusion criteria: all relevant studies on the assessment of therapeutic methods for hydatid cysts of the liver were considered for analysis.Information from editorials,letters to publishers,low quality review articles and studies done on animals were excluded from analysis.Additionally,well-structured abstracts from relevant articles were selected and accepted for analysis.Standardized forms were designed for data extraction; two investigators entered the data on patient demographics,methodology,recurrence of HC,mean cyst size and number of cysts per group.Four hundred and fourteen articles were identified using the previously described search strategy.After applying the inclusion and exclusion criteria detailed above,57 articles were selected for final analysis: one meta-analysis,9 randomized clinical trials,5 non-randomized comparative prospective studies,7 non-comparative prospective studies,and 34 retrospective studies(12 comparative and 22 noncomparative).Our results indicate that antihelminthic treatment alone is not the ideal treatment for liver hydatid cysts.More studies in the literature support the effectiveness of radical treatment compared with conservative treatment.Conservative surgery with omentoplasty is effective in preventing postoperative complications.A laparoscopic approach is safe in some situations.Percutaneous drainage with albendazole therapy is a safe and effective alternative treatment for hydatid cysts of the liver.Radical surgery with preand post-operative administration of albendazole is the best treatment option for liver hydatid cysts due to low recurrence and complication rates.

Role of hemostatic powders in the endoscopic management of gastrointestinal bleeding

Acute gastrointestinal bleeding(AGIB) is a prevalent condition with significant influence on healthcare costs. Endoscopy is essential for the management of AGIB with a pivotal role in diagnosis, risk stratification and management. Recently, hemostatic powders have been added to our endoscopic armamentarium to treat gastrointestinal(GI) bleeding. These substances are intended to control active bleeding by delivering a powdered product over the bleeding site that forms a solid matrix with a tamponade function. Local activation of platelet aggregation and coagulation cascade may be also boosted. There are currently three powders commercially available: hemostatic agent TC-325(Hemospray), EndoClotTM polysaccharide hemostatic system, and Ankaferd Bloodstopper. Although the available evidence is based on short series of cases and there is no randomized controlled trial yet, these powders seem to be effective in controlling GI bleeding from a variety of origins with a very favorable side effects profile. They can be used either as a primary therapy or a secondline treatment, and they seem to be especially indi-cated in cases of cancer-related bleeding and lesions with difficult access. In this review, we will comment on the mechanism of action, efficacy, safety and technical challenges of the use of powders in several clinical scenarios and we will try to define the main current indications of use and propose new lines of research in this area.

Stereotactic body radiation therapy:A good dance partner of oligometastatic non-small cell lung cancer to the sound of SINDAS study

The European Organization for Research on Treatment of Cancer Research published a consensus statement to establish the key criteria to define oligometastatic disease(OMD).According to those criteria,all lesions(both primary and metastatic)should be amenable to radical intent treatment with acceptable toxicity.Several retrospective studies have shown that adding local ablative therapy to the treatment of OMD improves outcomes;however,due to the diverse selection criteria and treatment strategies used in those studies,it is difficult to compare directly results to draw definitive conclusions.In recent years,prospective phase II trials,such as the SABR-COMET and"Oligomez"trials,have shown that stereotactic body radiation therapy(SBRT)improves outcomes in patients with OMD.More recently,interim results of the randomised phase 3 SINDAS trial were reported at the annual meeting of the American Society of Clinical Oncology 2020 demonstrating that upfront SBRT added to systemic treatment with tyrosine kinase inhibitors yielded a significant benefit in both progression-free survival and overall survival in patients with epidermal growth factor receptor-mutant oligometastatic non-small cell lung cancer.In the present editorial,we review the definition and historical context of advanced non-small cell lung cancer with OMD.In addition,we review the scientific evidence for local ablative therapy and SBRT and discuss the results of recently published prospective studies.We also discuss in depth the results of the SINDAS study,including the strengths and weaknesses of the study and the barriers to extrapolating these results to routine clinical practice.

Locoregional therapy and systemic cetuximab to treat colorectal liver metastases

AIM: To investigate efficacy and safety of second-line treatment with irinotecan-loaded drug-eluting beads(DEBIRI) and cetuximab(DEBIRITUX) of unresectable colorectal liver metastases.METHODS: Patients with the following characteristics were included in the study: unresectable hepatic metastases from colorectal carcinoma(CRC-LM), progression after first line chemotherapy(any type of chemotherapeutic drug and combination was allowed), second line treatment(mandatory), which included for each patient(unregarding the KRas status) two cycles of DEBIRI(using 100-300 μm beads loaded with irinotecan at a total dose 200 mg) followed by 12 cycles of cetuximab that was administered weekly at a first dose of 400 mg/m2 and then 250 mg/m2; good performance status(0-2) and liver functionality(alanine aminotransferase and gamma-glutamyl transferase not exceeding three times the upper limit of normal, total bilirubin not exceeding 2.5 mg/m L). Data were collected retrospectively and included: tumor response(evaluated monthly for 6 mo then every 3 mo), overall response rate(ORR), KRas status, type and intensity of adverse events(G according to the Common Terminology Criteria for Adverse Events v3.0, CTCAE), overall survival(OS) and progression free survival(PFS).RESULTS: Forty consecutive cases of CRC hepatic metastases were included in the study. Median duration of DEBIRITUX was 4.4 mo(range, 4.0-6.5). Sixteen patients(40%) received the planned 2 cycles of DEBIRI and an average of 10 cetuximab cycles. ORR of the whole sample was 50%, in particular 4 patients were complete responders(10%) and 16(40%) partial responders. The most observed side effects(G2) were: post-embolization syndrome(30%), diarrhea(25%), skin rushes(38%) and asthenia(35%). The retrospective evaluation of KRas status(24 wild type, 16 mutated) showed that the group of patients with wild type KRas had ORR significantly higher than mutant KRas. Median follow-up was 29 mo(8-48 range); median PFS was 9.8 mo and OS was 20.4 mo. Future randomized trials are required in this setting to establish a role for DEBIRITUX compared with systemic chemotherapy.CONCLUSION: DEBIRITUX seems to be efficacious after first line chemotherapy for the treatment of unresectable CRC-LM.

Role of capsule endoscopy in suspected celiac disease: A European multi-centre study

AIM To analyze the diagnostic yield(DY), therapeutic impact(TI) and safety of capsule endoscopy(CE).METHODS This is a multi-centre, observational, analytical, retrospective study. A total of 163 patients with suspicion of celiac disease(CD)(mean age = 46.4 ± 17.3 years, 68.1% women) who underwent CE from 2003 to 2015 were included. Patients were divided into four groups: seronegative CD with atrophy(Group-Ⅰ, n = 19), seropositive CD without atrophy(Group-Ⅱ, n = 39), contraindication to gastroscopy(Group-Ⅲ, n = 6), seronegative CD without atrophy, but with a compatible context(Group-Ⅳ, n = 99). DY, TI and the safety of CE were analysed.RESULTS The overall DY was 54% and the final diagnosis was villous atrophy(n = 65, 39.9%), complicated CD(n = 12, 7.4%) and other enteropathies(n = 11, 6.8%; 8 Crohn's). DY for groups Ⅰ to Ⅳ was 73.7%, 69.2%, 50% and 44.4%, respectively. Atrophy was located in duodenum in 24 cases(36.9%), diffuse in 19(29.2%), jejunal in 11(16.9%), and patchy in 10 cases(15.4%). Factors associated with a greater DY were positive serology(68.3% vs 49.2%, P = 0.034) and older age(P = 0.008). On the other hand, neither sex nor clinical presentation, family background, positive histology or HLA status were associated with DY. CE resultschanged the therapeutic approach in 71.8% of the cases. Atrophy was associated with a greater TI(92.3% vs 45.3%, P < 0.001) and 81.9% of the patients responded to diet. There was one case of capsule retention(0.6%). Agreement between CE findings and subsequent histology was 100% for diagnosing normal/other conditions, 70% for suspected CD and 50% for complicated CD.CONCLUSION CE has a high DY in cases of suspicion of CD and it leads to changes in the clinical course of the disease. CE is safe procedure with a high degree of concordance with histology and it helps in the differential diagnosis of CD.

林奇综合征患者中同时具有不同遗传性肿瘤综合征的种系变异

背景与目的林奇综合征(lynch syndrome,LS)是一种遗传性疾病,LS患者罹患结直肠癌、子宫内膜癌和其他与DNA错配修复基因发生种系突变相关肿瘤的风险较高。LS的传统遗传诊断方法为对与疑似综合征相关的基因进行桑格测序。二代测序技术(next-generation sequencing,NGS)可同时对大量遗传性癌基因进行测序。本研究旨在探究林奇综合征患者中是否存在其他遗传性种系病理癌基因变异。方法我们选取先前已利用桑格测序遗传诊断法确诊的84例LS先证者作为研究对象,通过杂交捕获一组94个商业化的遗传癌基因,随后对这些捕获的样本进行NGS测序。按照美国医学遗传学和基因组学标准,对这些变异的临床意义进行分类。利用桑格测序验证NGS的结果。在可能的情况下,利用桑格测序进一步在先证者的亲属中进行新发现种系变异基因的遗传分析。结果我们从84个家族中鉴定出5(6%)个至少含有2个种系致病变异的家族,这些变异具有高或中等的诱发不同显性癌症的风险,这些家族的种系致病变异如下:[MLH1-BRCA2-NBN]、[MLH1-BRCA1]、[MSH2-ATM]、[MSH6-NF1]和[MLH1-FANCA]。有趣的是,这5个家族中只有1个家族表现出与新的致病变异相关的临床表型。含有3个致病变异基因[MLH1-BRCA2-NBN]的家族显示出LS、乳腺和卵巢癌综合征相关肿瘤的高度聚集特性。结论我们的研究表明,癌症易感基因中,同时发生多个致病变异是LS病例的显著特点。在大部分的病例中,继发性致病变异与临床表型不相关。将来需要进一步验证这些结论并阐明其临床影响。只有表现出复杂的临床表型家族才有必要重新对LS进行分析。

Presacralhydatid Cyst: An Exceptional Presentation

Introduction: Hydatidosis is caused by the larvae of the cestode?Echinococcus granulosus. Liver and lung are the most frequent locations. We report a rare case of a primary hydatid disease location in pre-sacral space. Clinic case: A 64-year-old male patient who consulted due to right gluteal area pain radiating to outer side of the right leg. Physical examination showed a positive Lasègue with hypoesthesia in right L4 L5 S1 territories, with loss of strength in S1. The x-ray showed L3 vertebral wedging and a lumbar lordosis rectification. Laboratory tests and tumor markers were negative. Endorectal ultrasonography described a multilobulatedpresacral cystic tumor. Magnetic resonance imaging (MRI) showed a 16 × 10 × 11 cm retro rectal mass. Due to uncertain diagnosis, surgery was performed, with previous albendazol administration and surgical field protection with 20% hypertonic saline solution. Combined approach (laparotomy + Kraske incision) was realized. Postoperative course was uneventful. The patient remained asymptomatic 36 months after surgery. Summary: Presacralhydatid cysts are rare entities, but must be considered in differential diagnosis of space-occupying lesions in presacral region. Surgery is treatment of choice, and medical treatment may be useful to prevent recurrences.

Neonatal Alloimmune Thrombocytopenia Due to Maternal Anti HPA1a Antibodies: Case Report and Management of Subsequent Pregnancy

Fetoneonatal alloimmune thrombocytopenia is an infrequent and severe disease that is unexpectedly found after an uncomplicated first pregnancy. Affected infants might show unexplained purpura, intracranial hemorrhage, and/or gastrointestinal or genitourinary hemorrhage. Nevertheless, in asymptomatic newborns the thrombocytopenia may be discovered incidentally. We describe a case report that highlights that the incidental diagnosis of FNAIT allows both properly managing the newborn, and detecting maternal anti-HPA1a antibodies in order to prevent the disease in subsequent pregnancies. A non-invasive treatment based on IVIgG allowed to this patient to prevent FNAIT in her second pregnancy.

Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome.Next-generation sequencing(NGS)enables the simultaneous sequencing of a large number of hereditary cancer genes.Here,we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.Methods:A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture.The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants.The findings of NGS were confirmed by Sanger sequencing.When possible,genetic analyses of the new findings in the proband’s relativeswere also performed by Sanger sequencing.Results:We identified five families(6%),out of 84,with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes:[MLH1-BRCA2-NBN],[MLH1-BRCA1],[MSH2-ATM],[MSH6-NF1],and[MLH1-FANCA].Interestingly,only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants.The family with three pathogenic variants of the[MLH1-BRCA2-NBN]genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.Conclusions:Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS.Inmost cases,no clinicial manifestations were associated with the secondary pathogenic variants.Further studies are needed to confirm these findings and elucidate their clinical impact.Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.