Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Uric acid and acute kidney injury in high-risk patients for developing acute kidney injury undergoing cardiac surgery: A prospective multicenter study.

PURPOSE: It is unclear whether preoperative serum uric acid (SUA) elevation may play a role in the development of acute kidney injury (AKI) associated with cardiac surgery (CSA-AKI). We conducted a cohort study to evaluate the influence of preoperative hyperuricemia on AKI in patients at high risk for developing SC-AKI. DESIGN: Multicenter prospective international cohort study. SETTING: Fourteen university hospitals in Spain and the United Kingdom. PARTICIPANTS: We studied 261 consecutive patients at high risk of developing CSA-AKI, according to a Cleveland score ≥ 4 points, from July to December 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: AKIN criteria were used for the definition of AKI. Multivariable logistic regression models and propensity score-matched pairwise analysis were used to determine the adjusted association between preoperative hyperuricemia (≥7 mg/dL) and AKI. Elevated preoperative AUS (≥7 mg/dL) was present in 190 patients (72.8%), whereas CSA-AKI occurred in 145 patients (55.5%). In multivariable logistic regression models, hyperuricemia was not associated with a significantly increased risk of AKI (adjusted Odds Ratio [OR]: 1.58; 95% confidence interval [CI]: 0.81-3; P = .17). In propensity score-matched analysis of 140 patients, the hyperuricemia group experienced similar adjusted odds of AKI (OR 1.05, 95%CI 0.93-1.19, P = .37). CONCLUSIONS: Hyperuricemia was not associated with an increased risk of AKI in this cohort of patients undergoing cardiac surgery at high risk of developing CSA-AKI.

Retinal degeneration characterizes a spinocerebellar ataxia mapping to chromosome 3p.

A heterogeneous group of neurological disorders known as the spinocerebellar ataxias (SCA) are characterized by degeneration of the cerebellum, spinal cord and brainstem. We describe linkage analysis in four unusual SCA families revealing a distinct disease locus on chromosome 3p14-21.1. The disease in these families is distinguished from other forms of SCA by concomitant retinal degeneration. Initial visual problems leading to blindness, disabling ataxia and anticipation are seen in all kindreds. The anticipation in these families suggests a dynamic mutation at this locus. Eventual molecular characterization of this disease may provide valuable insights into the processes of both neural and retinal degeneration.

[Treatment of infected diabetic foot ulcers clinical effectiveness of a dressing of alginate and hydrocolloid, with silver fiber. Analysis of results of a series of cases]. / Tratamiento de úlceras infectadas de pie diabético.

INTRODUCTION: High levels of bacterial load have shown a deleterious influence on wound healing. Using antimicrobial dressings can control ulcers' bioburden. The aim of our study was to evaluate the improving of infected diabetic foot ulcers due an alginate's fiber and hydrocolloid silver dressing. MATERIAL AND METHODS: We analysed a case series of 6 patients with diabetic foot ulcers without peripheral vascular disease and diagnosed from critical colonization and/or local infection according the presence of inflammation clinical signs. Patients were treated for a minimum period of two weeks. We analysed the percentage reduction in ulcer area from the day of enrolment to antimicrobial dressing removal. RESULTS: The duration of treatment had a median of 5 weeks with a minimum of 2 weeks and up to 6. The median percentage of area reduction of the wounds was 47.7% (range: 0.5%-90%). The mean percentage reduction on the lesion was 58% from 2 weeks and 67.14% at 3 weeks. All patients had reduced significantly their size at 3 weeks from beginning of treatment (p < 0.05). CONCLUSION: The use of an alginate's fiber and hydrocolloid silver dressing promotes healing on diabetic foot ulcers with local infection, reducing the inflammatory clinical signs significantly over a period of three weeks.

Inter-observer reproducibility of probing to bone in the diagnosis of diabetic foot osteomyelitis.

AIMS: The objectives of our study were (i) to analyse the inter-observer reproducibility or diagnostic variability of the probing-to-bone test, depending on the training of the professional involved, and (ii) to assess whether the probing-to-bone test can be extrapolated to any professional specialty that deals with these patients. METHODS: This was a cross-sectional study, involving 75 patients with diabetic foot ulcer and clinical suspicion of osteomyelitis. A registration sheet was completed for all patients involved in the research study, gathering data relative to the results of the probing-to-bone test performed by three observers. Observer 1 was a very experienced professional with several years of experience in the treatment of the diabetic foot; observer 2 was a medium-experienced professional whose experience ranges from 6 to 12 months in the treatment of the diabetic foot; observer 3 was a healthcare professional without experience in the treatment of the diabetic foot. Data were gathered confidentially by a fourth researcher. RESULTS: The results showed a kappa index of 0.593 (95% CI 0.407-0.778) between observer 1 and observer 2, 0.397 (95% CI 0.188-0.604) between observer 1 and observer 3 and 0.53 (95% CI 0.335-0.725) between observer 2 and observer 3. CONCLUSIONS: The probing-to-bone test demonstrated moderate to fair concordance with an experienced examiner, although the degree of concordance is not significant between groups.

Evaluation of Plasma Disappearance Rate Indocyanine Green Clearance as a Predictor of Liver Graft Rejection in Donor Brain Death.

INTRODUCTION: There currently exist no quantitative methods to assess graft viability before the donor procurement procedure. In Europe, around 20% of liver grafts evaluated "in situ" by an experienced surgeon are discarded. The aim of this study is to evaluate the use of the plasma disappearance rate indocyanine green (PDR-ICG) clearance in predicting liver graft rejection to avoid this 20% of futile surgeries. OBJECTIVES: To evaluate PDR-ICG as a predictor of liver graft rejection in death brain donors compared with the gold standard evaluation by an experienced surgeon. MATERIAL AND METHODS: Prospective observational single center study. From March 2017 to July 2019, 29 donors were included in the study, 17 were men and 12 women with a median age of 68 years ± 16.9 years. Donors had an intensive care unit stay of 2 days ± 4 days. PDR-ICG was measured with PICCO2 monitor. Indocyanine green clearance dose was 0.25 mg/kg injected intravenously in the operating room just before donor procurement procedure is initiated. The surgeon was unaware of the PDR-ICG measure until the decision of graft acceptance was taken. Data regarding the donors and biopsy results were included in a prospective database. RESULTS: PDR-ICG measure could be obtained in 10 minutes in all of the cases included. The median PDR-ICG obtained was 18%/min (range, 2.4-31%/min). Graft rejection took place in 15 out of the 29 donors. PDR-ICG value was less than 10%/min in 6 of these rejected grafts and less than 15%/min in 10 donors. All donor grafts with PDR-ICG <15% were discarded. The graft had been discarded in 5 donors with a PDR-ICG >15%. CONCLUSIONS: In our study a plasma disappearance rate <10 would have identified the grafts that would be rejected, thus avoiding the displacement work and expense of the surgical team. These results should be confirmed in a multicentric study.

Radioembolization in liver tumours. / Radioembolización en tumores hepáticos.

The detection of malignant liver tumours is recently increasing. These lesions have frequently arterial vascularization which differs from healthy parenchyma with main portal flow making them especially susceptible to transarterial therapies. Transarterial Radioembolization (TARE) is an emerging treatment for the management of different liver tumours. Significant improvements in the procedure have been made so it is considered a safe and effective treatment. A multidisciplinary approach is necessary because of the complexity of the procedure. An optimal selection of the patients and good planning arteriography are essential to obtain benefit and reduce complication rate. Although TARE has been used mostly in hepatocellular carcinoma and liver metastases, indications are currently in expansion as the only treatment or in combination.

Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis.

BACKGROUND: Hepatic venous pressure gradient (HVPG) has prognostic value in complications and survival of patients with liver cirrhosis. However, the relationship between HVPG and the outcome of acute alcoholic hepatitis (AAH), as well as the specific features of portal hypertension syndrome in this setting, have not been defined. AIMS: To evaluate the prognostic value of HVPG and to analyse the degree of portal hypertension and hyperdynamic circulation in patients with severe AAH. METHODS: Early measurements of HVPG were performed in 60 patients with severe AAH, and compared with the haemodynamic findings of 37 and 29 liver transplantation candidates with alcoholic or viral end-stage cirrhosis respectively. RESULTS: Twenty-three patients (38%) died during hospitalization. Portal hypertension and hyperdynamic circulation were more severe in AAH patients. HVPG was greater in non-survivors [26.9 (7.4) vs. 19.4 (5.2) mmHg, P < 0.001]. Only 4/31 (13%) patients with HVPG 22 (P < 0.001). Encephalopathy (OR 9.4; CI 1.4-64.8), Model for End-Stage Liver Disease (MELD) score > 25 (OR 7.4; CI 1.4-39.9) and HVPG > 22 mmHg (OR 6.7; CI 1.1-39.9) were independently associated to in-hospital mortality. CONCLUSIONS: Early measurement of HVPG provides important prognostic information on the short-term outcome of patients with severe AAH. In addition, MELD score also seems to be a strong prognostic factor in these patients.

Stage- and tissue-expression of genes involved in the biosynthesis and signalling of ethylene in reproductive organs of damson plum (Prunus domestica L. subsp. insititia).

In this work, four cDNA clones (Pd-ACS1,AJ890088; Pd-ETR1 and Pd-ERS1, AJ890092, AJ890091; and Pd-CTR1, AJ890089) encoding an ACC-synthase, two putative ethylene (ET) receptors, and a putative MAPKKK, respectively, were isolated and phylogenetically characterized in Prunus domestica L. subsp. insititia. Their expression was studied by real-time PCR during flower (closed, open and senescent) and fruit (early green, late green, maturation and ripening) development of damson plum, which is climateric. While two peaks of ET production were quantified at early green and ripening stages in whole fruits, the seed was not able to produce it during maturation and ripening stages. All studied genes were differentially expressed during flower and fruit development. In general, the level of transcripts of Pd-ACS1 was higher in fruits than in flowers. However, it was noteworthy that: (1) Pd-ACS1 expression was hardly detected in closed flowers and at low levels during early green stage; and fruit development provoked a notable differential expression in seeds, and pericarp; (2) the results of Pd-ACS1 expression during fruit development suggest a preponderant role of this gene from late green stage onward. The stamen was the only floral organ in which expression of both Pd-ETR1 and Pd-ERS1 receptor genes was not significantly altered during development; however, their expression decreased concomitantly with development of pistil (only floral organ to register a net ET production when fertilized) and during first days of ovary development (the highest ET production during all fruit development). Contrary to Pd-ERS1, the level of Pd-ETR1 mRNA was temporally quite similar in the seed. With regard Pd-ETR1, even its expression was very scarce during maturation of mesocarp, was stimulated during ripening. In the epicarp, Pd-ERS1 and Pd-ETR1 were low expressed during pit hardening increasing onward and decreasing during ripening. Pd-CTR1 expression was in the seed>mesocarp>>epicarp. Spatial and temporal levels of Pd-ACS1, Pd-ETR1, Pd-ERS1 and Pd-CTR1 mRNAs described in this work demonstrate that the expression of these genes is not always constitutive and that control of its transcription may play an important role in regulating the development of reproductive organs of damson plum.

[Clinical heterogeneity and distinct outcomes in hepatic epithelioid hemangioendothelioma]. / Heterogeneidad clínica y evolutiva del hemangioendotelioma epitelioide hepático.

Epithelioid hemangioendothelioma is an infrequent mesenchymal tumor of unknown etiology and variable clinical symptoms. It usually affects black, middle-aged women. The most frequent symptoms are right hypochondrium pain, abdominal discomfort and constitutional syndrome with progressive liver damage. Diagnosis is difficult and detailed pathological analysis is required. Controlled clinical studies are lacking and there are no factors that predict the clinical course or serve as a guide to the most effective treatment. We report 3 cases with distinct clinical course ranging from clinical stability to dissemination and death. Treatment differed in the three patients.

Yolk sac tumors with pure and mixed polyvesicular vitelline patterns.

Four cases of polyvesicular vitelline tumor are presented; two were of a previously unreported pure type, and the other two were mixed with endodermal sinus tumor. The morphologic features of the vesicles favor an endodermal origin, as originally proposed by Teilum. Marked specialization of the vesicular lining cells, seen ultrastructurally, suggests a differentiation toward gut structures and mature yolk sac. One case of pure polyvesicular vitelline tumor showed massive erythropoiesis. We propose that the pure tumor reflects an intermediate degree of differentiation within the selectively endodermal yolk sac tumor group, that is, a further stage of organization than the endodermal sinus tumor. In our cases of pure polyvesicular vitelline tumor, the marked degree of differentiaiton was correlated with an improved prognosis, as in the case of the possible homologue of this tumor, the yolk sac tumor of the infant testis. In contrast, the two cases of the tumor admixed with endodermal sinus tumor illustrated the low survival rate expected in the pure endodermal sinus tumor; in these cases the metastases had no polyvesicular component. Because of the significance of such a difference in prognosis we emphasize the importance of an accurate diagnosis, suggesting that a large number of sections be taken in order to demonstrate any endodermal sinus tumor component that may be present, and that the possibility of pure polyvesicular vitelline tumor always be considered in the differential diagnosis of multicystic ovarian tumors.

Leiomyomatosis peritonealis disseminata. An ultrastructural study.

Electron microscopic features of the eighth documented case of leiomyomatosis peritonealis disseminata identify the main proliferative cell type as a mature leiomyocyte with all its associated ultrastructural features. The histogenesis of this neoplasm is considered to be a multicentric metaplastic change determined by an abnormal tissue response to the elevated hormonal levels occurring in pregnancy or ovarian functioning tumors. It is suggested that the cell of origin is the multipotent subcelomic mesenchymal cell, which retains the capacity to differentiate into several tissues, among them smooth muscle. To illustrate this possibility, myofibroblasts, cells with hybrid characters of fibroblasts and leiomyocytes, were observed; these may represent a transitional stage between the mesenchymal cell and the smooth muscle proliferating cell.

Prognostic factors in bladder cancer. A pathologic, immunohistochemical, and DNA flow-cytometric study.

Pathologic grade and stage, immunohistochemical analysis of eight cell and tumor markers, and DNA ploidy were studied in 36 cases of bladder cancer to determine the features of value in assessment of patients' survival. Tumors of high grade and advanced stage correlated with DNA aneuploidy, whereas low grade and early stage correlated with DNA diploidy when simultaneously evaluated with survival. In addition, blood group isoantigen A correlated with DNA ploidy in deceased patients, whereas blood group isoantigen H and oncogene-related protein p21 correlated with DNA ploidy in surviving patients. Despite the relatively small number of cases studied, these results suggest that pathologic grade and stage and immunohistochemical analysis of blood group isoantigens A and H and oncogene-related protein p21 hold additional value in the prediction of bladder cancer survival when evaluated simultaneously with DNA ploidy.

A light and electron microscopic study of the liver in case of erythrohepatic protoporphyria and in griseofulvin-induced porphyria in mice.

The light- and electron-microscopic appearances of a liver biopsy from a case of erythrohepatic protoporphyria are compared with the appearances of the liver in griseofulvin-induced porphyria in mice. Crystals are present in hepatocytes and in the bile secretory pathways in each case. The nature and significance of these is discussed.

A critique and case study of nodular sclerosing Hodgkin's disease.

This paper presents a critique of the present concepts of the pathology of nodular sclerosing Hodgkin's disease and particularly of the criteria required for diagnosis for the condition and its separation from other types of Hodgkin's disease. In addition, the natural history and histopathology of the condition have been studied among 104 cases of Hodgkin's disease presenting at The London Hospital, and the significance of the appearance is discussed.

Involvement of calcium in ACC-oxidase activity from Cicer arietinum seed embryonic axes.

Both in vivo and in vitro ACC-oxidase activities as well as ethylene production from embryonic axes of chickpea seeds were strongly inhibited by EGTA, a selective extracellular Ca2+ ion chelator, indicating that the influx of Ca2+ is important for enzymatic activity. EGTA inhibition was restored by exogenous Ca2+. Treatments of embryonic axes with either Verapamil and LaCl3 (both Ca2+ channel blockers) or TMB-8 (an intracellular Ca2+ antagonist) provoked an inhibition of both ACC-oxidase activity and ethylene production. These results suggest an involvement of calcium fluxes and intracellular calcium levels in the activity of the last step of the ethylene biosynthetic pathway, which is, in turn, intimately correlated with germination of Cicer arietinum seeds.

cis-Dichloro(alpha,omega-diamino carboxylate ethyl ester)palladium(II) as Palladium(II) versus Platinum(II) Model Anticancer Drugs: Synthesis, Solution Equilibria of Their Aqua, Hydroxo, and/or Chloro Species, and in Vitro/in Vivo DNA-Binding Properties.

cis-Dichloro(d,l-2,3-diaminopropionate ethyl ester)palladium(II), cis-[Pd(Etdap)Cl(2)] (I), and cis-dichloro(d,l-2,4-diaminobutyrate ethyl ester)palladium(II), cis-[Pd(Etdab)Cl(2)] (II), were synthesized and characterized by elemental analysis, IR spectroscopy, and TG-DTA thermal analysis. The equilibrium model and log beta(pqr) constants of hydrolytic species of I and II were also investigated by potentiometric methods (I = 0.15 M (NaClO(4)) and 37 degrees C). Aqueous solutions of cis-[Pd(Etdaa)(H(2)O)(2)](ClO(4))(2) (Etdaa = Etdap (III) or Etdab (IV)) were prepared by stoichiometric reaction of I or II with AgClO(4). Thus, log beta(pqr) of the corresponding cis-aquahydroxo (pqr = 1,0,-1) and di(&mgr;-hydroxo) (pqr = 2,0,-2) species were obtained from E(H(+)) data of alkalimetric titrations of solutions of III or IV. Such constants were then used as fixed values to obtain log beta(pqr)() of chloro-containing species (cis-dichloro (1,2,0), cis-chloroaqua (1,1,0), and cis-chlorohydroxo (1,1,-1)) from E(H(+)) and E(Cl(-)) data pairs simultaneously obtained by titration of solutions of III or IV with NaOH and NaCl. All log beta(pqr) were fitted by the SUPERQUAD program. Appropriate log beta(pqr)() sets give good simulations of experimental titration curves and several species distribution diagrams. In addition the interaction of I and/or II with DNA in vitro and in vivo was studied by various methods. UV spectral data and melting and renaturation curves indicate that both compounds destabilize the DNA helicoidal structure. Compound II disrupts in vivo the structure and transcription process of polytene chromosomes of Drosophila hydei.

cis-dichloro-palladium(II) complexes with diaminosuccinic acid and its diethyl ester: synthesis, molecular structure, and preliminary DNA-binding and antitumor studies.

The reactions of K2PdCl4 with meso-diaminosuccinic acid (H2dasa) in 0.1 M HCl or its diethyl ester dihydrochloride Et2dasa.2HCl in neutralized aqueous solution yield cis-[Pd(H2dasa)Cl2](I) and cis-[Pd(Et2dasa)Cl2](II), respectively. These products were characterized by elemental analysis, IR spectroscopy, and TG-DTA thermal analysis. The crystal of II is monoclinic, space group C2/c (a = 14.292(5), b = 14.636(5), c = 13.435(5) A, beta = 98.08(2) degrees, Z = 8, R = 0.041 and wR = 0.06). The Pd(II) atom exhibits a roughly square planar coordination with two Pd-N bonds (Et2dasa) (2.014(2) and 2.049(7) A) and two cis-imposed Pd-Cl bonds (2.294(2) and 2.303(2) A). Compound I reacts with 2,2'-bipyridine in neutral aqueous solution to give [Pd(2,2'-bipy)(dasa)].3H2O(III) in a process of cis-chloride substitution by 2,2'-bipy as a model N-heterocyclic chelating entity. The molecular and crystal structure of III is also reported. It was observed that both cis-dichloro-Pd(II) complexes having Pd(H2dasa) (acidic) and Pd-(Et2dasa)(esterified) chelate entities induce conformational changes in the covalent closed circular (ccc) form of pUC8 plasmid. Both compounds were assayed for antitumor activity in vitro against MDA-MB 468 and HL-60 human cancer cell lines. The results show that compounds I and II have values of ID50 lower than those of K2PdCl4, and also lower than those of diaminoacid ligands (meso-diaminosuccinic acid and meso-diaminosuccinate diethyl ester). Thus it is likely that the imposed cis-coordination of the chelating H2dasa or Et2dasa to the Pd(II) center increases the biological activity of these palladium(II) complexes.