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.

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.

Radioembolización en tumores hepáticos / Radioembolization in liver tumours

La enfermedad hepática tumoral es cada vez más frecuente. Su peculiar forma de irrigación, predominantemente arterial, a diferencia del resto del hígado con flujo fundamentalmente por vía portal, hace a los tumores susceptibles de terapias intraarteriales. La TARE o «transarterial radioembolization» ha irrumpido con fuerza como tratamiento de tumores hepáticos de diferentes tipos. Significativas mejoras en el procedimiento a lo largo del tiempo han hecho de la TARE un procedimiento cada vez más seguro y eficaz. Además, su naturaleza multidisciplinar y la complejidad en su ejecución hacen de esta técnica un reto para todos los especialistas implicados. Una adecuada selección de los pacientes y una correcta planificación del tratamiento son necesarios para conseguir un beneficio óptimo, reduciendo además las complicaciones. Utilizada hasta ahora en el carcinoma hepatocelular y en las metástasis hepáticas del cáncer colorrectal, sus indicaciones están actualmente en proceso de expansión como tratamiento único o combinado con otros tratamientos

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

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.

Severe maculopapular exanthema induced by regorafenib: successful desensitization and adaptation of a dosage regimen

No disponible

Tratamiento de úlceras infectadas de pie diabético. Efectividad clínica de un apósito de fibra de alginato e hidrocoloide, con plata. Análisis de resultados de una serie de casos / 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

Introducción. Niveles altos de carga bacteriana han demostrado una influencia negativa en la cicatrización de las úlceras. El uso de apósitos antimicrobianos con plata puede controlar el nivel de carga bacteriana de las heridas. El objetivo de este estudio fue evaluar la respuesta terapéutica de un apósito de fibra de alginato e hidrocoloide, con plata, en úlceras infectadas de pie diabético. Material y métodos. Se analizó una serie de casos de 6 pacientes con úlceras de pie diabético, sin enfermedad vascular periférica y diagnosticadas de colonización crítica y/o infección local mediante la recogida de signos clínicos inflamatorios. Los pacientes fueron tratados durante un período mínimo de 2 semanas. Se analizó el porcentaje de reducción del área de la úlcera desde el día de la inclusión hasta la retirada del apósito antimicrobiano. Resultados. El tratamiento tuvo una mediana de 5 semanas con una duración mínima de 2 y máxima de 6. La mediana del porcentaje de reducción de la superficie de las heridas fue de 47,7% (rango: 0,5%-90%). La media del porcentaje de reducción de la lesión a las 2 semanas fue del 58% y a la tercera semana del 67,14%. Todos los pacientes habían disminuido sus dimensiones a las 3 semanas de tratamiento de forma significativa (p<0,05). Conclusión. El uso de un apósito de fibra de alginato e hidrocoloide, con plata, favorece la cicatrización de las úlceras de pie diabético con infección local, reduciendo los signos clínicos inflamatorios de forma significativa en un período de 3 semanas (AU)

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 (AU)

[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.

Immunohistochemical expression of cyclooxygenase-2 in patients with advanced cancer of the larynx who have undergone induction chemotherapy with the intention of preserving phonation

INTRODUCTION: Cyclooxygenase-2 (COX2) is an enzyme that plays a role in different stages of the carcinogenic process and has prognostic and predictive values that have not yet been established. The objective of this study was to evaluate the role of COX2 overexpression in advanced squamous cell carcinoma of the larynx that has been treated with a phonation conservation protocol. MATERIALS AND METHODS: This study included a retrospective analysis of 59 patients with resectable tumours that were treated with chemotherapy (CT) and/or radiation therapy (RT). The expression levels of COX2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor (VEGFR-2) in collected biopsy specimens were determined via immunohistochemistry. RESULTS: Forty-four percent of the included samples demonstrated overexpression of COX2. In the statistical analysis, COX2 overexpression did not correlate with other clinical or treatment efficacy prognostic factors; however, the median global survival (OS) of patients whose tumours expressed COX2 was 79 months, whereas COX2-negative patients had a median OS of only 38 months, although this finding did not reach statistical significance. The other analysed biological parameters did not demonstrate a significant relationship with COX2. CONCLUSIONS: COX2 overexpression was a common finding in our study. The results obtained did not reveal relationships with established prognostic categories; however, the difference in survival between patients with and without COX2 expression justifies the need for future prospective studies that utilise a larger patient sample size (AU)

Immunohistochemical expression of cyclooxygenase-2 in patients with advanced cancer of the larynx who have undergone induction chemotherapy with the intention of preserving phonation.

INTRODUCTION: Cyclooxygenase-2 (COX2) is an enzyme that plays a role in different stages of the carcinogenic process and has prognostic and predictive values that have not yet been established. The objective of this study was to evaluate the role of COX2 overexpression in advanced squamous cell carcinoma of the larynx that has been treated with a phonation conservation protocol. MATERIALS AND METHODS: This study included a retrospective analysis of 59 patients with resectable tumours that were treated with chemotherapy (CT) and/or radiation therapy (RT). The expression levels of COX2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor (VEGFR-2) in collected biopsy specimens were determined via immunohistochemistry. RESULTS: Forty-four percent of the included samples demonstrated overexpression of COX2. In the statistical analysis, COX2 overexpression did not correlate with other clinical or treatment efficacy prognostic factors; however, the median global survival (OS) of patients whose tumours expressed COX2 was 79 months, whereas COX2-negative patients had a median OS of only 38 months, although this finding did not reach statistical significance. The other analysed biological parameters did not demonstrate a significant relationship with COX2. CONCLUSIONS: COX2 overexpression was a common finding in our study. The results obtained did not reveal relationships with established prognostic categories; however, the difference in survival between patients with and without COX2 expression justifies the need for future prospective studies that utilise a larger patient sample size.

Update on the diagnosis of cancer of unknown primary (CUP) origin

The cancer of unknown primary (CUP) concept encompasses a heterogeneous group of cancers that are difficult to diagnose and that show diverse clinical and histopathological features. Currently, CUP is the fifth most frequent cancer diagnosis in women and the eighth in men. The ongoing development of new therapies specific to the various cancer types makes mandatory the identification of the primary tumour in CUP patients, so that they may benefit from advances in therapy and improvements in prognosis. Molecular detection techniques provide very useful tools in the prediction of primary tumour types and must be used together with clinical, histopathological and IHC diagnostic techniques. Steady collaboration and fluid communication between oncologists and pathologists is of the utmost importance for the correct interpretation of tests and the personalised approach required by each individual case. Work in multidisciplinary teams will result in significant changes in the diagnosis and treatment of these patients (AU)

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.

Increased transcutaneous oxygen tension in the skin dorsum over the foot in patients with diabetic foot disease in response to the topical use of an emulsion of hyperoxygenated Fatty acids.

The aim of this study was to examine changes in the skin over the feet of patients with diabetic foot syndrome after local application of a product containing hyperoxygenated fatty acids (HOFAs) by measuring transcutaneous oxygen. In 64 patients, transcutaneous oxygen pressure (TcPo(2)) was measured on days 0, 7, 30, 60, and 90 of the study. Foot skin dryness, shedding, and skin color were also assessed using a clinical score. The patients were grouped on the basis of initial levels of transcutaneous oxygen; group 1 comprised patients with TcPo( 2) >30 mm Hg and group 2 comprised patients with TcPo(2) <30 mm Hg on the skin over the dorsum of the feet. Increases in local oxygenation values were observed at a local level in group 2 patients after 30 days of treatment. Skin trophism showed clinical improvement in all patients and these observations may be attributed to improved local microcirculation.

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.

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.

Increased intrahepatic and circulating levels of endoglin, a TGF-beta1 co-receptor, in patients with chronic hepatitis C virus infection: relationship to histological and serum markers of hepatic fibrosis.

Endoglin, a transforming growth factor (TGF)-beta1 co-receptor, has been associated with renal and cutaneous fibrosis, as overexpression of this protein has been observed in biopsies from patients with glomerulosclerosis and scleroderma, respectively. Our aim was to evaluate whether endoglin may be associated with hepatic fibrosis featuring chronic hepatitis C virus (HCV) infection. Fifty-two anti-HCV+ patients, five anti-HCV- patients and 27 healthy subjects were studied. Western blot and immunohistochemistry were used to quantify the expression levels of endoglin and TGF-beta1 in liver biopsy samples, and serum concentrations of endoglin and hyaluronic acid were determined by enzyme-linked immunosorbent assays (ELISAs). In patients with advanced fibrosis, intrahepatic expression levels of endoglin and TGF-beta1 were significantly higher than those in patients with early fibrosis (mean: 3- and 5.8-fold, respectively) and normal liver (mean: 3.9- and 12-fold, respectively). Interestingly, activated hepatic stellate cells as well as portal and septal myofibroblasts expressed endoglin. Serum levels of endoglin were also significantly higher in patients with advanced fibrosis than in those with early fibrosis (55.5 +/- 1.6 vs 47.5 +/- 0.9 ng/mL, P < 0.001), showing a positive correlation with serum hyaluronic acid concentrations (r = 0.57, P = 0.01). In conclusion, increased intrahepatic endoglin and TGF-beta1 expression is significantly associated with progressive hepatic fibrosis in chronic HCV infection. Circulating endoglin levels are elevated in HCV patients showing a significant correlation with histological and serum markers of hepatic fibrosis. These data suggest an active role for endoglin in the fibrotic process featuring chronic HCV infection.