Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

New aspects of diagnosis and therapy of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the major cancer killers. It affects patients with chronic liver disease who have established cirrhosis, and currently is the most frequent cause of death in these patients. The main risk factors for its development are hepatitis B and C virus infection, alcoholism and aflatoxin intake. If acquistion of risk factors is not prevented and cirrhosis is established, the sole option to improve survival is to detect the tumor at an early stage when effective therapy may be indicated. Early detection plans should be based on hepatic ultrasonography every 6 months, whereas determination of tumor markers is not efficient. Upon detection of a hepatic nodule, there is a need to establish unequivocal diagnosis, either through biopsy or through the application of non-invasive criteria based on the specific radiology appearance of the tumor: fast arterial uptake of contrast followed by venous washout. Effective treatment for liver cancer includes surgical resection, liver transplantation and percutaneous ablation. These options provide a high rate of complete responses and are assumed to improve survival that should exceed 50% at 5 years. If the tumor is diagnosed at an advanced stage, the sole option that improves survival is transarterial chemoembolization. Ongoing research should further advance the time at diagnosis and identify new and effective options targeting molecular pathways governing tumor progression.

Early detection of cancer: ideas for a debate.

Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

Systematic review: evidence-based management of hepatocellular carcinoma--an updated analysis of randomized controlled trials.

The treatment strategy of hepatocellular carcinoma applied following scientific guidelines is only supported by 77 randomized controlled trials published so far, a figure that clearly pinpoints hepatocellular carcinoma as an 'orphan' cancer in terms of clinical research when compared with other high-prevalent cancers worldwide. A systematic review analysing 61 randomized controlled trials (1978-2002) showed a modest survival benefit from chemoembolization in patients with intermediate tumours, and the lack of an effective first-line treatment option for patients with advanced disease. These conclusions have been endorsed by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. The present updated evidence-based approach includes 16 randomized controlled trials published from 2002 to 2005 assessing percutaneous ablation (seven), other loco-regional therapies (three) and systemic therapies (six). Eight showed high-quality methodological profiles. Four randomized controlled trials demonstrated a better local hepatocellular carcinoma control in tumours larger than 2 cm treated by radiofrequency ablation compared with ethanol injection. No survival advantages were obtained from systemic treatments in patients with advanced hepatocellular carcinoma, an area that is an unmet need. Therefore, there is an urgent request to conduct well-designed phase III investigations in hepatocellular carcinoma patients.

New molecular therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health problem. Mortality owing to liver cancer has increased in the past 20 years, with recent studies reporting an incidence of 780,000 cases/year. Most patients with hepatocellular carcinoma are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Afterwards, up to 7 randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve survival. Potential reasons for this include intertumor heterogeneity, issues with trial design and a lack of predictive biomarkers of response. Advance in our knowledge of the human genome has provided a comprehensive picture of commonly mutated genes in patients with HCC including mutations in the TERT promoter, CTNNB1, TP53 and ARID1A along with other amplifications (FGF19, VEGFA) or homozygous deletions (p16) as the most frequent alterations. This knowledge points toward specific drivers as candidate for druggable therapies. Thus, progressive implementation of proof-of-concept and enrichment might improve results in clinical trials testing of molecular targeted agents. Ultimately, these studies are aimed at long-term to improve current standards of care and influenced clinical decision-making and practice guidelines.

A phase II trial of oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma.

Only a minority of patients with hepatocellular carcinoma (HCC) may benefit from curative treatments, whereas there is no standard therapy for the remaining patients. The objective of this multicentre, open label phase II study was to estimate the objective tumour response rate of a 28-day regimen of oral eniluracil/5-fluorouracil (5-FU) in patients with chemotherapy-naïve, or anthracycline-refractory, inoperable HCC. 45 patients received courses of twice daily oral 5-FU (1.0 mg/m(2)) and eniluracil (10 mg/m(2)) for the first 28 days of each 5-week course. Patients were assessed at regular intervals to determine the tumour response and to evaluate toxicity. Patients were followed-up for a minimum of 6 months. No patient showed a partial or complete tumour response, and 18 patients (40%) had a best response of stable disease (95% confidence interval (CI) 25%, 55%). The median duration of progression-free survival (PFS) was 13.7 weeks (95% CI 10.0-20.0 weeks), and the median duration of overall survival (OS) was 50.3 weeks (range 1.1-64.1+ weeks). The combination of eniluracil/5-FU was well tolerated and had an acceptable safety profile. Only 7 patients (16%) reported at least one adverse event (AE) of grade 3 or 4 intensity considered reasonably attributable to the study medication. In conclusion, oral eniluracil/5-FU had minimal, if any, activity in patients with inoperable HCC, but the safety profile was acceptable.

The current status of liver transplantation for primary hepatic malignancy.

Several advances have been achieved during the last years in the management of patients with liver cancer. The refinement of the imaging techniques and the better knowledge of the biology of this neoplasm have facilitated the establishment of useful criteria to select patients for transplantation. Following a strict selection policy (solitary tumors < or = 5 cm or up to 3 foci each one < or = 3 cm) patients with liver cancer may achieve the same survival as nonneoplastic subjects. Currently, the main problem is how to diminish the risk of tumor progression while waiting for a liver. Although at present the benefits of invasive treatments are ill-defined, the ongoing studies exploring new treatment options hopefully will succeed in preventing this complication and further improve the current results.

Review article: natural history and prognostic prediction of patients with hepatocellular carcinoma.

The knowledge of the natural history of patients with hepatocellular carcinoma is important to estimate the prognosis at diagnosis and indicate the best therapy. Prognosis is related to tumour stage at diagnosis, degree of liver function impairment induced either by the tumour itself or by the underlying cirrhosis, general physical condition of the patients, and potential impact of therapy. Prognostic estimation should take into account all four aspects. Treatment is very relevant to be considered in patients with early stage tumours since surgical resection, transplantation or percutaneous ablation provide a high rate of complete responses and thus, improve survival. This might be as high as 50-75% at 5 years. Patients diagnosed at an intermediate/advanced stage will receive palliative treatment and prospective studies have recently redefined the outcome predictors of this stratum. Asymptomatic patients in whom the tumour has not invaded vessels or disseminated may reach a 50% survival at 3 years, while those with adverse predictors do not reach this time point. These data have to be taken into account not only in the conventional clinical practice, but also in the design and evaluation of prospective investigations that should be properly powered to reach an informative sample size. To achieve both aims, within the Barcelona Clinic Liver Cancer Group we have developed a staging system that combines prognosis prediction with decision making, thus becoming a useful tool both for practice and research.

[Prophylactic sclerosis of esophageal varices. Results of a controlled prospective study]. / Esclerosis profiláctica de varices esofágicas. Resultados de un estudio prospectivo controlado.

BACKGROUND: Endoscopic sclerosis of esophageal varices is effective both to treat active hemorrhage and to prevent recurrences. By contrast, its usefulness for the prophylaxis of the first episode of hemorrhage is not well established, the available data being contradictory. METHODS: Overall 46 patients with cirrhosis and esophageal varices of type B or higher, without previous upper gastrointestinal hemorrhage, were randomized to be treated with prophylactic sclerosis or not (n = 22 and 24, respectively). Both groups were comparable in age, sex, etiology of cirrhosis (mainly alcoholic), Child's degree of hepatic failure, coagulation studies, laboratory data and endoscopic findings. RESULTS: In a mean follow up of 16 months, the patients treated with sclerosis had a higher frequency of hemorrhage from gastroesophageal varices (27%) than those in the control group (8%) (n.s.). However, this difference reached significance (p = 0.02) when only patients from Child's classes A and B were considered (31% in the sclerosis group vs 5% in the control group). The mortality rate was similar in both groups, with a probability of one year survival of 80 and 76% in the sclerosis and control groups, respectively. CONCLUSIONS: The results indicate that prophylactic sclerotherapy does not improve short-term survival or reduce the risk of a first hemorrhage due to gastroesophageal varices of type B or higher in hepatic cirrhosis. It may even facilitate the development of this severe complication in Child's A and B class patients.

[Impact on the energetic-proteic nutritional status of total paracentesis combined with infusion of albumin or dextran-70 in the therapy of tension ascites in liver cirrhosis]. / Repercusión sobre el estado nutricional energético-proteico de la paracentesis total asociada a la infusión de albúmina o dextrano-70 en el tratamiento de la ascitis a tensión en la cirrosis hepática.

The aim of this study was to investigate the effect of total paracentesis plus albumin or dextran-70 infusion on the nutritional status in cirrhotics with tense ascites. Seventeen patients were studied. Eight patients (group I) were treated with total paracentesis and albumin infusion, and in 9 cases (group II) dextran-70 infusion was associated to total paracentesis. The nutritional status was assessed before and two days after the procedure by measuring triceps skinfold thickness, mid-arm muscle circumference and serum albumin. No changes in anthropometric parameters were observed in either group. Patients in group I showed a significant increase in serum albumin levels (from 26.6 +/- 1.4 to 28.9 +/- 1.3 g/l; p = 0.007), whereas this parameter decreased in group II (from 25.5 +/- 1.3 to 23.1 +/- 1.4 g/l; p = 0.005). However, serum albumin levels returned to initial values in both groups one month after total paracentesis. There were no differences between both groups regarding the appearance of complications and mortality rate during admission. These results suggest that total paracentesis plus either i.v. albumin or dextran-70 has no long-term effect on the protein-energy nutritional status.

[Adult living donor liver transplantation. Analysis of the first 30 cases]. / Trasplante hepático de donante vivo en adultos. Análisis de los 30 primeros casos.

INTRODUCTION: In the last 2-3 years, adult living donor liver transplantation (ALDLT) has been developed on an international scale, multiplying the number of procedures performed. Despite this, analysis of the results is still incomplete. The aim of the present study was to perform a descriptive analysis of the results after the first 3 years of the initiation of the program. MATERIAL AND METHODS: During this period, 30 ALDLT were performed. In all procedures, right lobe grafts were used. The mean age of donors and recipients was 31.8 and 52.7 years, respectively. The main indication for liver transplantation was liver cirrhosis due to hepatitis C virus (70%) and 38% of recipients were stage C in the Child-Pugh classification. A total of 46.7% of recipients had hepatocellular carcinoma. RESULTS: Donors: The mean volume of the remnant liver was 632 cc (40.5% of the previous hepatic mass). Ten donors (33%) presented complications. The most frequent complication was biliary fistula (20%) and three patients required reintervention. The mean length of hospital stay among donors was 11.7 days. Recipients: The mean weight of the graft was 775 g, with a mean difference between graft weight and that of the recipient of 1.11. Fifteen recipients (50%) presented biliary leaks and nine of these (30%) required reintervention. There were no graft losses for technical reasons. Four patients died. With a median follow-up of 14 months, actuarial survival at 18 months was 92.9%. CONCLUSION: ALDLT is an effective method for reducing the number of patients on the waiting list. The probability of survival is similar to that of cadaveric transplantation. Biliary complications in the recipient constitute a problem, the long-term repercussions of which remain to be resolved.

[Subgroups of drug abuse patients who consume buprenorphine]. / Subgrupos de pacientes toxicómanos consumidores de buprenorfina.

We assessed the buprenorphine use in a sample of studied 184 patients with DSM III-R diagnostic criteria for opioid dependence who attended the Sta. Eulalia's CAS (outpatients facility) during 18 months period The lifetime prevalence of buprenorphine was 79% (43.5% of them were occasional users and 35.5% habitual; whereas the point prevalence was 16.8% (6.5% occasional users and 10.3% habitual). We compared the clinical characteristics of this patients, those who use the drug habitually and those who take it occasionally. The first group showed a longer time of opioid abuse (p less than 0.05) and they were more involved in drug traffic (p less than 0.001), mostly buprenorphine. These patients may present higher levels of clinical severity and social conflicts. Anyway they are usually polydrug users who consume more frequently flurnitracempan, cocaine, heroine, alcohol and cannabis (p less than 0.001). The usual ways of obtaining the buprenorphine are illegal traffic and GP's prescription in the Public health care facilities often by menace and intimidation. For consuming buprenorphine the abusers crush the pill, dilute it and them inject the solution i.v. The subgroup of patients who use buprenorphine occasionally only take in when don't have heroine and clinically they are not so deteriorated.

Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.