Efficacy of immunotherapy in hepatocellular carcinoma: Does liver disease etiology have a role?

The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.

HIF-1α and VEGF as prognostic biomarkers in hepatocellular carcinoma patients treated with transarterial chemoembolization.

BACKGROUND: Neoangiogenesis plays a crucial role in the progression of hepatocellular carcinoma (HCC), and concerns have been raised about the role of neoangiogenesis on the effectiveness of transarterial chemoembolization (TACE). AIM: In this study, we aimed to evaluate Vascular Endothelial Growth Factor (VEGF) and Hypoxia-Inducible Factor-1α (HIF-1α) as circulating prognostic biomarkers in HCC patients treated with TACE. METHODS: Blood samples were collected from 163 patients before (t0) and four weeks after TACE (t1). RESULTS: Higher levels of VEGF after TACE were demonstrated (264.0 [78.7-450.8] vs. 278.6 [95.0-576.6] pg/mL; p < 0.0001). Responders to TACE had lower levels of VEGF than non-responders both at t0 (200.0 [58.9-415.8] vs. 406.6 [181.4-558.6] pg/mL; p = 0.006) and at t1 (257.3 [68.5-528.6] vs. 425.9 [245.2-808.3] pg/mL; p = 0.003), and in both groups there was an increase in VEGF compared to measurements before treatment (p = 0.001 and p = 0.005, respectively). VEGF was not associated with overall survival (OS), while patients with HIF-1α ≤ 0.49 ng/mL showed better prognosis (median OS 28.0 months [95% CI 19.7-36.3] vs. 17.0 months [95% CI 11.1-22.9]; p = 0.01). Moreover, HIF-1α was identified as an independent prognostic parameter. CONCLUSIONS: VEGF and HIF-1α can be considered useful prognostic biomarkers in HCC patients treated with TACE.

Angiogenesis and Hepatocellular Carcinoma: From Molecular Mechanisms to Systemic Therapies.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.

Physiopathology of nonalcoholic fatty liver disease: from diet to nutrigenomics.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is strongly associated with metabolic disorders, such as obesity, type 2 diabetes mellitus, and metabolic syndrome, to the extent that a new definition of metabolic associated fatty liver disease has been proposed. RECENT FINDINGS: Insulin resistance, worsened by a high-fat and high-carbohydrate diet, is the key to the physiopathology of hepatic steatosis. This is driven by several mechanisms that are mostly activated at a genetic level, such as de-novo lipogenesis and triglyceride synthesis. Therefore, many diet regimens have been studied, although significant controversies remain regarding their metabolic effects and long-term sustainability. SUMMARY: In this review, we summarized the role and effects of the main macronutrients on the development of NAFLD and discussed the molecular mechanisms involved. We also discussed the importance of genetic polymorphisms, epigenetic alterations, and dysbiosis to determine if lifestyle modification and a specific dietary regimen could be an essential part of NAFLD treatment.

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.

Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.

Temporomandibular joint disorders as the only manifestation of juvenile idiopathic arthritis: a case report.

Juvenile idiopathic arthritis is a term used to include all chronic childhood arthritis of unknown etiology. It is characterized by chronic inflammation persisting for at least 6 weeks, beginning before 16 years of age. The characteristics present are chronic synovitis, arthralgia, impaired joint mobility in at least one joint, and erosion with destruction of cartilage and subchondral bone, that could be associated or not with systemic involvement, according to each subtype of the disease. During the pathologic process, the temporomandibular joint can be involved by the juvenile idiopathic arthritis, resulting in severe mandibular dysfunction, with higher frequency in female patients. Initially, these lesions can show minor alterations like flattening of the condyle, erosions, and evolve to severe lesions, like destruction of the head of the condyle. We report a case of male patient who had destruction of both condyles, as a result from juvenile idiopathic arthritis. Proposed mechanisms to explain the juvenile idiopathic arthritis was reviewed. In this report the patient did not have pain or inflammatory process, and the temporomandibular diseases was the only manifestation.

Genetic and biochemical characterization of GES-16, a new GES-type ß-lactamase with carbapenemase activity in Serratia marcescens.

We evaluated the genetic environment of blaGES-16 found in 2 carbapenem-resistant Serratia marcescens clinical isolates recovered from patients hospitalized at a tertiary hospital located in Rio de Janeiro, Brazil. We also compared the kinetics constants for GES-16 and GES-5 against several ß-lactams. Both S. marcescens isolates showed identical PFGE pattern and carried the carbapenemase-encoding gene blaGES-16 and the extended-spectrum ß-lactamase encoding gene blaOXA-10. The blaGES-16 was inserted at the first position of a defective class 1 integron, composed by a fragmented integrase gene that lacked its attI1 recombination site, followed by dfr22, aac(6')-IIc, and aadA1 genes. This integron was located on a 30-kb nonconjugative plasmid. The GES-16 showed 2 amino acid substitutions (Gln38Glu and Gly170Ser) compared to GES-1. Kinetic analysis showed that GES-16 presented hydrolytic activity against all ß-lactams tested, except for aztreonam. Imipenem was the carbapenem more efficiently hydrolyzed (highest kcat/Km) by GES-16. The kinetic parameters of GES-16 were similar to those of GES-5. In conclusion, we identified a new GES-type enzyme with carbapenemase activity in S. marcescens. The increasing diversity of such resistance determinants confirms the ongoing evolution of these ß-lactamases towards a broader spectrum of activity.

Temporomandibular joint disorders as the only manifestation of juvenile idiopathic arthritis: a case report / Comprometimento da articulação temporomandibular como única manifestação da artrite idiopática juvenil: um relato de caso

ABSTRACT Juvenile idiopathic arthritis is a term used to include all chronic childhood arthritis of unknown etiology. It is characterized by chronic inflammation persisting for at least 6 weeks, beginning before 16 years of age. The characteristics present are chronic synovitis, arthralgia, impaired joint mobility in at least one joint, and erosion with destruction of cartilage and subchondral bone, that could be associated or not with systemic involvement, according to each subtype of the disease. During the pathologic process, the temporomandibular joint can be involved by the juvenile idiopathic arthritis, resulting in severe mandibular dysfunction, with higher frequency in female patients. Initially, these lesions can show minor alterations like flattening of the condyle, erosions, and evolve to severe lesions, like destruction of the head of the condyle. We report a case of male patient who had destruction of both condyles, as a result from juvenile idiopathic arthritis. Proposed mechanisms to explain the juvenile idiopathic arthritis was reviewed. In this report the patient did not have pain or inflammatory process, and the temporomandibular diseases was the only manifestation.

RESUMO Artrite idiopática juvenil é um termo usado para incluir toda artrite infantil crônica de etiologia desconhecida. É caracterizada por uma inflamação crônica, que persiste por pelo menos 6 semanas, com início antes dos 16 anos de idade. As características presentes são sinovite crônica, artralgia, mobilidade articular diminuída em pelo menos uma articulação, e erosão com destruição da cartilagem e do osso subcondral, podendo ser associada ou não com o envolvimento sistêmico, de acordo com cada subtipo da doença. Durante o processo patológico, a articulação temporomandibular pode ser envolvida pela artrite idiopática juvenil, resultando em disfunção mandibular severa, com maior frequência em pacientes do sexo feminino. Inicialmente, estas lesões podem mostrar pequenas alterações, como achatamento do côndilo e erosões, e evoluir para lesões graves, como a destruição da cabeça do côndilo. Relatou-se o caso de um paciente do sexo masculino, que apresentou destruição de ambos os côndilos, como resultado da artrite idiopática juvenil. Os mecanismos para explicar a artrite idiopática juvenil foram revisados na literatura. Neste relato de caso, o paciente não apresentou dor e nem processo inflamatório, sendo o comprometimento da articulação temporomandibular a única manifestação.

Nosewitness Identification: Effects of Lineup Size and Retention Interval.

Although canine identification of body odor (BO) has been widely used as forensic evidence, the concept of nosewitness identification by human observers was only recently put to the test. The results indicated that BOs associated with male characters in authentic crime videos could later be identified in BO lineup tests well above chance. To further evaluate nosewitness memory, we assessed the effects of lineup size (Experiment 1) and retention interval (Experiment 2), using a forced-choice memory test. The results showed that nosewitness identification works for all lineup sizes (3, 5, and 8 BOs), but that larger lineups compromise identification performance in similarity to observations from eye- and earwitness studies. Also in line with previous eye- and earwitness studies, but in disagreement with some studies on odor memory, Experiment 2 showed significant forgetting between shorter retention intervals (15 min) and longer retention intervals (1-week) using lineups of five BOs. Altogether this study shows that identification of BO in a forensic setting is possible and has limits and characteristics in line with witness identification through other sensory modalities.

Orbital pseudotumor: a differential diagnosis of Graves' ophthalmopathy.

The objective of this study is to report and discuss a rare and inflammatory cause of exophthalmos. This report describes a patient with exophthalmos, who was initially diagnosed with euthyroid Graves' with good response to therapy. After 8 years of follow-up, she had recurrence of symptoms and a new evaluation revealed the final diagnosis of orbital pseudotumor. Orbital pseudotumor is an uncommon disorder that both radiologically and clinically mimics a malignant process or other inflammatory disease, such as Graves' ophthalmopathy.

Orbital pseudotumor: a differential diagnosis of Graves' ophthalmopathy / Pseudotumor de órbita: um diagnóstico diferencial de oftalmopatia de Graves

The objective of this study is to report and discuss a rare and inflammatory cause of exophthalmos. This report describes a patient with exophthalmos, who was initially diagnosed with euthyroid Graves' with good response to therapy. After 8 years of follow-up, she had recurrence of symptoms and a new evaluation revealed the final diagnosis of orbital pseudotumor. Orbital pseudotumor is an uncommon disorder that both radiologically and clinically mimics a malignant process or other inflammatory disease, such as Graves' ophthalmopathy.

O objetivo deste estudo é relatar e discutir uma causa de exoftalmia rara e inflamatória. Este artigo relata uma paciente com exoftalmia que recebeu diagnóstico inicial de oftalmopatia de Graves eutireoideana com boa resposta à terapia. Após oito anos de seguimento, houve recorrência dos sintomas e uma nova avaliação revelou o diagnóstico final de pseudotumor orbitário. Pseudotumor orbitário é uma condição incomum que mimetiza clínica e radiologicamente uma doença maligna ou inflamatória, como a oftalmopatia de Graves.

NMR analysis of a series of substituted pyrazolo[3,4-d] pyrimidines-4-amines.

A series of 21 substituted pyrazolo[3,4-d]pyrimidines-4-amines were studied by (1)H and (13)C NMR. The application of two-dimensional techniques, HMQC and HMBC, allowed the complete assignment of the spectra for all the compounds.

Síndrome de Wyburn-Mason: relato de caso / Wyburn-Mason Syndrome: a case report

A síndrome de Wyburn-Mason (SWW) é caracterizada por malformaçöes arteriovenosas de retina e do sistema nervoso central ipsilateral. Tal patologia é extramente rara, provavelmente congênita, prograssiva durante o crescimento, e pode ser descrita como facomatose näo verdadeira devido ao seu grande potencial de complicaçöes cerebrais. É um quadro que pode estar associado a manifestaçöes clínicas oftalmológicas com ênfase á perda de campo visual, e neurológicas como cefaléia, acidente vascular cerebral agudo e epilepsia. Näo possui tratamento efetivo, porém, foram descritas técnicas de embolizaçäo, irradiaçäo e cirúrgicas com certo sucesso.

Efecto de la teofilina oral sobre la reactividad bronquial a adenosina e histamina en pacientes asmáticos / Effect of the oral theophylline on the bronchial reactivity to adenosine and histamine in asthmatic patients

Recientemente se ha sugerido que la acción terapéutica de la teofilina se debería al bloqueo específico de los receptores de adenosina, porque se ha demostrado que sua administración por vía inhalatoria bloquea específicamente la obstrucción bronquial causada por adenosina. Debido a que este efecto podría deberse a las altas concentraciones locales alcanzadas por vía inhalatoria, nosotros investigamos si este bloqueo específico puede lograrse con niveles terapéuticos alcanzados con teofilina adminstrada oralmente. Once sujetos asmáticos fueron sometidos a pruebas de provocación bronquial con adenosina e histamina previa administración de palcebo o 10 mg/Kg peso de teofilina oral, que produjo niveles terapéuticos en la mayoria de los casos. La teofilina aumentó significativamente el VEF1, y la PC20 histamina. Los cambios de PC20 observados no estuvieron relacionados con el grado de broncodilatación producido ni con la teofilinemia alcanzada. Se concluye que la teofilina adminstrada por vía sistématica también inhibe la broncoconstricción producida por adenosina, probablemente por bloqueo a nivel de los receptores

Adenosin Deaminasa (ADA) en líquido pleural: valor para la identificacion de la etiologia tuberculosa / Adenosina deaminase (ADA) in pleural fluid: value for the identification of tuberculous etiology

La concentración de adenosin deaminasa (ADA) en el líquido pleural se encuentra elevada en los derrames por tuberculosis, empiema, artritis reumatoidea y enfermedades linfoproliferativas, siendo sus niveles cercanos a los del plasma normal en las neoplasias, derrames para-neumónicos y transudados. Dado que los valores de tuberculosis se superponen con los de las neoplasia en grado diferente en las distintas publicaciones, no existe acuerdo respecto al nivel discrimnatorio entre estas patologías. Con el objeto de valorar este método en nuestro medio y definir un criterio diagnóstico, se determinó la concentración de ADA en el líquido pleural de 107 pacietnes consecutivos con diagnóstico comprobad. Al igual que en la literatura se observó un grupo con ADA promedio elevada (TBC 82.2 U/L ñ 26,3 DS; empiema 85,0 U/L ñ 85; artritis reumatóidea 81,8 U/L), y otro con un nivel bajo (neoplasias 23,5 U/L ñ 17,4; paraneumónicas 15,5 U/L ñ 11,3; insuficiencia cardíaca 9,3 U/L ñ 5,5; uremia 12,9 U/L ñ 3,8 y cirrosis 8,0 U/L 2,4). Los rangos esperables en el universo de las TBC y neoplasias fueron estadísticamente inferidos y de acuerdo a ello se propone como nivel de corte inferior el de 30 U/L, bajo el cual la probabilidad de TBC es sólo 1,6% y comi nivel de corte superior el de 80 U/L, sobre el cual la probabilidad de neoplasia es de 0,6%. Se concluye que la determinación de ADA es un método aplicable en nuestro medio que contribuye al diagnóstico diferencial de los derrames pleurales