Trifluridine-tipiracil plus bevacizumab versus trifluridine-tipiracil monotherapy for chemorefractory metastatic colorectal cancer: a systematic review and meta-analysis.

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.

Efficacy and safety of trifluridine/tipiracil (TAS-102) in patients with metastatic colorectal cancer: a systematic review and meta-analysis.

OBJECTIVES: The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. METHODS: The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs). RESULTS: There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events. CONCLUSION: TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable.

Abordaje de la esteatosis hepática en atención primaria / Approach to hepatic steatosis in primary care

Desde fines de 2023, la denominación hígado graso no alcohólico cambió por esteatosis hepática asociada a disfunción metabólica (MASLD, por sus iniciales en inglés), ya que el nombre anterior era considerado estigmatizante para los pacientes. No está recomendado rastrear esta entidad en la población general. Sin embargo, si por algún motivo se solicitó una ecografía y esta informa esteatosis hepática, se recomienda evaluar el riesgo de progresión a fibrosis hepática mediante el puntaje FIB-4. Los pacientes con puntaje mayor a 1,3 requieren mayor evaluación y se les solicita una elastografía transicional (Fibroscan®). El tratamiento de esta entidad apunta, en general, al descenso de peso mediante la actividad física y la dieta hipocalórica. (AU)

Since the end of 2023, the name non-alcoholic fatty liver has been changed to metabolic dysfunction-associated steatotic liver disease (MASLD), as the former denomination was considered stigmatizing for patients. It is not recommended to screen for this entity in the general population. However, if for some reason an ultrasound was performed and it reports hepatic steatosis, it is recommended to evaluate the risk of progression to liver fibrosis using the FIB-4 score. Patients with a score greater than 1.3 require further evaluation, and a transient elastography (FibroScan®) is requested. Treatment in general aims at weight loss through physical activity and a low-calorie diet. (AU)

Cylindrospermopsin exposure promotes redox unbalance and tissue damage in the liver of Poecilia reticulata, a neotropical fish species.

There is a growing concern regarding the adverse risks exposure to cylindrospermopsin (CYN) might exert on animals and humans. However, data regarding the toxicity of this cyanotoxin to neotropical fish species are scarce. Using the fish species Poecilia reticulata, the influence of CYN concentrations equal to and above the tolerable for drinking water may produce on liver was determined by assessing biomarkers of antioxidant defense mechanisms and correlated to qualitative and semiquantitative histopathological observations. Adult females were exposed to 0.0 (Control); 0.5, 1 and 1.5 µg/L pure CYN for 24 or 96 hr, in triplicate. Subsequently the livers were extracted for biochemical assays and histopathological evaluation. Catalase (CAT) activity was significantly increased only by 1.5 µg/L CYN-treatment, at both exposure times. Glutathione -S-transferase (GST) activity presented a biphasic response for both exposure times. It was markedly decreased after exposure by 0.5 µg/L CYN treatment but significantly elevated by 1.5 µg/L CYN treatment. All CYN treatments produced histopathological alterations, as evidenced by hepatocyte cords degeneration, steatosis, inflammatory infiltration, melanomacrophage centers, vessel congestion, and areas with necrosis. Further, an IORG >35 was achieved for all treatments, indicative of the presence of severe histological alterations in P. reticulata hepatic parenchyma and stroma. Taken together, data demonstrated evidence that CYN-induced hepatotoxicity in P. reticulata appears to be associated with an imbalance of antioxidant defense mechanisms accompanied by histopathological liver alterations. It is worthy to note that exposure to low environmentally-relevant CYN concentrations might constitute a significant risk to health of aquatic organisms.

Trifluridine/tipiracil (FTD/TPI) and regorafenib in older patients with metastatic colorectal cancer.

Colorectal cancer is a disease of older patients, but few guidelines directly address age in their recommendations. Older patients may present comorbidities that affect the choice of chemotherapy, and care must be taken when choosing the best approach. This narrative review aimed to describe the literature regarding approved oral agents for third-line treatment in older patients with refractory metastatic colorectal cancer, regorafenib, and trifluridine/tipiracil (FTD/TPI).

Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters.

The study of transporters is highly challenging, as they cannot be isolated or studied in suspension, requiring a cellular or vesicular system, and, when mediated by more than one carrier, difficult to interpret. Nucleoside analogues are important drug candidates, and all protozoan pathogens express multiple equilibrative nucleoside transporter (ENT) genes. We have therefore developed a system for the routine expression of nucleoside transporters, using CRISPR/cas9 to delete both copies of all three nucleoside transporters from Leishmania mexicana (ΔNT1.1/1.2/2 (SUPKO)). SUPKO grew at the same rate as the parental strain and displayed no apparent deficiencies, owing to the cells' ability to synthesize pyrimidines, and the expression of the LmexNT3 purine nucleobase transporter. Nucleoside transport was barely measurable in SUPKO, but reintroduction of L. mexicana NT1.1, NT1.2, and NT2 restored uptake. Thus, SUPKO provides an ideal null background for the expression and characterization of single ENT transporter genes in isolation. Similarly, an LmexNT3-KO strain provides a null background for transport of purine nucleobases and was used for the functional characterization of T. cruzi NB2, which was determined to be adenine-specific. A 5-fluorouracil-resistant strain (Lmex5FURes) displayed null transport for uracil and 5FU, and was used to express the Aspergillus nidulans uracil transporter FurD.

Evaluation of the Tasso-SST® capillary blood microsampling device for the measurement of endogenous uracil levels.

BACKGROUND: Uracil (U) plasma or serum levels can be used as surrogates of dihydropyrimidine dehydrogenase (DPD) activity, which is strongly related to the occurrence of severe or fatal toxicity after administration of fluoropyrimidines (FP) chemotherapy. Obtaining blood plasma or serum for U measurement usually requires a phlebotomy procedure by a qualified professional. An alternative to conventional blood drawn is the use of the Tasso-SST® device, which allows the collection of a small blood volume from skin capillaries. This study aimed to implement a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the determination of U in small serum samples and to compare U concentrations measured in venous plasma, obtained after phlebotomy, and serum obtained with the Tasso-SST® device. METHODS: Fifty microliter samples were prepared through simple protein precipitation with trichloroacetic acid. Chromatographic separation was performed with a porous graphitic carbon stationary phase and mass spectrometric detection used positive electrospray ionization. The assay was validated according to international guidelines. RESULTS: The linear range of the assay was 5-250 ng/mL. Measurement accuracy was in the range of 98.8-108.2%, inter-assay precision was 4.3-7.3%, and intra-assay precision was 3.4-6.1%. The average matrix effect was -6.42%. The extraction yield was 95-103.3%. U concentrations measured in serum obtained with the Tasso-SST® device and venous blood plasma were highly correlated (rs = 0.910, P < 0.0001), and no systematic or proportional bias between U levels measured in both matrices was found. CONCLUSIONS: The use of blood microsampling with the Tasso-SST® device is a useful alternative for the measurement of U and the identification of patients with DPD deficiency.

Dissociative electron attachment to 5-bromo-uracil: non-adiabatic dynamics on complex-valued potential energy surfaces.

Electron induced dissociation reactions are relevant to many fields, ranging from prebiotic chemistry to cancer treatments. However, the simulation of dissociation electron attachment (DEA) dynamics is very challenging because the auto-ionization widths of the transient negative ions must be accounted for. We propose an adaptation of the ab initio multiple spawning (AIMS) method for complex-valued potential energy surfaces, along the lines of recent developments based on surface hopping dynamics. Our approach combines models for the energy dependence of the auto-ionization widths, obtained from scattering calculations, with survival probabilities computed for the trajectory basis functions employed in the AIMS dynamics. The method is applied to simulate the DEA dynamics of 5-bromo-uracil in full dimensionality, i.e., taking all the vibrational modes into consideration. The propagation starts on the resonance state and describes the formation of Br- anions mediated by non-adiabatic couplings. The potential energies, gradients and non-adiabatic couplings were computed with the fractional-occupancy molecular orbital complete-active-space configuration-interaction method, and the calculated DEA cross section are consistent with the observed DEA intensities.

Cylindrospermopsin Disrupts Estrous Cycle and Increases Spermatogenesis in Mice.

Cylindrospermopsin (CYN) is a water-soluble cyanotoxin that has been linked to several cases of poisoning in the world. In vitro studies have shown that CYN acts as an endocrine disruptor by inhibiting progesterone synthesis in primary cell cultures of women, showing estrogenic activity. However, in vivo assessment of CYN in the female and male reproductive systems remains unknown. We thus aimed to evaluate the in vivo effects of CYN in both the female and male reproductive systems of mice. A single intraperitoneal exposure to 64 µg of CYN/kg body weight was performed in females. Estrous cycle was evaluated daily by vaginal cytology, and serum progesterone and estradiol levels were measured after 50 days. We showed an impairment in the estrous cycle as well as a decrease in circulating plasma progesterone levels. In males, weekly intraperitoneal doses of 20 µg of CYN/kg body weight were given and groups were killed after one, two, or four doses. CYN increased the testosterone levels in the groups that received one or two doses of CYN. Additionally, CYN induced a transient increase in spermatozoa in males after four doses. Our results highlight that CYN interferes with both male and female reproductive systems and may lead to infertility. As far as we know, this is the first report showing the impacts of CYN on the mammalian reproductive system, suggesting a threat from this cyanotoxin to human and environmental health.

Therapeutic potential of the cytosine deaminase::uracil phosphoribosyl transferase/5-fluorocytosine suicide system for canine melanoma.

We tested the efficacy of a yeast cytosine deaminase::uracil phosphoribosyl transferase/5-fluorocytosine (CDU/5-FC) non-viral suicide system on eight established canine melanoma cell lines. Albeit with different degree of sensitivity 5 days after lipofection, this system was significantly efficient killing melanoma cells, being four cell lines highly, two fairly and two not very sensitive to CDU/5-FC (their respective IC50 ranging from 0.20 to 800 µM 5-FC). Considering the relatively low lipofection efficiencies, a very strong bystander effect was verified in the eight cell lines: depending on the cell line, this effect accounted for most of the induced cell death (from 70% to 95%). In our assay conditions, we did not find useful interactions either with the herpes simplex thymidine kinase/ganciclovir suicide system (in sequential or simultaneous modality) or with cisplatin and bleomycin chemotherapeutic drugs. Furthermore, only two cell lines displayed limited useful interactions of the CDU/5-FC either with interferon-ß gene transfer or the proteasome inhibitor bortezomib respectively. These results would preclude a wide use of these combinations. However, the fact that all the tested cells were significantly sensitive to the CDU/5-FC system encourages further research as a gene therapy tool for local control of canine melanoma.

Photophysical Deactivation Mechanisms of the Pyrimidine Analogue 1-Cyclohexyluracil.

The photophysical relaxation mechanisms of 1-cyclohexyluracil, in vacuum and water, were investigated by employing the Multi-State CASPT2 (MS-CASPT2, Multi-State Complete Active-Space Second-Order Perturbation Theory) quantum chemical method and Dunning's cc-pVDZ basis sets. In both environments, our results suggest that the primary photophysical event is the population of the S11(ππ*) bright state. Afterwards, two likely deactivation pathways can take place, which is sustained by linear interpolation in internal coordinates defined via Z-Matrix scans connecting the most important characteristic points. The first one (Route 1) is the same relaxation mechanism observed for uracil, its canonical analogue, i.e., internal conversion to the ground state through an ethylenic-like conical intersection. The other route (Route 2) is the direct population transfer from the S11(ππ*) bright state to the T23(nπ*) triplet state via an intersystem crossing process involving the (S11(ππ*)/T23(nπ*))STCP singlet-triplet crossing point. As the spin-orbit coupling is not too large in either environment, we propose that most of the electronic population initially on the S11(ππ*) state returns to the ground following the same ultrafast deactivation mechanism observed in uracil (Route 1), while a smaller percentage goes to the triplet manifold. The presence of a minimum on the S11(ππ*) potential energy hypersurface in water can help to understand why experimentally it is noticed suppression of the triplet states population in polar protic solvent.

Evidence of cylindrospermopsin uptake and clearance in fish (Oreochromis niloticus) under laboratory conditions.

Cylindrospermopsin (CYN) is a cyanotoxin that has raised serious concerns about public health in many parts of the world. It can bioaccumulate and affect the health of aquatic organisms, but despite this, few studies have been conducted on CYN uptake and clearance in fish. In this paper, the authors evaluate the uptake and clearance of CYN in the muscle tissue and viscera of juvenile tilapia (Oreochromis niloticus) after exposure to aqueous extracts and whole cells of Cylindrospermopsis raciborskii (CYN-producer). CYN blended with commercial fish food, and three experiments were conducted. In the first trial, fish food, and aqueous extracts containing 0.31 µg CYN g-1 of food per day, was administered to tilapia for 15 days. In the second trial, fish were provided food and intact cells (5.4 µg CYN g-1 of food per day) for 15 days. In the last trial, they were provided fish food and aqueous extracts (0.8 µg CYN g-1 of food per day) for 12 days, and for the next 10 days, the animals were fed food without toxic cell extracts (to simulate a clearance period). The concentration of CYN in muscle tissue and viscera was analysed using ELISA. In the case of juvenile tilapia, the presence of CYN was higher in viscera than in muscle tissue, and the toxin remained in the tissues even after 10 days without the addition of contaminated food. The results suggest that tilapia represents a potential source of CYN transfer through the food web, and this shows the need for a continuous monitoring of this compound in organisms that are used for human and animal consumption.

'Real-life' experience with direct-acting antiviral agents for HCV after kidney transplant.

INTRODUCTIONS AND OBJECTIVES: The introduction of direct-acting antiviral (DAA) agents promises to change dramatically the management of hepatitis C in kidney transplant recipients, a patient group where the treatment of hepatitis C is historically challenging. The purpose of the current study was to assess (in a 'real-life' setting) the safety and efficacy of all-oral, interferon-free, direct-acting antiviral agents in kidney transplant recipients with HCV. MATERIAL AND METHODS: We performed a single-arm, multi-center study in a cohort (n = 95) of kidney transplant recipients who underwent antiviral therapy with DAAs. The primary end-point was sustained virologic response (SVR) (serum HCV RNA < 15 IU/mL, 12 weeks after treatment ended; SVR12). We recorded data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: Various regimens were adopted at the discretion of the treating physician: elbasvir/grazoprevir (n = 11), paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens ± ribavirin (n = 23), and sofosbuvir-based regimens ± ribavirin (n = 61). The SVR12 rate was 93.7% (89/95) (95% CI, 88%; 98%), according to intention-to-treat analysis; three patients without viral response (n = 3) were found. Ribavirin was administered in 8 (8.4%) allograft recipients. The frequency of drop-outs was 4.2% (4/95) (95% CI, 0.2%; 8.2%); these were related to arthralgia/myalgia (n = 2), fatigue (n = 1), and lowered estimated glomerular filtration rate (eGFR) (n = 1). There were no differences with regard to serum creatinine and eGFR before and after antiviral therapy and during follow-up in the whole cohort. The patient who interrupted antiviral treatment due to raised serum creatinine was on sofosbuvir/daclatasvir regimen; one of the four drop-outs obtained SVR. CONCLUSIONS: All-oral, interferon-free therapy with DAAs for chronic HCV after kidney transplantation was effective and well-tolerated in a 'real-life' clinical setting. Identical results have been observed in patients with intact kidneys or advanced chronic kidney disease. Careful evaluation of kidney function over follow-up in kidney transplant recipients who received DAAs regimens is recommended. Clinical trials aimed to assess whether sustained viral response translates into improved patient/graft survival are under way.

DNA damage induced by cylindrospermopsin on different tissues of the biomonitor fish Poecilia reticulata.

The cyanotoxin cylindrospermopsin (CYN) is the second biggest cause of poisoning worldwide, both in humans and animals. Although CYN primarily affects the aquatic environments and can be absorbed in fishes by multiple routes, data reporting its toxicity and mechanism of action are still scarce in this group. Using P. reticulata as model species, it was evaluated whether CYN promotes mutagenic and genotoxic effects in different fish target tissues. Adult females were exposed in a static way to 0 (control), 0.5, 1.0, and 1.5 µg L-1 of pure CYN for 24 and 96 hours. For the first time, DNA damage was detected in fish brain after CYN exposition. In brain cells, a concentration-response DNA damage was observed for both exposure times, suggesting a direct or indirect action of CYN in neurotoxicity. For the liver cells, 96 hours caused an increase in DNA damage, as well the highest percentage of DNA in the tail was reached when used 1.5 µg L-1 of CYN. In peripheral blood cells, an increase in DNA damage was observed for all tested concentrations after 96 hours. In erythrocytes, micronuclei frequency was higher at 1.5 µg L-1 treatment while the erythrocyte nuclear abnormalities (ENA) frequency was significantly higher even at the lowest CYN concentration. Such data demonstrated that acute exposition to CYN promotes genotoxicity in the brain, liver, and blood cells of P. reticulata, as well mutagenicity in erythrocytes. It rises an alert regarding to the toxic effects of CYN for aquatic organisms as well as for human health.

Construction of wild-type Yarrowia lipolytica IMUFRJ 50682 auxotrophic mutants using dual CRISPR/Cas9 strategy for novel biotechnological approaches.

Yarrowia lipolytica IMUFRJ 50682 is a Brazilian wild-type strain with potential application in bioconversion processes which can be improved through synthetic biology. In this study, we focused on a combinatorial dual cleavage CRISPR/Cas9-mediated for construction of irreversible auxotrophic mutants IMUFRJ 50682, which genomic information is not available, thought paired sgRNAs targeting upstream and downstream sites of URA3 gene. The disruption efficiency ranged from 5 to 28 % for sgRNAs combinations closer to URA3's start and stop codon and the auxotrophic mutants lost about 970 bp containing all coding sequence, validating this method for genomic edition of wild-type strains. In addition, we introduced a fluorescent phenotype and achieved cloning rates varying from 80 to 100 %. The ura3Δ strains IMUFRJ 50682 were also engineered for ß-carotene synthesis as proof of concept. Carotenoid-producing strains exhibited a similar growth profile compared to the wild-type strain and were able to synthesized 30.54-50.06 mg/L (up to 4.8 mg/g DCW) of ß-carotene in YPD and YNB flask cultures, indicating a promisor future of the auxotrophic mutants IMUFRJ 50682 as a chassis for production of novel value-added chemicals.

Solvent effects on the π* shape resonances of uracil.

We have investigated the effect of microsolvation on the π* shape resonances of uracil, referred to as π1 * and π2 * in the order of increasing energy. Our study considered uracil-water aggregates with six solvent molecules obtained from Monte Carlo simulations in the liquid phase. To explore the ensemble statistics, we combined scattering calculations, performed in the static exchange and static exchange plus polarization approximations, with linear regressions of virtual orbital energies to the scattering results. In general, the solvent molecules stabilize the anion states, and the lower lying π1 * resonance becomes a bound state in most of the solute-water clusters. We also discuss how the strength of the H bonds can affect the energies of the anion states, in addition to the number and donor/acceptor characters of those bonds. The thermal distributions for the vertical attachment energies, obtained from 133 statistically uncorrelated solute-solvent clusters, are significantly broad in the energy scale of the autoionization widths. The distributions for the π1 * and π2 * anion states slightly overlap, thus giving rise to a quasi-continuum of attachment energies below ≲2.5 eV, in contrast to the gas phase picture of electron attachment to well separated resonances below the electronic excitation threshold. Both the stabilization of the anion states and the spread of attachment energies could be expected to favor the dissociative electron attachment processes believed to underlie the electron-induced damage to biomolecules.

Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram.

INTRODUCTION: Trifluridine/tipiracil combination has shown a benefit over placebo in the treatment of patients with chemorefractory metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of this combination in the real-life setting at eight Galician centers in Spain. PATIENTS AND METHODS: This is a retrospective study of a cohort of patients with mCRC in treatment with trifluridine/tipiracil within usual clinical practice who have been previously treated or are not considered candidates for treatment with available therapies. RESULTS: A total of 160 mCRC patients were included. Our data showed that 11.9% of patients achieved disease control. Median progression-free survival was 2.75 months; at 5.66 months follow-up, median overall survival was 7.94 months. Asthenia and neutropenia (48.1% both) were the most frequent adverse events. Overall survival was lower in patients with ECOG 2, multiple metastatic sites, platelets count 350,000/µl, alkaline phosphatase > 500 IU/l, and carcinoembryonic antigen > 10 ng/ml. CONCLUSION: The results of this study confirm the efficacy and safety of trifluridine/tipiracil in chemorefractory mCRC patients. However, patients in clinical practice differ from patients in clinical trials. Due to this, prognostic factors have special importance to offer the best therapeutic approach.

Cost-effectiveness of trifluridine/tipiracil (TAS102) for heavily pretreated metastatic gastric cancer.

BACKGROUND AND AIM: Trifluridine/tipiracil (TAS102), a novel oral cytotoxic chemotherapy, significantly improved overall survival compared with placebo in heavily pretreated advanced gastric cancer. This study aimed to evaluate the cost-effectiveness of TAS102 in the third-line or later treatment for this population from the US payer perspective. METHODS: A Markov model was developed to simulate advanced gastric cancer, including three health states: progression-free survival (PFS), progressive disease (PD) and death. Model inputs were derived from a randomised, double-blind, placebo-controlled, phase 3 trial (TAGS trial, NCT02500043). Utilities were extracted from public resources. Costs were calculated from an American payer perspective. Sensitivity analyses were conducted to explore the impact of uncertainty. RESULTS: From the US payer perspective, treatment with TAS102 for patients with heavily pretreated advanced gastric cancer was estimated to increase costs by $59,180 compared with the placebo, with a gain of 0.06 quality-adjusted life years (QALYs) for an incremental cost-effectiveness ratio (ICER) of $986,333 per QALY. The costs for progression-free survival of TAS102 group had the greatest impact on the ICERs, as well as the cost of TAS102. CONCLUSION: Trifluridine/tipiracil (TAS102) is not a cost-effective choice for patients with heavily pretreated metastatic gastric cancer from an American payer perspective.

Response to direct-acting antiviral agents in chronic hepatitis C patients with end-stage renal disease: a clinical experience

SUMMARY OBJECTIVE The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice. METHODS Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks. RESULTS The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b. CONCLUSION In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.

RESUMO O recente desenvolvimento de agentes antivirais de ação direta (DAAs) mudou drasticamente o tratamento da hepatite C crônica, e os regimes livres de interferon tornaram-se pobres escolhas para tratamento na prática clínica. Hoje os DAAs oferecem terapias curativas mais curtas, bem toleradas e altamente eficazes. O objetivo deste estudo foi avaliar a eficácia e segurança dos DAAs em pacientes com doença renal em estágio terminal e infecção pelo genótipo 1 do HCV na prática clínica real. MÉTODOS Trinta e seis pacientes, que se inscreveram em nossa clínica com diagnóstico de hepatite C crônica (CHC), inclusive no programa de hemodiálise, e preencheram os critérios de idade >18 anos, foram considerados para infecção pelo genótipo 1 com nível detectável de RNA do HCV. Os pacientes com infecção por GT1a receberam OBV/PTV/r mais DSV mais RBV por 12 semanas. Os pacientes infectados com GT1b receberam este regime sem RBV por 12 semanas. RESULTADOS O estudo foi realizado em 33 pacientes. A idade média foi de 52,30±13,77 anos e 70% deles eram do sexo masculino. Na semana 4 do tratamento, os níveis de ARN do VHC diminuíram para menos de 15 UI/ml em todos os pacientes. A taxa de resposta virológica sustentada (RVS) 12 foi de 100%. Nove pacientes apresentaram efeitos colaterais durante o tratamento. Dos pacientes com efeitos colaterais, 89,9% estavam no grupo 1a e 11,1% no grupo 1b. CONCLUSÃO Neste estudo, o tratamento com OBV/PTV/r e DSV com ou sem RBV resultou em altas taxas de resposta virológica sustentada em pacientes infectados pelo VGC GT1 com doença renal em estágio final (ESRD). A RVS foi alcançada em todos os pacientes com poucos efeitos colaterais.