Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience.

Limited data are available on direct-acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15-29 mL/min/1.73m2 ) or 5 (eGFR<15 mL/min/1.73m2 or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty-six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention-to-treat population was 95.7%. Twenty-one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4-5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.

Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

Assisted reproductive technology and ovarian cancer.

Ovarian cancer has the highest mortality among all gynaecological cancers, being multiparity and oral contraceptive use the most important protective factors. According to both the "incessant ovulation" and "increased gonadotrophin" theories, fertility drugs might have an association with the development of ovarian cancer, as has been reported by some studies. However, infertility and nulliparity may act as confounding factors and most studies regarding this issue are hampered by methodological limitations. It seems that female infertility may be associated with a modest increase in ovarian cancer risk in those patients who remain nulligravid despite long periods of unprotected intercourse. Globally, most studies are reassuring in not showing a link between the use of fertility drugs and an increased risk of ovarian cancer. Nonetheless, further research in well-designed studies is warranted.

Predictive baseline criteria of primary therapeutic failure in chronic hepatitis C genotype 1.

BACKGROUND AND AIMS: more than half of patients with genotype 1 chronic hepatitis C (CHC) do not achieve a sustained viral response (SVR) to current antiviral therapy due to primary non-response, relapse or intolerance. Factors related to each of these unfavorable outcomes are different and the last two may be partially prevented. Our aim was to identify basal criteria to predict the risk of primary failure. PATIENTS AND METHODS: we included 251 consecutive patients (152 males) from a single centre, infected with HCV genotype 1 and not previously treated. SVR was achieved in 141 patients and primary failure in 110. RESULTS: high vs. low viral load (> 400,000 IU/mL, OR = 6.17; 95% CI: 2.50-15.23), high serum GGT (> 60 IU/mL, OR = 4.25; 95% CI: 2.49-7.24), low serum cholesterol ( < 178 mg/dL, OR = 2.93; 95% CI: 1.75-4.92) and older age (> 47 yrs., OR = 1.79; 95% CI: 1.08-2.96) were associated to the risk of primary failure in the lineal logistic regression analysis. From the 58 patients carrying all the first three negative criteria, 46 (79.3%) were primary non-responders. CONCLUSIONS: the negative basal profile identified in this study is based on easily available data and provides information about the risk of primary therapeutic failure, and may help to decide whether antiviral therapy should be offered to a single patient.

Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C.

BACKGROUND: Hyperferritinemia is often found in patients with chronic hepatitis C (CHC) and is predictive of poorer response to antiviral therapy. OBJECTIVE: To investigate changes in ferritinemia during and after antiviral therapy. PATIENTS AND METHODS: serum ferritin levels were measured in 262 CHC patients (163 males, mean age 48.5 years +/- 10.1) before and during antiviral therapy, and six months post-treatment in all 154 patients with undetectable serum HCV-RNA after therapy completion. RESULTS: Baseline serum ferritin was higher in patients with primary therapeutic failure than in those reaching sustained viral response (330 +/- 291 ng/mL vs. 211 +/- 192 ng/mL, p = 0.002). Serum ferritin transiently increased during therapy from baseline (257 +/- 242 ng/mL vs. 875 +/- 630 ng/mL, p < 0.001). Six months after finishing therapy, serum ferritin decreased under baseline values both in sustained responders (117 +/- 102 ng/mL vs. 211+/- 192 ng/mL, p < 0.001) and, to a lesser extent, in relapsers (217 +/- 174 ng/mL vs. 257 +/- 221 ng/mL, p = 0.047). CONCLUSIONS: Baseline serum ferritin may predict response to antiviral treatment in chronic hepatitis C. Combined antiviral therapy induces a marked increase in serum ferritin that falls below baseline values after sustained viral response, suggesting that the cause of hyperferritinemia in many patients is HCV infection itself rather than iron overload.

[Results of the treatment of chronic hepatitis C genotype 4--a comparative analysis with genotype 1]. / Resultados del tratamiento de la hepatitis crónica por VHC genotipo 4. Un análisis comparativo con el genotipo 1.

INTRODUCTION: nearly all the data on the efficacy of combined antiviral therapy on chronic hepatitis C genotype 4 have been obtained in countries of Middle East. Genotype 4 is quite unusual in Spain. We report our experience in a group of Spanish patients treated with homogeneous criteria. PATIENTS AND METHODS: between 2001 and 2007 we have treated 30 patients with chronic hepatitis C genotype 4 (20 males) with pegylated Interferon alpha-2b (26 cases) or alpha-2a (4 cases) combined with ribavirin at a weight-adjusted dose. Results of therapy are known in all patients and liver biopsy is available in 24 cases. RESULTS: ten patients (33.3%) obtained sustained viral response (SVR: HCV-RNA undetectable in blood 6 months after the end of therapy), 12 were primary non-responders, 4 relapsed after reaching undetectable HCV-RNA at the end of therapy and 4 interrupted the treatment due to severe adverse events. These results are very close to those obtained in 355 patients infected with HCV genotype 1. CONCLUSION: HCV genotype 4 should be considered as "difficult to treat". The better results of therapy in other geographical areas (Middle East) may be due to a different distribution of the subtypes of HCV genotype 4.

Characterization of the antibody reactivity to synthetic peptides from different parts of the hepatitis C virus genome.

Infection by hepatitis C virus (HCV)*, the aetiologic agent responsible for the majority of non-A-non-B posttransfusion hepatitis, is detected by assaying for antibodies against structural and nonstructural recombinant proteins or synthetic peptides. The aim of this study was to characterize the antibody reactivity of selected sera against antigenic peptides spanning immunodominant regions of the core, NS4 and NS5 HCV proteins. Reactivity to synthetic peptides was determined by enzyme immunoassay (EIA) for 11 selected sera from blood donors (good responders), for 27 selected sera from hemodialysis patients (poor responders), all positive for HCV antibodies (tested by different second and third-generation assays), and for 7 negative sera. Some peptides from the core and the NS4 region were widely recognized by the tested sera. Sera not reactive with core, NS4, or NS5 region by some immunoblot assays exhibited reactivity against peptides from these proteins. Autoimmune reactivity associated with HCV infection was evaluated by using a synthetic peptide derived from the GOR peptide; 8/11 HCV-positive sera were found reactive against this peptide. No correlation was found between reactivity to any of the peptides tested and the presence of HCV RNA in the serum or with HCV genotype. The EIA reactivity of peptides from the core region suggested a multideterminant antigenic structure, where reactivity of each epitope may be differentially affected by neighboring amino acids depending on individual sera. This situation was particularly evidenced in selected sera from poor responder specimens where a more restricted antibody response to core peptides was observed. Reactivity of sera from HCV-infected patients with synthetic peptides from the core, NS4, and NS5 regions indicated the presence of multiple linear epitopes (particularly in the core region) that may be used in a mixture for immunodiagnosis; however, the length and exact position of the synthetic peptides must be chosen carefully.

The role of multimodality therapy for resectable esophageal cancer.

BACKGROUND: There is an increasing interest in the role of combined therapy to achieve long-term survival for patients with resectable esophageal neoplasms. Surgery provides excellent palliation with relatively low morbidity and mortality rates, but cure remains elusive. MATERIAL AND METHODS: From January 1988 to January 1998, a total of 137 patients met eligibility criteria for a combined multimodal therapy, prospective, nonrandomized protocol of induction chemoradiation therapy followed by surgical resection, based on radiological and endoscopic assessment of the extension (all patients were initially considered to be at clinical stages I to III, locoregional). Consequently, patients with high grade Barrett's dysplasia or any squamous carcinoma in situ (stage 0) and those with distant metastatic disease (stage IV) were excluded. Among this group, 48 operable patients with biopsy-proven esophageal cancer finally entered and completed the protocol and are the sample of the present study. Multivariate logistic regression models were used to identify risk factors for death or recurrence. Actuarial survival was calculated since the beginning of the induction protocol by the Kaplan-Meier method, and comparisons between groups were made by the log-rank test. RESULTS: Mean age was 61.6 (range 45 to 71), and 72.9% were male. The majority of the tumors (70.8%) were located at the lower third/cardia and as many as 18.8% were adenocarcinoma. After a mean of 7.5 weeks (range 5 to 12) after the completion of the induction phase, 68.7% underwent a transthoracic esophagectomy and 31.3% a transhiatal esophagectomy. The in-hospital mortality rate was 10.4% (5 patients). A complete response (no evidence of tumor within the specimen: pT0) was achieved in 25% (12 patients). After a mean follow-up of 20.2 months, mean survival for the entire group was 18.2 months (95% confidence interval 14 to 22). At the end of the study, 25% (12) remained alive. Actuarial survival rates at 12, 23, and 37 months were 56.2%, 36.9%, and 21.9%, respectively. CONCLUSIONS: Esophageal resection after induction therapy seems to be related to a slightly higher mortality rate compared with historical series, and for this reason, neoadjuvant therapy must be considered still experimental. However, no statistical significant difference in survival is showed in those cases with complete pathological response (pT0). Factors influencing survival are recurrence and age. Surgery alone remains the standard therapy for esophageal cancer.

Immunocytochemical typification of mesothelial cells in effusions: in vivo and in vitro models.

We have performed immunocytochemical, immunoelectron microscopy, Western blot, and culture techniques using monoclonal antibodies against cytokeratin, vimentin, and desmin on 17 benign and 20 malignant effusions of pleural and ascitic origin. Triple coexpression of these three antigens was observed in benign reactive mesothelial cells as well as in one case of mesothelioma. All metastatic adenocarcinoma cells were consistently negative to desmin and positive to cytokeratin and vimentin. Present results were helpful to distinguish reactive and malignant mesothelioma from metastatic carcinoma cells in effusions.

[Cystic pyeloureteritis. A review of the literature in the period of 1946-1994 and a report of a new case]. / Pieloureteritis quística. Revisión de la literatura, periodo 1946-1994 y presentación de un nuevo caso.

Presentation of a new case of unilateral cystic pyeloureteritis in a 46-year old female patient. The condition presented as a right renoureteral colic. A revision is made of the 69 national cases published on such an uncommon condition, of obscure etiologic, pathogenic and therapeutical features. The accent is placed on its most significant aspects, such as: difficulties of differential diagnosis with other repletion defect imagen in the excretory tract and their frequent association to other diseases.

[Adipose retroperitoneal tumors. Apropos a giant myxoid liposarcoma]. / Tumores adiposos retroperitoneales. A propósito de un liposarcoma mixoide gigante.

Liposarcomas are the most frequent retroperitoneal tumours, second only to lymphomas. We present a new case of giant retroperitoneal liposarcoma treated in our hospital. A discussion is presented on the most peculiar aspects of this tumour, such us: multicentricity, tendency to local relapse, and need to post-operative (adjuvant) radiotherapy. A review of all nationwide cases over the last few years is included.

[Subscapular/triceps index: percentile values in Cuban children and adolescents]. / Indice subescapular/tricipital: valores percentilares en niños y adolescentes cubanos.

The percentiles (3,10,25,50,75,90 and 97) of the subscapular/triceps Index (SS/TR), obtained in a sample of 7286 subjects (3721 males and 3765 females) aged 5 to 20 years, were calculated. Median values of SS/TR are generally higher in females up to the age of 13 years approximately, and show a pattern of peripheral distribution of fat during all the period of study. In males, a pattern of central distribution of fat develops starting from age fourteen and becomes more central as age increases. Values obtained were higher than those reported in the literature at all ages and in both sexes. The results reported in this paper show that SS/TR is useful for assessing changes in the pattern of fat distribution during childhood and adolescence.

IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas.

To clarify the relationships between marginal zone lymphomas (MZLs) and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (WM/LPLs), immunoglobulin heavy chain variable gene (IGHV) features were analyzed and the occurrence of MYD88 L265P mutations was identified in a series of 123 patients: 53 MZLs from the spleen (SMZLs), 11 from lymph nodes (NMZLs), 28 mucosa-associated lymphatic tissue (MALT) lymphomas and 31 WM/LPLs. SMZLs were characterized by overrepresentation of IGHV1-2 gene rearrangements with a canonical motif, without selection pressure and with long CDR3 segments. NMZLs had increased frequencies of IGHV3 genes. The IGHV gene was unmutated in most cases, often with long CDR3 segments. MALT lymphomas were usually associated with a mutated IGHV gene, but with the absence of selection pressure. WM/LPLs were associated with an IGHV3-23 overrepresentation and high IGHV mutation rate, with features of selection pressure and short CDR3 segments. MYD88 L265P mutations were almost restricted exclusively to WM/LPL patients. Taken all diagnoses together, all patients with MYD88 L265P mutations had an immunoglobulin M peak and almost all patients except one had bone marrow infiltration. These results demonstrate that the history of antigen exposure of the four entities studied was different and MYD88 L265P was specifically associated with WM/LPLs. WM/LPL may thus be functionally associated with constitutive nuclear factor-κB activation.

Subgenotype diversity of hepatitis B virus American genotype F in Amerindians from Venezuela and the general population of Colombia.

The objective of this study was the evaluation of the genetic diversity found in HBV circulating among Venezuelan Amerindians and the general population in Colombia. Phylogenetic analysis of the S region in 194 isolates showed that genotype F is highly predominant in Colombia and Venezuela. This might be related to the genetic background of the population. F3 is the main subgenotype which circulates in both countries. Phylogenetic analysis of 61 complete genome sequences of HBV American genotypes confirms the presence of two genotypes F and H, and 4 F subgenotypes. In Venezuela, subgenotypes F1, F2, and F3 circulate in East and West Amerindians, while only F3 was found among South Amerindians. Japreira community derived from Yucpa Amerindians around 150 years ago. However, several Japreira HBV sequences were forming a clade that can be classified as subgenotype 2b, differing from Yucpa sequences that belong mainly to subgenotype F3. The apparent absence of correlation between the phylogenetic groupings of HBV isolates with the ethnical origin in aboriginal populations might be suggesting a recent origin of HBV American subgenotypes, or a genetic drift effect.

Benign rectovaginal fistulas: management and results of a personal series.

BACKGROUND: Treatment of benign rectovaginal fistula has a high failure rate and entails difficult decisions. The purpose of this retrospective study was to clarify the concepts which may improve its management. METHODS: Between 1983 and 2004, 46 consecutive women of median age 41 years were treated by the same surgeon. Etiology of simple fistulas was iatrogenic (n=6), obstetric (n=4) and septic (n=3). Complex fistulas were due to inflammatory bowel diseases (IBD) (n=18, 11 pouchvaginal) or were iatrogenic (n=9), actinic (n=5) or septic (n=1). Surgical techniques included endorectal or vaginal advancement flaps, fistulectomy and sphincteroplasty, vaginal/rectal closure and epiploplasty, restorative proctectomy and restorative proctocolectomy. In 20 patients, a diverting stoma was performed as a single procedure or concomitant to the curative attempt. RESULTS: Overall, 33 of the 39 fistulas (85%) treated for cure healed, including all simple fistulas and 20 complex fistulas (8 iatrogenic, 3 actinic, 2 ulcerative colitis without restorative proctocolectomy; 5 pouch vaginal; 1 septic; 1 Crohn's disease) (p=0.009). The first operation for the fistula was curative in 20 of 39 fistulas, including 10 of 13 simple and 10 of 26 complex fistulas (p=0.023). There was no significant age difference between cured and not-cured patients. CONCLUSIONS: Simple versus complex fistulas is the most determinant factor for healing. In IBD fistulas, ulcerative colitis shows better prognosis than Crohn's disease. For complex fistulas, a temporary diverting stoma seems necessary.

[Economics, health, and health care]. / Economía, salud y asistencia sanitaria.

Since the seventies the growing of sanitary expenses has become the first worry for our authorities and the seeking of solutions has brought the presence of economists to solve the health problems. Therefore the health economy studies the production and distribution of health and sanitary attention in two senses: one like a discipline (usually located in universities and publications in the area of economy) and another one to the resolution of health problems and care, favouring interdisciplinary cooperation and its application to management. When speaking about the relation ship between economy and health, it is necessary to consider three areas: first that of basic concepts in economy: demand, offer, elasticity, market faults and state intervention in economy. The second aspect goes to the specific characteristics of sanitary care from economic perspective and the application of economic concepts to health field. And finally the third one is the field of the most important techniques of economic evaluation for sanitary programs and the analysis of sanitary systems reforms in some countries.

Percentiles of the waist-hip ratio in Cuban scholars aged 4.5 to 20.5 years.

Values of the waist-hip ratio (WHR), expressed as percentiles and stratified by sex and age, were obtained from a simple judgment sample of 7285 schoolchildren and adolescents (3721 males and 3564 females) aged between 4.5 and 20.5 years. WHR is higher with age in males, and it changes more gradually chronologically also. The graph for males shows three relative maxima at 6, 11-12 and 15-16 years; and for females, two relative maxima at 10 and 13 years. In females, there are two sharp reductions between 10 and 13 and between 13 and 16 years of age. The changes in WHR are associated with age and sexual maturation in both sexes. We conclude that WHR might be useful in assessing body fat distribution in late childhood and adolescence.

A double sandwich monoclonal enzyme immunoassay for detection of hepatitis B surface antigen.

An enzyme immunoassay for detection of hepatitis B surface antigen based on the use of 3 monoclonal antibodies (mAbs) was developed: an IgM as capture and 2 IgG1 for detection. The system biotin-streptavidin was compared with direct conjugation of mAbs to peroxidase and was preferred because of its higher signal to noise ratio. The possibility of simultaneous addition of human serum and biotin-mAb was discarded because of an evident prozone effect with some sera containing high HBsAg levels. The conjugation of biotin to IgG1 mAbs through a spacer arm (amidocaproyl) and the use of a highly sensitive substrate (tetramethylbenzIdine) improved the assay detection limit by about 10 times.