Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial

Background Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. Materials and methods Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. Results In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8–34.4), 26.2 (95% CI, 18.2–36.6) and 25.4 months (95% CI, 17.4–36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx–hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. Conclusion After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx–hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team (AU)

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial.

BACKGROUND: Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. MATERIALS AND METHODS: Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. RESULTS: In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8-34.4), 26.2 (95% CI, 18.2-36.6) and 25.4 months (95% CI, 17.4-36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx-hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. CONCLUSION: After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx-hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team. ClinicalTrials.gov identifier NCT00261703.

Epidemiology of human papillomavirus-related oropharyngeal cancer in a classically low-burden region of southern Europe.

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012-2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

EUS-guided tissue acquisition in the study of the adrenal glands: Results of a nationwide multicenter study.

BACKGROUND: There are limited data about the role of endoscopic ultrasound-guided tissue acquisition (EUS-TA), by fine needle aspiration (EUS-FNA) or biopsy (EUS-FNB), in the evaluation of the adrenal glands (AG). The primary aim was to assess the diagnostic yield and safety. The secondary aims were the malignancy predictors, and to create a predictive model of malignancy. METHODS: This was a retrospective nationwide study involving all Spanish hospitals experienced in EUS-TA of AGs. Inclusion period was from April-2003 to April-2016. Inclusion criteria: all consecutive cases that underwent EUS-TA of AGs. EUS and cytopathology findings were evaluated. Statistical analyses: diagnostic accuracy of echoendoscopist's suspicion using cytology by EUS-TA, as gold standard; multivariate logistic regression model to predict tumor malignancy. RESULTS: A total of 204 EUS-TA of AGs were evaluated. Primary tumor locations were lung70%, others19%, and unknown11%. AG samples were adequate for cytological diagnosis in 91%, and confirmed malignancy in 60%. Diagnostic accuracy of the endosonographer's suspicion was 68%. The most common technique was: a 22-G (65%) and cytological needle (75%) with suction-syringe (66%). No serious adverse events were described. The variables most associated with malignancy were size>30mm (OR2.27; 95%CI, 1.16-4.05), heterogeneous echo-pattern (OR2.11; 95%CI, 1.1-3.9), variegated AG shape (OR2.46; 95%CI, 1-6.24), and endosonographer suspicion (OR17.46; 95%CI, 6.2-58.5). The best variables for a predictive multivariate logistic model of malignancy were age, sex, echo-pattern, and AG-shape. CONCLUSIONS: EUS-TA of the AGs is a safe, minimally invasive procedure, allowing an excellent diagnostic yield. These results suggest the possibility of developing a pre-EUS procedure predictive malignancy model.

Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients.

BACKGROUND: RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice. PATIENTS AND METHODS: RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients. RESULTS: Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment. CONCLUSION: The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.

Cost-effectiveness analysis of pazopanib in second-line treatment of advanced soft tissue sarcoma in Spain

Purpose. To assess the efficiency of pazopanib compared with trabectedin in the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) after chemotherapy failure. Methods. The progression of STS was modeled using a partitioned survival analysis model. Survival curves for pazopanib and trabectedin were modeled using data from PALETTE phase III clinical trial and based on unadjusted indirect comparison. Effectiveness was measured in quality-adjusted life years (QALY). The Spanish National Health System perspective was considered over a 10-year time horizon, including direct health care costs (Euros, 2014). A discount rate of 3 % was applied to both costs and outcomes. The robustness of the results was evaluated using univariate and probabilistic sensitivity analyses (PSA). Results. Pazopanib was associated with better health outcomes than trabectedin (0.705 versus 0.686 QALY). Pazopanib also showed lower direct health care costs (€21,861 versus €45,338), mainly due to lower cost of pharmacological treatment (€13,762 versus €33,392), administration (€57 versus €2,955) and AE management (€658 versus €1,695) costs. PSA confirmed that pazopanib was a dominant option in 71 % of the simulations performed. Conclusions. In this analysis, and from a health economics perspective, pazopanib was the option of choice versus trabectedin in the treatment of adult patients with advanced soft-tissue sarcoma after chemotherapy failure (AU)

No disponible

Cost-effectiveness analysis of pazopanib in second-line treatment of advanced soft tissue sarcoma in Spain.

PURPOSE: To assess the efficiency of pazopanib compared with trabectedin in the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) after chemotherapy failure. METHODS: The progression of STS was modeled using a partitioned survival analysis model. Survival curves for pazopanib and trabectedin were modeled using data from PALETTE phase III clinical trial and based on unadjusted indirect comparison. Effectiveness was measured in quality-adjusted life years (QALY). The Spanish National Health System perspective was considered over a 10-year time horizon, including direct health care costs (, 2014). A discount rate of 3% was applied to both costs and outcomes. The robustness of the results was evaluated using univariate and probabilistic sensitivity analyses (PSA). RESULTS: Pazopanib was associated with better health outcomes than trabectedin (0.705 versus 0.686 QALY). Pazopanib also showed lower direct health care costs (21,861 versus 45,338), mainly due to lower cost of pharmacological treatment (13,762 versus 33,392), administration (57 versus 2,955) and AE management (658 versus 1,695) costs. PSA confirmed that pazopanib was a dominant option in 71% of the simulations performed. CONCLUSIONS: In this analysis, and from a health economics perspective, pazopanib was the option of choice versus trabectedin in the treatment of adult patients with advanced soft-tissue sarcoma after chemotherapy failure.

New agents for bladder cancer.

Muscle-invasive bladder cancer is an aggressive disease with at least 50% of patients dying from metastases within 2 years of diagnosis. The 5-year survival rate for metastatic bladder cancer is <15%. Although modern combination chemotherapy regimens have improved median survival from 6 to 14 months compared with best supportive care, there is still a great opportunity for improvement. New therapies and strategies for better patient and treatment selection are now being investigated for advanced bladder cancer. These include agents that target several pathways involved in the pathogenesis of the disease--such as growth factor receptors, angiogenic pathways, p53, cell cycle checkpoints and apoptosis--as well as novel chemotherapeutic agents. Results from recent and ongoing trials suggest that some of these agents could soon emerge as useful players to overcome the limitations of our present therapies.

Enzyme entrapment by ß-cyclodextrin electropolymerization onto a carbon nanotubes-modified screen-printed electrode.

A novel enzyme entrapment approach based on an electropolymerization process utilizing multi-walled carbon nanotubes (MWCNT), ß-cyclodextrin (ß-CD) and glucose oxidase (GOx) is shown. Dopamine (DA) quantification is presented using a screen-printed electrode modified by electropolymerization of cyclodextrin with glucose oxidase, SPE/MWCNT/ß-CD-GOx. In order to show the relevance of the enzyme entrapment strategy controlled by electropolymerization to develop a specific and efficient biosensor, the various parts composing the electrode: SPE, SPE/ß-CD, SPE/GOx, SPE/ß-CD/GOx, SPE/MWCNT/ß-CD, SPE/MWCNT/GOx and SPE/MWCNT/ß-CD/GOx were tested separately. It was shown that although DA determination can be achieved with all of them, the electrodes modified with MWCNT presented better analytical features that those built without MWCNT, the best being the one including all components. This biosensor displayed good reproducibility, repeatability, and prolonged life-time under cold storage conditions. Its DA limit of detection (LOD) was 0.48±0.02 µA in a linear range of 10-50 µM with a sensitivity of 0.0302±0.0003 µA µM(-1) that makes it comparable or even better than many other electrodes reported in the literature. Moreover, it was also shown that using this electrode, DA quantification can be done in the presence of interfering agents such as ascorbic and uric acid. These findings demonstrate that the approach employed is feasible for enzyme entrapment and may find applications in other biosensing systems, where better sensitivity, stability and fast response are required.

Stable and sensitive flow-through monitoring of phenol using a carbon nanotube based screen printed biosensor.

A stable and sensitive biosensor for phenol detection based on a screen printed electrode modified with tyrosinase, multiwall carbon nanotubes and glutaraldehyde is designed and applied in a flow injection analytical system. The proposed carbon nanotube matrix is easy to prepare and ensures a very good entrapment environment for the enzyme, being simpler and cheaper than other reported strategies. In addition, the proposed matrix allows for a very fast operation of the enzyme, that leads to a response time of 15 s. Several parameters such as the working potential, pH of the measuring solution, biosensor response time, detection limit, linear range of response and sensitivity are studied. The obtained detection limit for phenol was 0.14 x 10(-6) M. The biosensor keeps its activity during continuous FIA measurements at room temperature, showing a stable response (RSD 5%) within a two week working period at room temperature. The developed biosensor is being applied for phenol detection in seawater samples and seems to be a promising alternative for automatic control of seawater contamination. The developed detection system can be extended to other enzyme biosensors with interest for several other applications.

[Importance of 5569G/A polymorphism in intron 4 of HFE gene in the diagnosis of hereditary hemochromatosis]. / Importancia del polimorfismo 5569G/A del intrón 4 del gen HFE en el diagnóstico de la hemocromatosis hereditaria.

BACKGROUND: The presence of the 5569A polymorphism may lead to misdiagnosis of patients susceptible of hereditary hemochromatosis (HH). For that reason, samples containing the Cys282Tyr mutation were revised and the frequency of this polymorphism in our environment was assessed. PATIENTS AND METHOD: Twenty samples were retested and 56 controls were included. The study was performed by PCR-RFLP. RESULTS: The diagnosis was confirmed in 8 cases susceptible of error. However, an amplification deficiency of normal alleles was detected in 2 heterozygous (17%). The allelic frequency of the 5569A polymorphism in the control population was 14.3%. CONCLUSIONS: Although misdiagnosis was not committed, we recommend changing to any primer that does not include the 5569G/A polymorphism in the study of HH.

Elastofibroma dorsi as a cause of shoulder pain or snapping scapula.

Elastofibroma dorsi is a benign soft tissue tumor, not well-known because of its low incidence, located in the chest wall in the subscapular area. In 10 patients with elastofibroma dorsi, the clinical symptoms were snapping scapula or shoulder pain. In three of the patients, the previous diagnosis was shoulder impingement, and the patients were treated without success. The clinical diagnosis was confirmed by magnetic resonance imaging. Surgical treatment resolved the symptoms in all patients. This tumor should be considered in the differential diagnosis of snapping scapula or shoulder impingement.

Participation of blood cells in the changes of blood amino acid concentrations during maximal exercise.

We determined the participation of the cellular compartment in the changes of plasma amino acid concentrations during maximal exercise test on a cycle ergometer. Following an overnight fast, male athletes were submitted to a maximal exercise test until fatigue (for 25 min approximately) to determine maximal oxygen uptake. The amino acid concentrations in total blood, plasma, and blood cells were determined before and after the maximal exercise test. Most essential amino acids were decreased significantly in the total blood concentration as a result of the maximal exercise test. However, the concentrations of most nonessential amino acids tended to be significantly increased. Amino acid concentration was increased most in plasma. Concentrations of blood cell alanine and proline were significantly increased by 26% and 15%, respectively, after the maximal exercise test. No significant differences in blood cell concentrations of other amino acids induced by the exercise test were found, although the amount of tryptophan in blood cells was increased after exhaustive exercise.

Regulation of erythrocyte antioxidant enzyme activities in athletes during competition and short-term recovery.

We have determined "in vivo" the influence of strenuous prolonged exercise and short-term recovery on erythrocyte antioxidant enzyme activities. We have also determined the "in vitro" effects of the xanthine/xanthine-oxidase-generating superoxide anion system on catalase activity in haemolysed erythrocytes. Haematological parameters and erythrocyte superoxide dismutase (SOD), glutathione peroxidases and catalase activities were measured in nine healthy duathlon athletes under basal conditions, at the finish of a competition and after 1 h of recovery. We also measured catalase activity in haemolysed erythrocytes--obtained from four overnight-fasted well-trained sportsmen before and after an 80% submaximal exercise test on a cycle-ergometer--prior to and after incubation for 3 min with the superoxide-anion-generating system. Duathlon competition and/or short-term recovery produced a slight haemolysis and increased the activity of catalase and peroxidases but not SOD enzymes. The observed changes in catalase activity were mimicked "in vitro" by the superoxide-anion-generating system.

[Normal values of valvular annular areas. Comparison of the results of a necropsy and an echocardiographic series]. / Valores normales de las áreas de los anillos valvulares. Comparación de los resultados de una serie necrópsica y otra ecocardiográfica.

INTRODUCTION AND OBJECTIVES: Measurement of valvular annular area is necessary for valvular flow volumen quantification by Doppler echocardiography. The aim of this work was to compare normal valvular annular area values obtained in a necropsic and an echocardiographic series and to ascertain whether a relationship exists between these areas and several anthropometric variables. METHODS: Necropsic series: valvular annular area was measured in 20 hearts from deceased patients (age range: 9-79 years; mean 52 +/- 18) without cardiovascular disease. Echocardiographic series: Valvular annular area was determined in 156 patients (age range: 6-86 years; mean 37 +/- 20) without cardiovascular disease. RESULTS: Necropsic series: multiple regression analysis showed valvular annular area values to be related mainly to height (p < 0.001) but also to weight (p < 0.01). Correlations between valvular annular area and body surface were low (r = 0.64-0.75). Aortic annular area index was slightly lower than the pulmonary annular area index and half that of the mitral annular area index (2.2 +/- 0.4, 2.5 +/- 0.5 and 4.4 +/- 0.8 cm2/m2, respectively). Tricuspid annular area index was the largest (6.7 +/- 1.0 cm2/m2). ECHOCARDIOGRAPHIC SERIES: Multiple regression analysis also showed a relationship between valvular annular area and height (p < 0.00001) and weight (p < 0.004). Correlations between valvular annular real values and body surface were poor (r = 0.45-0.71). Mean values of aortic, pulmonary and mitral valvular annular area indices were similar to those obtained in the necropsic series (2.1 +/- 0.2, 2.1 +/- 0.3, 4.1 +/- 0.6 cm2/m2, respectively). However, the tricuspid annular area index was clearly lower (4.5 +/- 0.6 cm2/m2, p < 0.001). CONCLUSIONS: Valvular annular area is influenced mainly by height, but also by weight. The correlation between these values and body surface is poor. Aortic annular area is similar to the pulmonary annular area and half that of the mitral annulus. Normal values determined by echocardiography and necropsy are similar, although tricuspid annular area by apical view is smaller than that obtained in the necropsic series.

Fertility and histology after rabbit ovarian wedge resection with CO2 laser or electrocautery using posterior reconstruction with nylon or polyglactin sutures.

In an experimental study in rabbits, the CO2 laser and electrocautery were compared in performing microsurgical ovarian wedge resection; polyglactin and nylon sutures were compared for ovarian reconstruction. Histologic reaction, adhesion formation, and functional parameters (number of corpora lutea, number of pregnancies, nidation index) were evaluated 30 and 90 days postoperatively. Thirty days after surgery, the tissue inflammatory response was very similar in the four groups; fibrosis was not detected. Significant reductions (P less than 0.01) were found for the experimental (operated right ovary) vs. the control (unoperated left ovary) groups when comparing the number of corpora lutea and the number of pregnancies. No significant differences in the nidation index were demonstrated. Adhesion formation was not different between any of the experimental procedures; adhesions were not detected in the control ovaries. At 90 days, the polyglactin suture was entirely absorbed and no inflammatory reaction persisted. Minimal giant cell infiltration was found around the nylon suture. The histologic differences between the two sutures were statistically significant (P less than 0.02). No fibrosis was observed. The functional parameters did not reveal statistically significant differences between the two sutures.

[Gastric carcinoma with a lymphoid stroma]. / Carcinoma gástrico con estroma linfoide.

Carcinomas with lymphoid stroma have been described in different locations: breast, uterine cervix, nasopharynx, esophagus and stomach. These neoplasms have a better prognosis probably due to the lymphoid reaction that takes place in the tumoral stroma. For this reason many authors prefer to consider this entity separate from the rest of gastric carcinomas. We present a case of gastric carcinoma with lymphoid stroma and neuroendocrine features. Such association has not been previously described in the Spanish literature.

Hepatoid gastric adenocarcinoma.

A case of hepatoid gastric adenocarcinoma is reported. The tumor had the histological and immunohistochemical features of both liver cell carcinoma and conventional intestinal-type adenocarcinoma. We discuss the main clinical and pathological features of this uncommon variety of gastric cancer.