Sequential chemotherapy regimen of induction with panitumumab and paclitaxel followed by radiotherapy and panitumumab in patients with locally advanced head and neck cancer unfit for platinum derivatives. The phase II, PANTERA/TTCC-2010-06 study.

BACKGROUND: Sequential treatment of Panitumumab (Pb) plus Paclitaxel (Px) as induction treatment (IT) followed by concurrent bioradiotherapy (Bio-RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy. METHODS: Phase II, single-arm, multicentre study, with two-stage design, in patients ≥ 18 years with stage III-IVa-b LA-SCCHN unfit for platinum. Patients received Px + Pb (9 weeks) as IT followed by Bio-RT + Pb. Primary endpoint: overall response rate (ORR) after IT, defined as: more than 70% of patients achieving complete response (CR) or partial response (PR) to IT. Secondary end-points: progression-free survival, organ preservation rate, safety profile. RESULTS: Study ended prematurely (51 patients) due to slow recruitment. ORR: 66.7% (95% CI: 53.7-79.6), 8 (15.7%) CR and 26 (51.0%) PR. 39 patients (76%) completed radiotherapy (RT). Pb and/or Px-related adverse events (AEs) grade 3-4: 56.9% during IT and 63.4% during the concomitant phase, of which most common were skin toxicity (33.3%). Five deaths occurred during treatment, two of them (3.9%) were Pb and/or Px-related. CONCLUSIONS: Although underpowered, ORR was higher than the pre-specified boundary for considering the treatment active. Although Px + Pb as IT provides some benefit, the safety profile is worse than expected. To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further research/investigation would be needed.

LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Mejora en la eficacia de la intervención entre el fisioterapeuta y el equipo de Atención Primaria / Improving the efficacy of the intervention between the physiotherapist and primary care team

Objetivos. Con este trabajo pretendemos mejorar la eficacia y coordinación de los mecanismos de derivación entre los médicos de familia y el equipo de fisioterapia de Atención Primaria (AP). Aumentar el número de derivaciones correctas (incluidas en los protocolos) realizadas por estos a fisioterapia y disminuir el número de derivaciones incorrectas. Así como disminuir la demora en la asistencia. Material y métodos. Estudio cuasi-cuantitativo, prospectivo. Muestreo secuencial no aleatorio de 198 pacientes derivados tanto de AP como especializada. Se evaluó tanto la demora (medida en días), como el número de derivaciones correctas e incorrectas (según las guías de intervención) antes y después de la sesión clínica informativa realizada con los médicos de familia de la zona básica del Centro de Salud de Níjar. Resultados. En cuanto al número de derivaciones incorrectas (no cumplen los protocolos especificados en la guía), usando la prueba Chi-cuadrado de Pearson con corrección de Yates obtenemos una p=0,0127. Sobre el incremento del número de derivaciones desde AP, usando la prueba Z de comparación de proporciones, con un nivel de confianza del 95% obtenemos una p=0,0015. Con respecto al tiempo de demora, utilizamos la prueba t de Student con un nivel de confianza del 95% y obtenemos una p<0,001. Conclusiones. Se aumentan las derivaciones directas desde AP y se disminuyen los tiempos de espera del tratamiento de fisioterapia beneficiando así al usuario, por lo que se mejora la integración de la labor del fisioterapeuta dentro del equipo de AP(AU)

Objectives. With this work, we are aiming to improve the efficacy and coordination of referral mechanisms between primary care physicians and the primary care physiotherapy team, to increase the number of correct referrals (including in the protocols) performed by former to physiotherapy and to reduce the incorrect referrals as well as to reduce waiting times for treatment. Material and methods. A quasi-quantitative, prospective study was performed using a non-randomized, sequential sample of 198 patients referred by primary and specialized care. Delay (measured in days) and number of correct and incorrect referrals (guideline-based intervention) before and after the clinical session carried out by the primary care physicians of the Basic health care area of Nijar were evaluated. Results. In regards to number of incorrect referrals (those not fulfilling the specified protocols in the guideline), P=0.0127 was obtained when using the Chi-square test with Yates correction Pearson. In regards to the number of referrals from primary care, a P=0.0015 was obtained when using the Z test for comparison of proportions, with a 95% confidence level. For delay time, the using the Student's T test with a confidence level of 95%, a P<0.001 was obtained. Conclusions. Direct referrals from primary care are increasing and waiting times for physiotherapy treatment are decreasing, with improved integration of the work of the physiotherapist within the Primary Care Team, thus benefiting the user(AU)

Phase II trial: concurrent radio-chemotherapy with weekly docetaxel for advanced squamous cell carcinoma of head and neck.

INTRODUCTION: Standard fractionation radiation therapy (RT) combined with concomitant chemotherapy (CT) based on cisplatin schemes is actually the standard treatment for locally advanced non-resectable squamous cell carcinoma of head and neck (SCCHN). The appearance of taxoids has introduced a new kind of treatment with high antitumoral power. The aim of this study is to add more information about the role of this new approach. MATERIALS AND METHODS: Twenty-six patients with locally advanced non-resectable SCCHN were recruited at six institutions in Spain, between January 2001 and January 2003. Docetaxel was administered weekly, for 6 weeks, concurrently with RT. RESULTS: The mean total delivered dose of RT was 70'2 Gy (range 64-74 Gy). The median and mean duration of time were 63 days and 61 days (range 49-103 days) respectively. After a median time control of 19 months (range 3.3-42.2 months), the response rate was 83.4%. The median time to local progression was 16.4 months (95% confidence interval [CI]=4.4-28.4 months). The median survival time was 26.9 months, with one- and two-year overall survival of 66.9% (95% CI=48.1-85.7%) and 57.5% (95% CI=37.3-77.7%) respectively. The median duration time response was 15.1 months (95% CI=3.7-26.5 months). The median time until treatment failure was 9.4 months (95% CI=4.7-14.1). Incidence of grade III-IV mucositis was 88%, neutropenia 72% and skin toxicity 92% (24% grade III-IV). The incidence of severe late toxicity (grade III and IV) due to RT/CT was 31.4%. CONCLUSIONS: Although therapeutics results are equivalent to cisplatin schemes of concurrent CT-RT, mucositis and cutaneous toxicity registered in this trial must be considered as limiting factors to application of this new approach.

Phase II trial: concurrent radio-chemotherapy with weekly docetaxel for advanced squamous cell carcinoma of head and neck

INTRODUCTION: Standard fractionation radiation therapy (RT) combined with concomitant chemotherapy (CT) based on cisplatin schemes is actually the standard treatment for locally advanced non-resectable squamous cell carcinoma of head and neck (SCCHN). The appearance of taxoids has introduced a new kind of treatment with high antitumoral power. The aim of this study is to add more information about the role of this new approach. MATERIALS AND METHODS: Twenty-six patients with locally advanced non-resectable SCCHN were recruited at six institutions in Spain, between January 2001 and January 2003. Docetaxel was administered weekly, for 6 weeks, concurrently with RT. RESULTS: The mean total delivered dose of RT was 70'2 Gy (range 64-74 Gy). The median and mean duration of time were 63 days and 61 days (range 49-103 days) respectively. After a median time control of 19 months (range 3.3-42.2 months), the response rate was 83.4%. The median time to local progression was 16.4 months (95% confidence interval [CI]=4.4-28.4 months). The median survival time was 26.9 months, with one- and two-year overall survival of 66.9% (95% CI=48.1-85.7%) and 57.5% (95% CI=37.3-77.7%) respectively. The median duration time response was 15.1 months (95% CI=3.7-26.5 months). The median time until treatment failure was 9.4 months (95% CI=4.7-14.1). Incidence of grade III-IV mucositis was 88%, neutropenia 72% and skin toxicity 92% (24% grade III-IV). The incidence of severe late toxicity (grade III and IV) due to RT/CT was 31.4%. CONCLUSIONS: Although therapeutics results are equivalent to cisplatin schemes of concurrent CT-RT, mucositis and cutaneous toxicity registered in this trial must be considered as limiting factors to application of this new approach (AU)

La fibromialgia en el año 2002 / Fibromyalgia in 2002

No disponible

La fibromialgia en el año 2002 / Fibromyalgia in 2002

No disponible

Essential role of residue H49 for activity of Escherichia coli 1-deoxy-D-xylulose 5-phosphate synthase, the enzyme catalyzing the first step of the 2-C-methyl-D-erythritol 4-phosphate pathway for isoprenoid Synthesis.

The first step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis in plant plastids and most eubacteria is catalyzed by 1-deoxy-D-xylulose 5-phosphate synthase (DXS), a recently described transketolase-like enzyme. To identify key residues for DXS activity, we compared the amino acid sequence of Escherichia coli DXS with that of E. coli and yeast transketolase (TK). Alignment showed a previously undetected conserved region containing an invariant histidine residue that has been described to participate in proton transfer during TK catalysis. The possible role of the conserved residue in E. coli DXS (H49) was examined by site-directed mutagenesis. Replacement of this histidine residue with glutamine yielded a mutant DXS-H49Q enzyme that showed no detectable DXS activity. These findings are consistent with those obtained for yeast TK and demonstrate a key role of H49 for DXS activity.

A fluorometric assay for the determination of 1-deoxy-D-xylulose 5-phosphate synthase activity.

We report a novel fluorometric end-point assay for the determination of 1-deoxy-d-xylulose 5-phosphate synthase (DXS) activity based on the reaction of 1-deoxy-D-xylulose 5-phosphate (DX5P) with 3,5-diaminobenzoic acid in an acidic medium to form a highly fluorescent quinaldine derivative. The assay was validated in three ways: (a) for a fixed amount of DXS in the reaction mixture the emitted fluorescence increased linearly with the reaction time, (b) for a fixed reaction time fluorescence intensity increased with the concentration of DXS in the reaction mixture, and (c) the increase in fluorescence intensity correlated (r = 0.99; P < 0.002) with the amount of DX5P formed in the reaction mixture determined radiometrically. The sensitivity of the fluorometric assay is similar to that of the previously described radiometric methods. This assay can be useful for the functional characterization of DXS as well as for the screening of DXS inhibitors with potential antibiotic, herbicidal, or antimalarial action.

Therapeutic drug monitoring of tobramycin: once-daily versus twice-daily dosage schedules.

OBJECTIVE: To evaluate the effect of dosage regimen (once-daily vs. twice-daily) of tobramicyn on steady-state serum concentrations and toxicity. MATERIALS AND METHODS: Patients undergoing treatment with i.v. tobramycin (4 mg/kg/day) were randomised to two groups. Group OD (n = 22) received a once-daily dose of tobramycin and group TD (n = 21) received the same dose divided into two doses daily. Tobramycin serum concentrations (peak and trough) were measured by enzyme multiplied immunoassay. The renal and auditory functions of the patients were monitored before, during and immediately after treatment. RESULTS: The two groups were comparable with respect to sex, age, body weight and renal function. No statistically significant differences were found in mean daily dose, duration of treatment, or cumulative dose. Trough concentrations were < 2 g/ml in the two groups (100%). Peak concentrations were > 6 microg/ml in 100% of the OD group and in 67% of the TD group (P< 0.01). Mean peak concentrations were markedly different: 11.00+/-2.89 microg/ml in OD vs. 6.53+/-1.45 microg/ml in TD (P< 0.01). The pharmacokinetics parameters were: Ke, (0.15+/-0.03/h in OD vs. 0.24+/-0.06/h in TD), t1/2, (4.95+/-1.41 h in OD vs. 3.07+/-0.71 h in TD), Vd (0.35+/-0.11 l/kg in OD vs. 0.33+/-0.09 l/kg in TD), Cl (0.86+/-0.29 ml/min/kg in OD vs. 1.28+/-0.33 ml/min/kg in TD). Increased serum creatinine was observed in 73% of patients in OD versus 57% of patients in TD, without evidence of nephrotoxicity. In TD group, three patients developed decreased auditory function, of which one presented with an auditory loss of -30 dB, whereas in the OD group only one patient presented decreased auditory function. CONCLUSION: This small study suggests that a once-daily dosing regimen of tobramycin is at least as effective as and is no more and possibly less toxic than the twice-daily regimen. Using a single-dose therapy, peak concentration determination is not necessary, only trough samples should be monitored to ensure levels below 2 microg/ml.

[Applications of the polymerase chain reaction (PCR) to the diagnosis of central nervous system infections]. / Aplicaciones de la reacción en cadena de polimerasa (PCR) al diagnóstico de infecciones del sistema nervioso central.

The utility of polymerase chain reaction (PCR) is described for the diagnosis in three patients suffering from central nervous system infections, tuberculous meningitis, herpetic encephalitis and cerebral toxoplasmosis. PCR was performed in the cerebrospinal fluid after processing the specimen by two methods, proteinase K digestion and phenol extraction of DNA. Amplification was realized using primers previously described that amplify specific DNA fragments of each microorganisms (insertion sequence IS6110 of Mycobacterium tuberculosis, B1 gene of Toxoplasma gondii, and DNA polymerase gene of Herpes simplex virus). In all three cases, PCR was positive after amplification of the specimen extracted with proteinase K, as well as when a complete DNA extraction with phenol was realized. In all cases a band of amplified products was observed in agarose gels. In conclusion, in all three patients described, PCR would had allowed the diagnosis in seven hours, and PCR should be consider a rapid sensitive and relatively simple method.

Rapid diagnosis of pleural tuberculosis by polymerase chain reaction.

We have investigated the use of polymerase chain reaction (PCR) for the rapid diagnosis of pleural tuberculosis. The study was composed of 21 patients with pleural tuberculosis, confirmed by culture or pleural biopsy, and 86 control subjects. The PCR assay was based on detecting a 123-bp DNA segment belonging to the insertion sequence IS6110, specific of Mycobacterium tuberculosis complex. In 21 patients diagnosed with pleural tuberculosis, Ziehl-Neelsen staining was positive in three (14%) (95% CI, 7 to 21%) and pleural fluid culture in 11 (52%) (95% CI, 43 to 61%). Pleural biopsy revealed granulomas with caseous necrosis in 72%, and the culture was positive in 67% of the patients. Adenosine deaminase activity determination was positive (> 45 IU/L) in 86% (95% CI, 79 to 93%). The sensitivity and specificity for PCR was 81% (95% CI, 74 to 88%) and 100% (95% CI, 95 to 100%), respectively. All culture-positive specimens were PCR positive. We conclude that PCR is a rapid, sensitive, and specific method for the diagnosis of pleural tuberculosis. However, further prospective studies are required to properly evaluate the yield of the technique.

The utility of polymerase chain reaction (PCR) in the diagnosis of pulmonary tuberculosis.

A fragment of DNA of 123 bp belonging to insertion sequence IS6110, specific of Mycobacterium tuberculosis complex, was amplified by polymerase chain reaction (PCR) of respiratory samples, for the diagnosis of pulmonary tuberculosis. A total of 314 samples (286 sputum and 28 bronchoalveolar lavages) from 242 patients were evaluated by PCR, and the results were compared with the those obtained by acid-fast-stained smears, culture, and clinical diagnosis. Mycobacterium tuberculosis was detected by PCR in 102 of 105 patients with clinical diagnosis of pulmonary tuberculosis. All smear and culture-positive samples were PCR positive. The sensitivity of PCR, culture, and staining was 97%, 88%, and 65%, respectively, and the specificity was 100% in all cases. In ten patients with old residual lesions, but no active disease, M tuberculosis genome was detected by PCR. In our experience, PCR proved to be a useful method for the rapid diagnosis of pulmonary tuberculosis.

[Usefulness of IgG and IgM detection against antigen 60 in the diagnosis of thoracic tuberculosis]. / Utilidad de la determinación de IgG e IgM frente al antígeno 60 para el diagnóstico de la tuberculosis torácica.

We conducted a prospective study in order to assess the use of the "ELISA" method (Anda-Tb) for the detection of antibodies IgG and IgM against antigen 60 in mycobacterias for the initial diagnosis of thoracic tuberculosis. 215 serum samples from 44 patients with tuberculosis and 171 control cases were studied. The threshold value for IgG in our environment is 200 U, resulting in a specificity of 98% and a sensitivity of 34%. The IgM test has a low sensitivity, although when combined with the IgG, the sensitivity of the test increases while its specificity is reduced. This method is not useful in patients with HIV infection and immunodepression (AIDS). We have not observed any relationship between the serology and the response to PPD intradermorreaction. We conclude that this method could be used in our environment as a supplementary test, but in any case as a substitute of the traditional microbiological diagnosis.