Growth patterns and outcomes of growth hormone therapy in patients with acrodysostosis.

INTRODUCTION: Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations). METHODS: We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5. RESULTS: We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median - 2.2 SDS vs. - 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median - 2.8 SDS vs. - 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1-2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6-5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5-3.1 for rhGH-treated iPPSD5 (n = 2). CONCLUSION: Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.

Expert consensus to optimize the treatment of elderly patients with luminal metastatic breast cancer

Most patients diagnosed with luminal metastatic breast cancer (MBC) who are seen in oncology consultations are elderly. MBC in elderly patients is characterized by a higher percentage of hormone receptor (HR) expression and a lower expression of human epidermal growth factor receptor 2 (HER2). The decision regarding which treatment to administer to these patients is complex due to the lack of solid evidence to support the decision-making process. The objective of this paper is to review the scientific evidence on the treatment of elderly patients with luminal MBC. For this purpose, the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Breast Cancer Research Group (GEICAM) and the SOLTI Group appointed a group of experts who have worked together to establish consensus recommendations to optimize the treatment of this population. It was concluded that the chronological age of the patient alone should not guide therapeutic decisions and that a Comprehensive Geriatric Assessment (CGA) should be performed whenever possible before establishing treatment. Treatment selection for the elderly population should consider the patient’s baseline status, the expected benefit and toxicity of each treatment, and the impact of treatment toxicity on the patient’s quality of life and functionality.

Expert consensus to optimize the treatment of elderly patients with luminal metastatic breast cancer.

Most patients diagnosed with luminal metastatic breast cancer (MBC) who are seen in oncology consultations are elderly. MBC in elderly patients is characterized by a higher percentage of hormone receptor (HR) expression and a lower expression of human epidermal growth factor receptor 2 (HER2). The decision regarding which treatment to administer to these patients is complex due to the lack of solid evidence to support the decision-making process. The objective of this paper is to review the scientific evidence on the treatment of elderly patients with luminal MBC. For this purpose, the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Breast Cancer Research Group (GEICAM) and the SOLTI Group appointed a group of experts who have worked together to establish consensus recommendations to optimize the treatment of this population. It was concluded that the chronological age of the patient alone should not guide therapeutic decisions and that a Comprehensive Geriatric Assessment (CGA) should be performed whenever possible before establishing treatment. Treatment selection for the elderly population should consider the patient's baseline status, the expected benefit and toxicity of each treatment, and the impact of treatment toxicity on the patient's quality of life and functionality.

Surface-guided radiation therapy for breast cancer: more precise positioning

Introduction Hypofractionated radiation therapy for breast cancer requires highly precise delivery through the use of image-guided radiotherapy (IGRT). Surface-guided radiation therapy (SGRT) is being increasingly used for patient positioning in breast radiotherapy. We aimed to assess the role of SGRT for verification of breast radiotherapy and the tumour bed. Materials and method Prospective study of 252 patients with early stage breast cancer. A total of 1170 determinations of daily positioning were performed. Breast surface positioning was determined with SGRT (AlignRT) and correlated with the surgical clips in the tumour bed, verified by IGRT (ExacTrac). Results SGRT improved surface matching by a mean of 5.3 points compared to conventional skin markers (98.0 vs. 92.7), a statistically significant difference (p < 0.01, Wilcoxon Test). For surface matching values > 95%, ≥ 3 clips coincided in 99.7% of the determinations and all markers coincided in 92.5%. For surface matching rates > 90%, the location of ≥ 3 clips coincided in 99.55% of determinations. Conclusions SGRT improves patient positioning accuracy compared to skin markers. Optimal breast SGRT can accurately verify the localisation of the tumour bed, ensuring matching with ≥ 3 surgical clips. SGRT can eliminate unwanted radiation from IGRT verification systems (AU)

Surface-guided radiation therapy for breast cancer: more precise positioning.

INTRODUCTION: Hypofractionated radiation therapy for breast cancer requires highly precise delivery through the use of image-guided radiotherapy (IGRT). Surface-guided radiation therapy (SGRT) is being increasingly used for patient positioning in breast radiotherapy. We aimed to assess the role of SGRT for verification of breast radiotherapy and the tumour bed. MATERIALS AND METHODS: Prospective study of 252 patients with early stage breast cancer. A total of 1170 determinations of daily positioning were performed. Breast surface positioning was determined with SGRT (AlignRT) and correlated with the surgical clips in the tumour bed, verified by IGRT (ExacTrac). RESULTS: SGRT improved surface matching by a mean of 5.3 points compared to conventional skin markers (98.0 vs. 92.7), a statistically significant difference (p < 0.01, Wilcoxon Test). For surface matching values > 95%, ≥ 3 clips coincided in 99.7% of the determinations and all markers coincided in 92.5%. For surface matching rates > 90%, the location of ≥ 3 clips coincided in 99.55% of determinations. CONCLUSIONS: SGRT improves patient positioning accuracy compared to skin markers. Optimal breast SGRT can accurately verify the localisation of the tumour bed, ensuring matching with ≥ 3 surgical clips. SGRT can eliminate unwanted radiation from IGRT verification systems.

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.

PURPOSE: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. MATERIALS AND METHODS: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. RESULTS: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). CONCLUSION: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

Clinical significance of epithelial-mesenchymal transition-related markers expression in the micrometastatic sentinel lymph node of NSCLC.

OBJECTIVES: Metastatic lymph node affectation is the main prognostic factor in localised lung cancer. However, the pathological study of lymph nodes reveals tumour relapse for 20% of patients after oncological curative surgery. Recently, EMT (epithelial-mesenchymal transition) has been established as one of the main factors related to lymphatic dissemination and metastasis. This study evaluated the prognostic value of EMT-related gene expression in micrometastatic sentinel lymph nodes (SLN) of non-small cell lung cancer (NSCLC) patients. METHODS: The presence of genes CDH1, CDH2, VIM, TWIST1, SNAI1, SNAI2, ZEB1, and ZEB2 in mRNA was analysed in tumours and in the SLN of NSCLC patients for whom surgery was planned for treatment. The significant association between the expression level of EMT-related markers and patients' clinicopathological characteristics and relapse was assessed. RESULTS: Of the 96 patients, 56 (58.33%) presented molecular micrometastasis in SLN, which showed higher CDH1, CDH2, and VIM expressions than non-micrometastatic ones. An association linking a low CDH1/CDH2 ratio in SLN with molecular micrometastasis, adenocarcinoma, and non-smoking patients was found. The multivariate Cox regression analysis proved the prognostic accuracy of the CDH1/CDH2 ratio in SLN. CONCLUSIONS: The molecular EMT status of SLN could be used as an independent prognosis predictor in early stage NSLCL patients, and as a new tool to better stratify and predict patient outcomes.

Failure modes and effects analysis of total skin electron irradiation technique

Purpose. Total skin electron irradiation (TSEI) is a radiotherapy technique which consists of an homogeneous body surface irradiation by electrons. This treatment requires very strict technical and dosimetric conditions, requiring the implementation of multiple controls. Recently, the Task Group 100 report of the AAPM has recommended adapting the quality assurance program of the facility to the risks of their processes. Materials and methods. A multidisciplinary team evaluated the potential failure modes (FMs) of every process step, regardless of the management tools applied in the installation. For every FM, occurrence (O), severity (S) and detectability (D) by consensus was evaluated, which resulted in the risk priority number (RPN), which permitted the ranking of the FMs. Subsequently, all the management tools used, related to the TSEI process, were examined and the FMs were reevaluated, to analyze the effectiveness of these tools and to propose new management tools to cover the greater risk FMs. Results. 361 FMs were identified, 103 of which had RPN ≥80, initially, and 41 had S ≥ 8. Taking this into account the quality management tools FMs were reevaluated and only 30 FMs had RPN ≥80. The study of these 30 FMs emphasized that the FMs that involved greater risk were related to the diffuser screen placement and the patient’s position during treatment. Conclusions. The quality assurance program of the facility has been adapted to the risk of this treatment process, following the guidelines proposed by the TG-100. However, clinical experience continually reveals new FMs, so the need for periodic risk analysis is required (AU)

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Failure modes and effects analysis of total skin electron irradiation technique.

PURPOSE: Total skin electron irradiation (TSEI) is a radiotherapy technique which consists of an homogeneous body surface irradiation by electrons. This treatment requires very strict technical and dosimetric conditions, requiring the implementation of multiple controls. Recently, the Task Group 100 report of the AAPM has recommended adapting the quality assurance program of the facility to the risks of their processes. MATERIALS AND METHODS: A multidisciplinary team evaluated the potential failure modes (FMs) of every process step, regardless of the management tools applied in the installation. For every FM, occurrence (O), severity (S) and detectability (D) by consensus was evaluated, which resulted in the risk priority number (RPN), which permitted the ranking of the FMs. Subsequently, all the management tools used, related to the TSEI process, were examined and the FMs were reevaluated, to analyze the effectiveness of these tools and to propose new management tools to cover the greater risk FMs. RESULTS: 361 FMs were identified, 103 of which had RPN ≥80, initially, and 41 had S ≥ 8. Taking this into account the quality management tools FMs were reevaluated and only 30 FMs had RPN ≥80. The study of these 30 FMs emphasized that the FMs that involved greater risk were related to the diffuser screen placement and the patient's position during treatment. CONCLUSIONS: The quality assurance program of the facility has been adapted to the risk of this treatment process, following the guidelines proposed by the TG-100. However, clinical experience continually reveals new FMs, so the need for periodic risk analysis is required.

Topography of the sentinel node according to the affected lobe in lung cancer

Purpose. The objective of this study is to describe the anatomic location of the sentinel lymph node (SLN) of patients with lung carcinoma and to analyze its relationship with the characteristics of the tumor. Patients and methods. 98 Stage I lung cancer patients were included in the study. SLN was marked just after performing the thoracotomy by injecting peritumorally 0.25 mCi of nanocolloid of albumin (Nanocol1) labeled with Tc-99 m in 0.3 ml, and later, it was resected. For SLN micrometastasis analysis, CEACAM5, BPIFA1, and CK7 gene expression at mRNA level was studied. Possible relation between tumor characteristics and SLN location was analyzed. Results. While most of the SLN were located in hilar area, we find a significantly higher number of SLN located in mediastinal stations when the lesion is in the left upper lobe (LUL). This difference disappears in the group of SLN with a positive result in the micrometastasis study. Regarding tumor size, squamous tumors and tumors located in the left lower lobe (LLL) were found significantly larger. Conclusion. The location of the SLN in patients with stage I lung cancer is predominantly hilar, being less consistent in the left hemithorax. The tumor size or histological type is not variables that affect this distribution. The distribution of SLNs with a positive result in the analysis of micrometastasis suggests further spread to the hilar areas when the lesion is in the LUL and to the mediastinal zones when it is in the LLL (AU)

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Topography of the sentinel node according to the affected lobe in lung cancer.

PURPOSE: The objective of this study is to describe the anatomic location of the sentinel lymph node (SLN) of patients with lung carcinoma and to analyze its relationship with the characteristics of the tumor. PATIENTS AND METHODS: 98 Stage I lung cancer patients were included in the study. SLN was marked just after performing the thoracotomy by injecting peritumorally 0.25 mCi of nanocolloid of albumin (Nanocol1) labeled with Tc-99 m in 0.3 ml, and later, it was resected. For SLN micrometastasis analysis, CEACAM5, BPIFA1, and CK7 gene expression at mRNA level was studied. Possible relation between tumor characteristics and SLN location was analyzed. RESULTS: While most of the SLN were located in hilar area, we find a significantly higher number of SLN located in mediastinal stations when the lesion is in the left upper lobe (LUL). This difference disappears in the group of SLN with a positive result in the micrometastasis study. Regarding tumor size, squamous tumors and tumors located in the left lower lobe (LLL) were found significantly larger. CONCLUSION: The location of the SLN in patients with stage I lung cancer is predominantly hilar, being less consistent in the left hemithorax. The tumor size or histological type is not variables that affect this distribution. The distribution of SLNs with a positive result in the analysis of micrometastasis suggests further spread to the hilar areas when the lesion is in the LUL and to the mediastinal zones when it is in the LLL.

Síndrome de Phelan-McDermid: un caso clínico con una deleción de 1, 7 Mb en 22q13.3 / Phelan-McDermid syndrome: a case with a 1.7 Mb deletion in 22q13.3

Introducción: El síndrome de Phelan-McDermid está producido por una microdeleción en la región 22q13.3. Esta microdeleción se ve asociada a una gran variabilidad fenotípica, y recientemente se ha sugerido una correlación entre el tamaño de la deleción y la gravedad de la sintomatología. Caso clínico: En el presente trabajo describimos el caso clínico de un niño atendido en nuestro hospital con un importante retraso en el área del lenguaje y el aprendizaje, en el que se realizó un análisis genético mediante MLPA (multiplex ligation-dependent probe amplification) y microarray. Resultados: Se detectó en el paciente una deleción terminal de 1,7 Mb en el cromosoma 22 con una pérdida de los genes ARSA-1, SHANK3 y RABL2B. Conclusión: El análisis de las microdeleciones en el cromosoma 22q13.3 mediante la técnica de microarray permite determinar qué genes están afectados en los casos de síndrome de Phelan-McDermid, y establecer una mejor correlación genotipo-fenotipo para predecir la evolución de cada paciente de una forma más precisa (AU)

Introduction: Phelan-McDermid syndrome is caused by a microdeletion in the 22q13.3 region that has been related to high phenotypic variability. Recently, it has been suggested a correlation between the size of the deletion and the severity of the symptoms presented by patients. Case report: We report the case of a child treated at our Hospital with a significant delay in the area of language and learning, and the results of the genetic analysis performed using multiplex ligation-dependent probe amplification (MLPA) and microarray techniques. Results: A 1.7 Mb terminal deletion was detected on chromosome 22 with a loss of ARSA-1, SHANK3 and RABL2B genes. Conclusion: Microdeletion analysis of 22q13.3 region should be performed by microarray technique in order to detect which genes are involved in Phelan-McDermid syndrome, finding a better phenotype-genotype correlation that will allow predicting patient’s prognosis more accurately (AU)

Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer

Introduction: Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. Patients and methods: ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by realtime quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient’s disease-free survival was assessed. Results: We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. Conclusion: Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients (AU)

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Meat Consumption and Risk of Developing Type 2 Diabetes in the SUN Project: A Highly Educated Middle-Class Population.

BACKGROUND: Meat consumption has been consistently associated with the risk of diabetes in different populations. The aim of our study was to investigate the incidence of type 2 diabetes according to baseline total meat consumption in a longitudinal assessment of a middle-aged Mediterranean population. METHODS: We followed 18,527 participants (mean age: 38 years, 61% women) in the SUN Project, an open-enrolment cohort of a highly educated population of middle-class Spanish graduate students. All participants were initially free of diabetes. Diet was assessed at baseline using a semi-quantitative food frequency questionnaire of 136-items previously validated. Incident diabetes was defined according to the American Diabetes Association's criteria. RESULTS: We identified 146 incident cases of diabetes after a maximum of 14 years of follow-up period (mean: 8.7 years). In the fully adjusted model, the consumption of ≥3 servings/day of all types of meat was significantly associated with a higher risk of diabetes (HR: 1.85; 95% CI: 1.03-3.31; p for trend = 0.031) in comparison with the reference category (<2 servings/day). When we separated processed from non-processed meat, we observed a non-significant higher risk associated with greater consumption of processed meat and a non-significant lower risk associated with non-processed meat consumption (p for trend = 0.123 and 0.487, respectively). No significant difference was found between the two types of meat (p = 0.594). CONCLUSIONS: Our results suggest that meat consumption, especially processed meat, was associated with a higher risk of developing diabetes in our young Mediterranean cohort.

Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer.

INTRODUCTION: Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. PATIENTS AND METHODS: ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient's disease-free survival was assessed. RESULTS: We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. CONCLUSION: Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.

The impact of a computerized physician order entry system on medical errors with antineoplastic drugs 5 years after its implementation.

WHAT IS KNOWN AND OBJECTIVE: Computerized physician order entry (CPOE) systems reduce medical errors (MEs). Nevertheless, a CPOE system may also lead to new types of errors, especially when it is first implemented. The objectives of this study were to determine the impact of a CPOE on the number of MEs and to identify the types of MEs in prescriptions issued by the Haematology Department 5 years after the implementation of the CPOE system. METHODS: We conducted a prospective analytical study on the implementation of a CPOE system at the Pharmacy Department of the Hospital Ramon y Cajal (Madrid, Spain). The study comprised three phases: a pre-implementation phase, an implementation phase conducted in the Haematology Department and a post-implementation phase, which was conducted 5 years after the implementation of the CPOE system. One hundred and fifty prescriptions per pre- and post-implementation phase were consecutively included in the study. A previously described classification scheme was used to detect and classify MEs. RESULTS AND DISCUSSION: The implementation of a CPOE system was associated with a large reduction in MEs. One hundred and fourteen patients (pre-implementation phase) were compared to 82 patients (post-implementation phase). The total number of MEs per 100 patients decreased from 236·8 (95% CI: 212·1-261·3) to 10·9 (95% CI: 5·8-19·6), with an absolute risk reduction of 36·2 (95% CI: 32·6-39·9). The percentage of prescriptions with an ME decreased from 37·5% to 1·2% (P < 0.001). In the pre-implementation phase, the drugs most frequently associated with MEs were rituximab (35·9%), cyclophosphamide (13%) and methotrexate (7%). In the post-implementation phase, 44·4% of prescription errors involved methotrexate. Five years after the implementation of the CPOE system, the majority of MEs were eliminated, the number of remaining errors (quantity, concentration and ambiguous prescription errors) decreased, and no new types of ME were detected. WHAT IS NEW AND CONCLUSION: The CPOE system almost completely eliminated MEs with antineoplastic drugs in the Haematology Department. No new types of MEs were observed once physicians had become accustomed to using the system. However, some MEs were not eliminated. Constant diligence is needed to analyse and evaluate MEs associated with the CPOE system and their causes, such that the limitations of CPOE can be identified and overcome and the medication-use process associated with antineoplastic agents improved.

Looking for complementary alternatives to CTCAE for skin toxicity in radiotherapy: quantitative determinations

INTRODUCTION: Radiotherapy (RT) is an essential part of the patient's treatment diagnosed with cancer. Determination of the most common RT secondary effect, the cutaneous toxicity, is usually based on visual rating scales, like Common Terminology Criteria for Adverse Events with an inherent subjectivity. The aim of this work is to perform an objective method to evaluate the radiodermatitis using a non-invasive imaging technique based on laser Doppler flowmetry (LDF). MATERIALS AND METHODS: A prospective study was performed analysing 1,824 measurements. A LDF was used to measure the cutaneous microcirculation in real time. A basal measurement was taken prior to radiotherapy treatment. To be able to observe the microcirculation changes related to the delivered dose, several sets of measurements were taken in the irradiated area along the RT treatment and in the contralateral non-irradiated area. RESULTS: A relative increase in blood flow at all measured points was found in the irradiated area. This relative increase in blood flow increases with the dose administered. In the non-irradiated contralateral area, the relative increase in blood flow is not significant and is independent of the dose administered. After treatment, a decrease in blood flow was detected with a trend towards returning to the baseline measurements. CONCLUSIONS: LDF is an objective technique that assesses early radiodermatitis. This method is useful to develop strategies to prevent onset of radiation dermatitis in patients irradiated, such as the modification and individualization of fractionation parameters of the RT. This allows the reduction of radiation morbidities and maintains patient quality of life (AU)

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Changes in nerve- and endothelium-mediated contractile tone of the corpus cavernosum in a mouse model of pre-mature ageing.

Erectile dysfunction (ED) is very prevalent in the older population, although the ageing-related mechanisms involved in the development of ED are poorly understood. We propose that age-induced differences in nerve- and endothelium-mediated smooth muscle contractility in the corpus cavernosum (CC) could be found between a senescent-accelerated mouse prone (SAMP8) and senescent-accelerated mouse resistant (SAMR1) strains. We analysed the changes in muscle tension induced by electrical field stimulation (EFS) or agonist addition 'in vitro', assessing nerve density (adrenergic, cholinergic and nitrergic), the expression of endothelial nitric oxide synthase (eNOS), cGMP accumulation and the distribution of interstitial cells (ICs) by immunofluorescence. We observed no change in both the nerve-dependent adrenergic excitatory contractility at physiological levels of stimulation and in the nitrergic inhibitory response in SAMP8 animals. Unlike cholinergic innervation, the density of adrenergic and nitrergic nerves increased in SAMP8 mice. In contrast, smooth muscle sensitivity to exogenous noradrenaline (NA) was slightly reduced, whereas cGMP accumulation in response to EFS and DEA/NO, and relaxations to DEA/NO and sildenafil, were not modified. No changes in the expression of eNOS and in the distribution of vimentin-positive ICs were detected in the aged animals. The ACh induced atropine-sensitive biphasic endothelium-dependent responses involved relaxation at low concentrations that turned into contractions at the highest doses. CC relaxation was mainly because of the production of NO together with some relaxant prostanoid, which did not change in SAMP8 animals. In contrast, the contractile component was considerably higher in the aged animals and it was completely inhibited by indomethacin. In conclusion, a clear imbalance towards enhanced production of contractile prostanoids from the endothelium may contribute to ED in the elderly. On the basis of these data, we propose the senescence-accelerated mouse model as a reliable tool to analyse the basic ageing mechanisms of the CC.

Looking for complementary alternatives to CTCAE for skin toxicity in radiotherapy: quantitative determinations.

INTRODUCTION: Radiotherapy (RT) is an essential part of the patient's treatment diagnosed with cancer. Determination of the most common RT secondary effect, the cutaneous toxicity, is usually based on visual rating scales, like Common Terminology Criteria for Adverse Events with an inherent subjectivity. The aim of this work is to perform an objective method to evaluate the radiodermatitis using a non-invasive imaging technique based on laser Doppler flowmetry (LDF). MATERIALS AND METHODS: A prospective study was performed analysing 1,824 measurements. A LDF was used to measure the cutaneous microcirculation in real time. A basal measurement was taken prior to radiotherapy treatment. To be able to observe the microcirculation changes related to the delivered dose, several sets of measurements were taken in the irradiated area along the RT treatment and in the contralateral non-irradiated area. RESULTS: A relative increase in blood flow at all measured points was found in the irradiated area. This relative increase in blood flow increases with the dose administered. In the non-irradiated contralateral area, the relative increase in blood flow is not significant and is independent of the dose administered. After treatment, a decrease in blood flow was detected with a trend towards returning to the baseline measurements. CONCLUSIONS: LDF is an objective technique that assesses early radiodermatitis. This method is useful to develop strategies to prevent onset of radiation dermatitis in patients irradiated, such as the modification and individualization of fractionation parameters of the RT. This allows the reduction of radiation morbidities and maintains patient quality of life.

Changes in nerve-mediated contractility of the lower urinary tract in a mouse model of premature ageing.

BACKGROUND AND PURPOSE: A high incidence of lower urinary tract disorders is associated with ageing. In the senescent-accelerated prone (SAMP8) mouse strain and the senescent-accelerated resistant (SAMR1) strain, we compared smooth muscle contractility in responses to intrinsic neurotransmitters, both in the bladder and urethra. EXPERIMENTAL APPROACH: We analysed micturition frequency, the changes in muscle tension induced by electrical field stimulation or agonist administration, the density of nerves (adrenergic, cholinergic and nitrergic) and interstitial cells (ICs), as well as cGMP accumulation in bladder and urethral preparations. KEY RESULTS: Senescent mice of the SAMP8 strain displayed increased micturition frequency and excitatory contractility of neurogenic origin in the bladder. While cholinergic nerve density remained unchanged, there was a mild sensitization to ACh in male mice. Potentiation in the detrusor may be also provoked by the stronger contribution of ATP, together with reduced adrenergic innervation in males and COX-derived prostanoid production in females. The greater excitatory contractility in the urethra was probably due to the sensitization to noradrenaline, in conjunction with attenuated nitrergic relaxation. There were also fewer neuronal NOS immunoreactive (ir) nerves and vimentin-positive ICs, although the sildenafil- and diethylamine-NONOate-induced relaxations and cGMP-ir remained unchanged. CONCLUSIONS AND IMPLICATIONS: Premature senescent mice exhibit bladder and urethral hyperexcitability, coupled with reduced urethral relaxation of neurogenic origin, which could model the impaired urinary function in elderly humans. We propose that senescence-accelerated mice provide a useful tool to analyse the basic mechanisms of age-related changes in bladder and urethral function.