Clinical Outreach Training and Supportive Supervision Quality-of-Care Analysis: Impact of Readiness Factors on Health Worker Competencies in Malaria Case Management in Cameroon, Mali, and Niger.

Improving the quality of malaria clinical case management in health facilities is key to improving health outcomes in patients. The U.S. President's Malaria Initiative Impact Malaria Project has supported implementation of the Outreach Training and Supportive Supervision (OTSS) approach in 11 African countries to improve the quality of malaria care in health facilities through the collection and analysis of observation-based data on health facility readiness and health provider competency in malaria case management. We conducted a secondary analysis of longitudinal data collected during routine supervision in Cameroon (April 2021-March 2022), Mali (October 2020-December 2021), and Niger (November 2020-September 2021) using digitized checklists to assess how service readiness affects health worker competencies in managing patients with fever correctly and providing those with confirmed uncomplicated malaria cases with appropriate treatment and referral. Linear or logistic regression analyses were conducted to assess the effect of facility readiness and its components on observed health worker competencies. All countries demonstrated significant associations between health facility readiness and malaria case management competencies. Data from three rounds of OTSS visits in Cameroon, Mali, and Niger showed a statistically significant positive association between greater facility readiness scores (including the availability of commodities, materials, and trained staff) and health worker competency in case management. These findings provide evidence that health worker performance is likely affected by the tools and training available to them. These results reinforce the need for necessary tools and properly trained staff if high-quality malaria case management services are to be delivered at health facilities.

Impact of Geriatric Assessment on the Tolerability of Combination Chemotherapy in Older Patients with Advanced Cancer: A Matched-Pair Analysis.

Because of their individual vulnerabilities, treatment decisions for older patients can be difficult. Geriatric assessment (GA) may help to select patients for systemic treatment, but its value is still unproven. Older cancer patients (≥65 years of age) with and without complex GA followed by discussion in the geriatric-oncologic conference, who had been treated in palliative intention with standard combination chemotherapy at the Evang. Kliniken Essen-Mitte, were retrospectively evaluated. All patients had been orally informed about the treatment options and had chosen chemotherapy beside supportive care. To reduce selection bias, the method of propensity-score matching was performed. Patient groups treated in the years 2011-2013 (without GA, group 1) and in the years 2014-2015 (with GA, group 2) were compared regarding different toxicity endpoints. The primary endpoint of the study was defined as numbers of patients with unplanned admission to the hospital or death during first-line chemotherapy and GA should reduce these events by 15%. Overall, 114 patients were evaluated in both groups. The median age was 74 years. Patients suffered from gastrointestinal carcinomas (47%), lung cancer (28%), breast cancer (12%), and other cancer types (3%). Consequently, most patients were treated with platinum-based (41%), fluoropyrimidine-based (35%), or anthracycline-based (13%) combination chemotherapy. In group 2, the events were numerically lower for all toxicity endpoints. The need for a premature stop of treatment was 54.4% in group 1 compared to 29.8% in group 2 (p < 0.01) and also the treatment-related mortality was significantly lower in group 2 (17.5% vs. 5.3%; p = 0.04). The primary endpoint, the rate of unplanned hospital admission, and death was 49.1% versus 35.1% (difference 14.0%), which did not reach the predefined border of 15%. There was a nonsignificant overall survival benefit in the group with GA (22.6 vs. 18.4 months). GA appears useful to better select older patients with advanced cancer for combination chemotherapy. The significant reduction of mortality during chemotherapy justifies the efforts and costs which need to be expended. To evaluate the effect of GA on overall survival, prospective trials are required.

Analysis of attitudes and practices influencing adherence to seasonal malaria chemoprevention in children under 5 years of age in the Dosso Region of Niger.

BACKGROUND: Seasonal malaria chemoprevention (SMC) consists of the intermittent administration of a 3 day course of anti-malarial medications during the months of highest malaria risk in the Sahel region, where malaria transmission is highly seasonal. SMC is an effective intervention to reduce episodes of uncomplicated and severe malaria in children. However, morbidity cannot be lowered without adherence to medications. The objective of this study was to examine SMC medication adherence and to identify the attitudes and practices of caregivers during the 2020 SMC campaign in the Dosso region. METHODS: This study was conducted based on data from independent monitoring using random cluster sampling. Adherence levels and the attitudes and practices of caregivers were evaluated using data from caregivers' self-reports and analysed according to Bernard Vrijens' taxonomy. RESULTS: At the initiation of treatment phase, 99% of children (N = 2296) received their first administration of medication, with 90% of caregivers (N = 1436) knowing that the medications help prevent malaria. However, only 56% of caregivers (N = 1856) reported that treatment initiation took place under direct observation by the distributor. At the implementation of treatment phase, 90% of children (N = 2132) took their medication on the second day and 84% (N = 1068) took it the third day. "Forgetting," "not having time," and "the mother's absence" were the main reasons caregivers gave to explain discontinuation of the 3 day course of medication. CONCLUSION: This simple, low-cost survey demonstrated that coverage of SMC and adherence by caregivers to completing the full 3 day medication course was high. The survey also showed that knowledge, attitudes, and practices of some caregivers regarding adherence to medications during the SMC campaign could be improved. Expanding distributors' training, developing and providing them with tools for interpersonal communication, and strengthening supervision could lead to even higher adherence.

Mortalidade por suicídio na 5a mesorregião de perícia Santa Catarina: Análise dos casos / Mortalidad por suicidio en el mesoregion experto de la 5a fronteira de Santa Catarina / Mortality by suicide in the 5th fronteira de Santa Catarina expert mesoregion

Objetivo: analisar o perfil dos óbitos por suicídio necropsiados pelo Instituto Geral de Perícias/Chapecó, entre janeiro 2007 e dezembro 2016. Método: estudo exploratório descritivo retrospectivo, obteve aprovação ética do Comitê de Ética em Pesquisa com Seres Humanos (CEP/UFFS) sob parecer no 1.826.221. Dados obtidos nos registros de necropsia e declarações de óbito de mortes por suicídio, organizados em planilhas eletrônicas, analisados pelo teste qui quadrado, e discutidos com base na literatura. Resultados: analisados 335 óbitos. À análise estatística univariada, significância para sexo, faixa etária, escolaridade e situação conjugal. Análise de tendência temporal apontou incremento nas taxas entre 30-39 anos e acima de 60 anos. Conclusão: o fortalecimento de políticas públicas voltadas à saúde mental é necessário.(AU)

Objective: to analyze the profile of deaths by suicide autopsied by the Instituto Geral de Perícias/Chapecó, between January 2007 and December 2016. Method: a retrospective descriptive exploratory study, which obtained ethical approval from the Ethics Committee for Research with Human Beings (CEP/UFFS) under opinion No. 1,826,221. Data obtained from autopsy records and death certificates of deaths by suicide, organized in electronic spreadsheets, analyzed by the chi-square test, and discussed based on the literature. Results: analyzed 335 deaths. Univariate statistical analysis revealed significance for sex, age group, education and marital status. Time trend analysis showed an increase in rates between 30-39 years and over 60 years. Conclusion: the strengthening of public policies aimed at mental health is necessary.(AU)

Objetivo: analizar el perfil de las muertes por suicidio autopsiadas por el Instituto Geral de Perícias/Chapecó, entre enero de 2007 y diciembre de 2016. Método: estudio exploratorio descriptivo retrospectivo, obtuvo aprobación ética del Comité de Ética en Investigación con Seres Humanos (CEP/ UFFS) bajo dictamen N° 1.826.221. Datos obtenidos de autopsias y certificados de defunción de muertes por suicidio, organizados en hojas de cálculo electrónicas, analizados por la prueba de chi-cuadrado y discutidos con base en la literatura. Resultados: se analizaron 335 defunciones. El análisis estadístico univariado reveló significancia para sexo, grupo de edad, educación y estado civil. El análisis de tendencia temporal mostró un aumento en las tasas entre 30-39 años y mayores de 60 años. Conclusión: es necesario el fortalecimiento de las políticas públicas dirigidas a la salud mental.(AU)

A randomized, multicenter phase II study comparing efficacy, safety and tolerability of two dosing regimens of cisplatin and pemetrexed in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor-chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. METHODS: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 (arm A), or pemetrexed 500 mg/m2 (day 1) and cisplatin 40 mg/m2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. RESULTS: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1-6) and five (1-6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34-1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68-1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17-2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. CONCLUSION: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) number 2011-001963-37.

Predictive model estimating the decrease of postoperative gastrointestinal quality of life index (GIQLI) in patients after elective laparoscopic sigmoid resection for diverticular disease.

BACKGROUND: Growing consideration in quality of life (QoL) has changed the therapeutic strategy in patients suffering from diverticular disease. Patients' well-being plays a crucial role in the decision-making process. However, there is a paucity of studies investigating patients' or surgery-related factors influencing the postoperative gastrointestinal function. The aim of this study was to investigate in a predictive model patients or surgical variables that allow better estimation of the postoperative gastrointestinal QoL. METHODS: This observational study retrospectively analyzed patients undergoing elective laparoscopic sigmoidectomy for diverticulitis between 2004 and 2017. The one-time postoperative QoL was assessed with the gastrointestinal quality of life index (GIQLI) in 2019. A linear regression model with stepwise selection has been applied to all patients and surgery-related variables. RESULTS: Two hundred seventy-two patients with a mean age of 62.30 ± 9.74 years showed a mean GIQLI of 116.39±18.25 at a mean follow-up time of 90.4±33.65 months. Women (n=168) reported a lower GIQLI compared to male (n=104; 112.85±18.79 vs 122.11±15.81, p<0.001). Patients with pre-operative cardiovascular disease (n=17) had a worse GIQLI (106.65 ±22.58 vs 117.08±17.66, p=0.010). Finally, patients operated less than 5 years ago (n=63) showed a worse GIQLI compared to patients operated more than 5 years ago (n=209; 111.98±19.65 vs 117.71±17.63, p=0.014). CONCLUSIONS: Female gender and the presence of pre-operative cardiovascular disease are predictive for a decreased postoperative gastrointestinal QoL. Furthermore, patients' estimation of gastrointestinal functioning seems to improve up to 5 years after surgery.

Complete metabolic response in patients with advanced nonsmall cell lung cancer with prolonged response to immune checkpoint inhibitor therapy.

INTRODUCTION: Immunotherapy is the new standard of care in advanced nonsmall cell lung cancer (NSCLC). Recently published data show that treatment discontinuation after 12 months of nivolumab treatment is associated with shorter survival. Therefore, the ideal duration of immunotherapy remains unclear, and finding markers of beneficial outcomes is of great importance. Here, we determine the proportion of complete metabolic responses (CMR) in patients who have not progressed after 24 months of immunotherapy. METHODS: This is a retrospective analysis of 45 patients with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose imaging for assessment of residual metabolic activity after at least 24 months. CMR was defined as uptake in tumor lesions below background levels, using mediastinum as a reference. ResultsOut of 45 patients, 29 patients had a CMR (64%). CMR was observed more frequently in non-first-line patients. Patients with CMR were younger (median 65.7 vs 75.5, p=0.03). Fourteen patients with CMR have discontinued therapy and have not progressed until time of analysis; however, median follow-up was only 5.6 (range 0.8-17.0) months. CONCLUSION: After a minimum of 24 months of palliative immunotherapy for NSCLC, CMR occurred in almost two thirds of patients. Potentially, achievement of CMR might identify patients, for whom palliative immunotherapy may be safely discontinued.

Long-term urogenital assessment after elective laparoscopic sigmoid resection for diverticulitis: a comparison between central and peripheral vascular resection.

AIM: Increasing attention has been given to postoperative gastrointestinal functional outcome and quality of life after sigmoid resection for diverticulitis. Conversely, very little has been described about postoperative urogenital functional outcome and even less about its potential relationship to the type of vascular approach. The aim of this study was to evaluate whether central ligation of the inferior mesenteric artery (IMA) compared with peripheral dissection could impair urinary and sexual function in the long term. METHOD: Patients undergoing elective laparoscopic sigmoid resection for diverticulitis from 2004 to 2017 were retrospectively analysed. They were asked to complete the American Urological Association Symptom Index (AUASI) questionnaire. Men received the five-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Patients were then divided according to the type of vascular resection. RESULTS: A response rate of the 36.4% to the AUASI and 43.8% to the IIEF-5 questionnaires was achieved. Three hundred and twenty four patients with a mean age of 62 ± 9.85 years were analysed for their urinary function (IMA preserved n = 217; IMA resected n = 107) in a median follow-up of 87 months. Furthermore, 115 men with a mean age of 60 ± 8.97 years were investigated for their sexual function (IMA preserved n = 80; IMA resected n = 35) in a median follow-up of 89 months. No difference (AUASI: 8 ± 6.32 IMA preserved vs. 7 ± 6.26 IMA resected, P = 0.204; IIEF-5: 15 ± 7.67 IMA preserved vs. 15 ± 8.61 IMA resected, P = 0.674) was found regarding the type of vascular approach during sigmoid resection. CONCLUSIONS: No association was found between the type of vascular approach and the long-term urogenital functional outcome in patients undergoing sigmoid resection for diverticulitis.

Short- and long-term outcomes for primary anastomosis versus Hartmann's procedure in Hinchey III and IV diverticulitis: a multivariate logistic regression analysis of risk factors.

PURPOSE: The management of perforated diverticulitis with generalized peritonitis is still controversial and no preferred standardized therapeutic approach has been determined. We compared surgical outcomes between Hartmann's procedure (HP) and primary anastomosis (PA) in patients with Hinchey III and IV perforated diverticulitis. METHODS: Multicenter retrospective analysis of 131 consecutive patients with Hinchey III and IV diverticulitis operated either with HP or PA from 2015 to 2018. Postoperative morbidity was compared after adjustment for known risk factors in a multivariate logistic regression. RESULTS: Sixty-six patients underwent HP, while PA was carried out in 65 patients, 35.8% of those were defunctioned. HP was more performed in older patients (74.6 vs. 61.2 years, p < .001), with Hinchey IV diverticulitis (37% vs. 7%, p < .001) and in patients with worse prognostic scores (P-POSSUM Physiology Score, p < .001, Charlson Comorbidity Index p < .001). Major morbidity and mortality were higher in HP compared to PA (30.3% vs. 9.2%, p = .002 and 10.6% vs. 0%, p = .007, respectively) with lower stoma reversal rate (43.9% vs. 86.9%, p < .001). In a multivariate logistic regression, PA was independently associated with lower postoperative morbidity and mortality (OR 0.24, 95% CI 0.06-0.96, p = .044). CONCLUSIONS: In comparison to PA, HP is associated with a higher morbidity, higher mortality, and a lower stoma reversal rate. Although a higher prevalence of risk factors in HP patients may explain these outcomes, a significant increase in morbidity and mortality persisted in a multivariate logistic regression analysis that was stratified for the identified risk factors.

Single-cell proteomics reveals changes in expression during hair-cell development.

Hearing and balance rely on small sensory hair cells that reside in the inner ear. To explore dynamic changes in the abundant proteins present in differentiating hair cells, we used nanoliter-scale shotgun mass spectrometry of single cells, each ~1 picoliter, from utricles of embryonic day 15 chickens. We identified unique constellations of proteins or protein groups from presumptive hair cells and from progenitor cells. The single-cell proteomes enabled the de novo reconstruction of a developmental trajectory using protein expression levels, revealing proteins that greatly increased in expression during differentiation of hair cells (e.g., OCM, CRABP1, GPX2, AK1, GSTO1) and those that decreased during differentiation (e.g., TMSB4X, AGR3). Complementary single-cell transcriptome profiling showed corresponding changes in mRNA during maturation of hair cells. Single-cell proteomics data thus can be mined to reveal features of cellular development that may be missed with transcriptomics.

Bortezomib sensitivity is tissue dependent and high expression of the 20S proteasome precludes good response in malignant pleural mesothelioma.

BACKGROUND: Bortezomib is an approved proteasome inhibitor for the treatment of certain lymphoma subtypes. Two clinical trials investigated bortezomib in patients with malignant pleural mesothelioma (MPM) and failed to improve outcome. We present a potential explanation for this event. METHODS: 171 patients with MPM were analyzed for their mRNA expression of proteasomal subunits PSMA1, PSMA5, PSMB1, PSMB2, PSMB4 and PSMB5 via qPCR (n=84) or sequencing (n=87 TCGA/cBioPortal data set "Mesothelioma"). Outcome and subunit expression were correlated. Four mesothelial and one fibroblast cell line were treated with bortezomib and cisplatin. Cellular response was measured after 0, 6, 12, 24, 48 and 72 hrs. Enzyme activity of proteasomal subunits was assessed via functional enzyme activity assays. RESULTS: Patients with MPM presented with elevated expression of proteasomal subunits compared to benign controls (p<0.001). PSMB4 correlated with outcome (Cox propotiortional-hazards model (COXPH): p<0.0175, TCGA/cBioPortal data). In cell lines, apoptosis was the main event with a peak after 48 hr incubation for bortezomib or cisplatin. Only two cell lines with comparably low proteasome activity (PSMB2 and PSMB5) responded to 50 nM and 100 nM bortezomib better than to cisplatin (MRC-5, NCI-H2052). MSTO-211H responded to cisplatin only, whereas the other two cell lines were considered therapy resistant (Met-5A, NCI-H2452). INTERPRETATION: Two clinical trials testing bortezomib in MPM failed, although MPM presents with high proteasome expression, which predicts bortezomib sensitivity in several tumors. Bortezomib induced apoptosis in MPM cell lines with low proteasome activity only. Bortezomib is not suitable for the treatment of MPM, and biomarker-based stratification could have improved both clinical trials. TRIAL REGISTRATION: NCT00513877 and NCT00458913.

Idiopathic localised dilatation of the intestine in adults.

Idiopathic localised dilatation of the intestine (ILDI) presenting in adults is rare and difficult to diagnose. Only 18 cases have been reported in the literature. We report a case of a 32-year-old woman presenting with abdominal pain and intermittent small bowel obstruction. After detailed radiological studies, the patient, known for Crohn's disease, was scheduled for laparoscopy in the suspicion of small bowel stricture. A localised dilatation of the ileum was found intraoperatively and subsequently resected. A systematic review of this rare pathology in adults is carried out. ILDI should be part of the differential diagnosis in patients with unexplained abdominal pain or gastrointestinal bleeding in the presence of segmental dilatation of the intestine. Surgical resection is the treatment of choice.

Design, optimisation and testing of a compact, inexpensive elastic element for series elastic actuators.

This paper presents the development of a compact torsion spring for use as an elastic element in a lightweight series elastic actuator for an active orthosis. This orthosis is going to be utilised as an assistive device for motorically impaired stroke-patients. In the design a two-step optimisation strategy was implemented to meet all requirements for the torsion spring. The first step was to identify a promising topology for the element. In the second step, the shape was optimised based on a finite element model using two different optimisation methods in order to minimise the von Mises equivalent stresses. Four promising variants of the identified topology were extracted from these calculations, one of which was then chosen as the final design. A prototype was manufactured by a laser cutting process, which is a new procedure in the context of elastic elements for series elastic actuators. The calculation results were validated successfully by measurement of the spring properties of this prototype.

miRNA regulation is important for DNA damage repair and recognition in malignant pleural mesothelioma.

Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.

Folic acid phenotype (FAP) is a superior biomarker predicting response to pemetrexed-based chemotherapy in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. RESULTS: Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1/TYMS-ratio (p=0.0076) as well as FPGS/TYMS-ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). METHODS: 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. CONCLUSION: Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.

Sclerotherapy is a safe method of treatment of chronic venous disorders in older patients: A prospective and comparative study of consecutive patients.

Objectives An aging population requires evaluation of methods of treatment for older patients. Our objective was to evaluate the indications, practical modalities, safety and tolerability of sclerotherapy in patients 75 years of age and older (group 1) and compare with a control group of patients 18 to74 years of age (group 2). Method This observational, multicentre, prospective and comparative study was conducted by the French Society of Phlebology. Each centre collected in 10 to 20 patients ≥75 years of age and an equal number of patients <75 years of age treated by sclerotherapy, the treatment indication, the patient's personal history, the CEAP clinical class, the type of the veins being treated, the characteristics of sclerotherapy and the complications (immediately after treatment and at one-month follow-up). Results Population: In total, 418 patients were enrolled in 15 centres: 176 patients in group 1 (mean: 79.4 years) and 242 patients in group 2 (mean: 52.7 years).CEAP clinical classes C4, C5 and C6, history of deep vein thrombosis (12.5%) and superficial vein thrombosis (11.9%), long-term anticoagulant therapy (9.1%) and antiplatelet therapy (16.5%) were more frequent in older patients.All types of veins were treated from saphenous veins to telangiectasias. Sclerotherapy features: There was no difference in concentration of the sclerosing agents. When foam sclerotherapy was used (84% of patients), the injected volume was lower in group 1. COMPLICATIONS: One vasovagal syncope occurred in group 1. One asymptomatic distal deep vein thrombosis, confined to the Medial Gastrocnemius Veins, was reported in both groups at one-month follow-up. Conclusions This study shows the feasibility and safety of sclerotherapy in older patients, with no specific complications nor need for special precautions.

ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP Were Identified as Reference Genes in Neuroendocrine Lung Cancer via the nCounter Technology.

BACKGROUND: Neuroendocrine lung cancer (NELC) represents 25% of all lung cancer cases and large patient collectives exist as formalin-fixed, paraffin-embedded (FFPE) tissue only. FFPE is controversially discussed as source for molecular biological analyses and reference genes for NELC are poorly establishes. MATERIAL AND METHODS: Forty-three representative FFPE-specimens were used for mRNA expression analysis using the digital nCounter technology (NanoString). Based on recent literature, a total of 91 mRNA targets were investigated as potential tumor markers or reference genes. The geNorm, NormFinder algorithms and coefficient of correlation were used to identify the most stable reference genes. Statistical analysis was performed by using the R programming environment (version 3.1.1). RESULTS: RNA integrity (RIN) ranged from 1.8 to 2.6 and concentrations from 34 to 2,109 ng/µl. However, the nCounter technology gave evaluable results for all samples tested. ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP were identified as constantly expressed genes with high stability (M-)values according to geNorm, NormFinder and coefficients of correlation. CONCLUSION: FFPE-derived mRNA is suitable for molecular biological investigations via the nCounter technology, although it is highly degraded. ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP are potent reference genes in neuroendocrine tumors of the lung.

Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumour leading to a dismal prognosis. Multimodality therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons for the rather poor efficacy of platinum compounds remain largely unknown. MATERIAL AND METHODS: For this exploratory mRNA study, 24 FFPE tumour specimens were screened by digital gene expression analysis. Based on data from preliminary experiments and recent literature, a total of 366 mRNAs were investigated using a Custom CodeSet from NanoString. All statistical analyses were calculated with the R i386 statistical programming environment. RESULTS: CDC25A and PARP1 gene expression were correlated with lymph node spread, BRCA1 and TP73 expression levels with higher IMIG stage. NTHL1 and XRCC3 expression was associated with TNM stage. CHECK1 as well as XRCC2 expression levels were correlated with tumour progression in the overall cohort of patients. CDKN2A and MLH1 gene expression influenced overall survival in this collective. In the adjuvant treated cohort only, CDKN2A, CHEK1 as well as ERCC1 were significantly associated with overall survival. Furthermore, TP73 expression was associated with progression in this subgroup. CONCLUSION: DNA-damage response plays a crucial role in response to platin-based chemotherapeutic regimes. In particular, CHEK1, XRCC2 and TP73 are strongly associated with tumour progression. ERCC1, MLH1, CDKN2A and most promising CHEK1 are prognostic markers for OS in MPM. TP73, CDKN2A, CHEK1 and ERCC1 seem to be also predictive markers in adjuvant treated MPMs. After a prospective validation, these markers may improve clinical and pathological practice, finally leading to a patients' benefit by an enhanced clinical management.

Folic-acid metabolism and DNA-repair phenotypes differ between neuroendocrine lung tumors and associate with aggressive subtypes, therapy resistance and outcome.

PURPOSE: 25% of all lung cancer cases are neuroendocrine (NELC) including typical (TC) and atypical carcinoid (AC), large-cell neuroendocrine (LCNEC) and small cell lung cancer (SCLC). Prognostic and predictive biomarkers are lacking. EXPERIMENTAL DESIGN: Sixty patients were used for nCounter mRNA expression analysis of the folic-acid metabolism (ATIC, DHFR, FOLR1, FPGS, GART, GGT1, SLC19A1, TYMS) and DNA-repair (ERCC1, MLH1, MSH2, MSH6, XRCC1). Phenotypic classification classified tumors (either below or above the median expression level) with respect to the folic acid metabolism or DNA repair. RESULTS: Expression of FOLR1, FPGS, MLH1 and TYMS (each p<0.0001) differed significantly between all four tumor types. FOLR1 and FPGS associated with tumor differentiation (both p<0.0001), spread to regional lymph nodes (FOLR1 p=0.0001 and FPGS p=0.0038), OS and PFS (FOLR1 p<0.0050 for both and FPGS p<0.0004 for OS). Phenotypic sorting revealed the Ft-phenotype to be the most prominent expression profile in carcinoids, whereas SCLC presented nearly univocal with the fT and LCNEC with fT or ft. These results were significant for tumor subtype (p<0.0001). CONCLUSIONS: The assessed biomarkers and phenotypes allow for risk stratification (OS, PFS), diagnostic classification and enhance the biological understanding of the different subtypes of neuroendocrine tumors revealing potential new therapy options and clarifying known resistance mechanisms.

microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour first-line treated with a combination of cisplatin and pemetrexed. MDM2 and P14/ARF (CDKN2A) are upstream regulators of TP53 and may contribute to its inactivation. In the present study, we now aimed to define the impact of miRNA expression on this mechanism. MATERIAL AND METHODS: 24 formalin-fixed paraffin-embedded (FFPE) tumour specimens were used for miRNA expression analysis of the 800 most important miRNAs using the nCounter technique (NanoString). Significantly deregulated miRNAs were identified before a KEGG-pathway analysis was performed. RESULTS: 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A are significantly downregulated in MDM2-expressing mesotheliomas. TP53 is downregulated in MDM2-negative tumours through miRNAs with a miSVR prediction score of 11.67, RB1 with a prediction score of 8.02, MDM2 with a prediction score of 4.50 and CDKN2A with a prediction score of 1.27. CONCLUSION: MDM2 expression seems to impact miRNA expression levels in MPM. Especially, miRNAs involved in TP53-signaling are strongly decreased in MDM2-positive mesotheliomas. A better understanding of its tumour biology may open the chance for new therapeutic approaches and thereby augment patients' outcome.