Aesthetic perception of black spaces between lower incisors by laypeople of different ethnicities and age groups

Objective: To evaluate the degree of perception among lay people of different age groups about black spaces between lower incisors. Methodology: digital changes were performed in a frontal photograph of a smiling 30 year-old patient, simulating different dimensions of black spaces. The images were printed on photographic paper and applied with a questionnaire in order to evaluate the attractiveness using as tool a visual analogue scale (VAS). The participants were divided into 6 groups, considering race (Caucasian and Negroid) and age (15-19 years, 35-44 years and 65-74 years old). The differences between the examiners were checked by the Mann-Whitney test and the significance level was 5% (α = 0.05) for all analyzes. Results: The photographs that did not have black spaces were better graded and the ones that had larger black spaces scored worse. The older age group and the Negroid race group graded better the photograph with the largest black spaces, compared to the younger age groups and the group of Caucasians. Conclusion: black spaces between lower incisors are esthetically unattractive and their perception decreases with aging, besides being less relevant to older and Negroid people.

Shifting incidence and survival of epithelial ovarian cancer (1995-2014): A SurvMark-2 study.

The aim of the study is to provide a comprehensive assessment of incidence and survival trends of epithelial ovarian cancer (EOC) by histological subtype across seven high income countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom). Data on invasive EOC diagnosed in women aged 15 to 99 years during 1995 to 2014 were obtained from 20 cancer registries. Age standardized incidence rates and average annual percentage change were calculated by subtype for all ages and age groups (15-64 and 65-99 years). Net survival (NS) was estimated by subtype, age group and 5-year period using Pohar-Perme estimator. Our findings showed marked increase in serous carcinoma incidence was observed between 1995 and 2014 among women aged 65 to 99 years with average annual increase ranging between 2.2% and 5.8%. We documented a marked decrease in the incidence of adenocarcinoma "not otherwise specified" with estimates ranging between 4.4% and 7.4% in women aged 15 to 64 years and between 2.0% and 3.7% among the older age group. Improved survival, combining all EOC subtypes, was observed for all ages combined over the 20-year study period in all countries with 5-year NS absolute percent change ranging between 5.0 in Canada and 12.6 in Denmark. Several factors such as changes in guidelines and advancement in diagnostic tools may potentially influence the observed shift in histological subtypes and temporal trends. Progress in clinical management and treatment over the past decades potentially plays a role in the observed improvements in EOC survival.

Outcome in Elderly Patients With Cardiogenic Shock Complicating Acute Myocardial Infarction.

INTRODUCTION: Despite advances in treatment of patients with cardiogenic shock following acute myocardial infarction (AMICS) in-hospital mortality remains around 50%. Outcome varies among patient subsets and the elderly often have a poor a priori prognosis. We sought to investigate outcome among elderly AMICS patients referred to evaluation and treatment at a tertiary university hospital. METHODS: Current analysis was based on the RETROSHOCK registry comprising consecutive AMICS patients admitted to tertiary care. Patients in the registry were individually identified and validated. RESULTS: Of 1,716 admitted patients, 496 (28.9%) patients were ≥75 years old. Older patients were less likely to be admitted directly to a tertiary centre (59.4% vs. 69.9%, P = 0.003), receive mechanical support devices (i.e., Impella® (8.9% vs. 15.0%, P = 0.003), and undergo revascularization attempt (76.8% vs. 90.2%, P < 0.001). Thirty-day survivors ≥75 years were characterized by having higher left ventricular ejection fraction (30.2% ±â€Š12.5% vs. 26.5% ±â€Š11.8%, P = 0.004) and lower arterial lactate (3.2[2.2-5.2] mmol/L vs. 5.5[3.3-8.2] mmol/L, P < 0.001) at admission. In a multivariable analysis of patients ≥75 years, higher age (HR 1.09, 95% CI 1.05-1.14, P < 0.001), higher heart rate (HR 1.01, 95% CI 1.001-1.014, P = 0.03), and higher lactate (HR 1.11, 95% CI 1.07-1.16, P < 0.001) at admission were associated with an increased risk of 30-day mortality. CONCLUSION: Among patients ≥75 years with AMICS referred for tertiary specialized treatment, 30-day mortality was 73.4%. Survivors were characterized by lower arterial lactate and heart rate at admission.

Exploring international differences in ovarian cancer treatment: a comparison of clinical practice guidelines and patterns of care.

INTRODUCTION: The International Cancer Benchmarking Partnership demonstrated international differences in ovarian cancer survival, particularly for women aged 65-74 with advanced disease. These findings suggest differences in treatment could be contributing to survival disparities. OBJECTIVE: To compare clinical practice guidelines and patterns of care across seven high-income countries. METHODS: A comparison of guidelines was performed and validated by a clinical working group. To explore clinical practice, a patterns of care survey was developed. A questionnaire regarding management and potential health system-related barriers to providing treatment was emailed to gynecological specialists. Guideline and survey results were crudely compared with 3-year survival by 'distant' stage using Spearman's rho. RESULTS: Twenty-seven guidelines were compared, and 119 clinicians completed the survey. Guideline-related measures varied between countries but did not correlate with survival internationally. Guidelines were consistent for surgical recommendations of either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery with the aim of complete cytoreduction. Reported patterns of surgical care varied internationally, including for rates of primary versus interval debulking, extensive/'ultra-radical' surgery, and perceived barriers to optimal cytoreduction. Comparison showed that willingness to undertake extensive surgery correlated with survival across countries (rs=0.94, p=0.017). For systemic/radiation therapies, guideline differences were more pronounced, particularly for bevacizumab and PARP (poly (ADP-ribose) polymerase) inhibitors. Reported health system-related barriers also varied internationally and included a lack of adequate hospital staffing and treatment monitoring via local and national audits. DISCUSSION: Findings suggest international variations in ovarian cancer treatment. Characteristics relating to countries with higher stage-specific survival included higher reported rates of primary surgery; willingness to undertake extensive/ultra-radical procedures; greater access to high-cost drugs; and auditing.

Deteção precoce do cancro infantojuvenil nos cuidados de saúde primários: possibilidades e limitações / Early detection of childhood and adolescent cancer in Primary Health Care: possibilities and limitations / Detección precoz del cáncer infantojuvenil en la atención primaria de salud: posibilidades y limitaciones

Enquadramento: A deteção precoce do cancro tem grande impacto na vida de crianças e adolescentes, uma vez que estes iniciam o tratamento em melhores condições, influenciando, assim, no seu prognóstico e na sobrevida. Objetivo: Investigar as possibilidades e limitações no que diz respeito à deteção precoce do cancro infantojuvenil, a partir de relatos de profissionais que atuam nos Cuidados de Saúde Primários. Metodologia: Estudo exploratório, desenvolvido em 3 unidades básicas de saúde. Participaram no estudo 11 profissionais de saúde. A colheita de dados foi realizada por meio de entrevista semiestruturada. O material empírico foi analisado qualitativamente, de acordo com a Técnica de Análise de Conteúdo. Resultados: Apresentaram-se como possibilidades - a contextualização e interpretação dos resultados clínicos, além de uma assistência sistematizada e interdisciplinar. Como limitações - a falta de especificidade dos sinais e sintomas do cancro infantojuvenil, não observância do princípio de acessibilidade, assim como a necessidade de formação/capacitação. Conclusão: Sendo assim, constatou-se que este estudo possibilitará uma melhor atuação destes profissionais a respeito do diagnóstico precoce do cancro em crianças e adolescentes assistidos nos CSP.

Background: The early detection of cancer has a major impact on the lives of children and adolescents because they start treatment in better conditions, thus influencing their prognosis and survival. Objective: To investigate the possibilities and limitations regarding the early detection of childhood and adolescent cancer, based on reports from professionals working in Primary Health Care. Methodology: Exploratory study conducted in three basic health units. Eleven health professionals participated in the study. Data were collected through semi-structured interviews. The empirical material was qualitatively analyzed based on the Content Analysis Technique. Results: The possibilities found were contextualization and interpretation of clinical findings, as well as systemized and interdisciplinary care. The limitations found were lack of specificity of the signs and symptoms of childhood and adolescent cancer, non-compliance with the principle of accessibility, and need for training/capacity building. Conclusion: This study will contribute to improving the performance of these professionals regarding the early diagnosis of cancer in children and adolescents receiving care in PHC.

Marco contextual: La detección precoz del cáncer tiene un gran impacto en la vida de los niños y adolescentes, ya que estos comienzan el tratamiento en mejores condiciones, lo que influye en el pronóstico y la supervivencia. Objetivo: Investigar las posibilidades y limitaciones respecto a la detección precoz del cáncer infantojuvenil, a partir de informes de profesionales que trabajan en la atención primaria de salud. Metodología: Estudio exploratorio, desarrollado en tres unidades básicas de salud. Once profesionales de la salud participaron en el estudio. La recopilación de datos se llevó a cabo mediante una entrevista semiestructurada. El material empírico se analizó cualitativamente, de acuerdo con la técnica de análisis de contenido. Resultados: Se presentaron como posibilidades, la contextualización e interpretación de los hallazgos clínicos, así como la asistencia sistemática e interdisciplinaria. Como limitaciones, la falta de especificidad de los signos y síntomas del cáncer infantojuvenil, el incumplimiento del principio de accesibilidad, así como la necesidad de formación/capacitación. Conclusión: Por lo tanto, se constató que este estudio permitirá un mejor desempeño de estos profesionales en cuanto al diagnóstico precoz del cáncer de niños y adolescentes atendidos en los CSP.

Exploring variations in ovarian cancer survival by age and stage (ICBP SurvMark-2): A population-based study.

OBJECTIVE: The study aims to evaluate the differences in ovarian cancer survival by age and stage at diagnosis within and across seven high-income countries. METHODS: We analyzed data from 58,161 women diagnosed with ovarian cancer during 2010-2014, followed until 31 December 2015, from 21 population-based cancer registries in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. Comparisons of 1-year and 3-year age- and stage-specific net survival (NS) between countries were performed using the period analysis approach. RESULTS: Minor variation in the stage distribution was observed between countries, with most women being diagnosed with 'distant' stage (ranging between 64% in Canada and 71% in Norway). The 3-year all-ages NS ranged from 45 to 57% with Australia (56%) and Norway (57%) demonstrating the highest survival. The proportion of women with 'distant' stage was highest for those aged 65-74 and 75-99 years and varied markedly between countries (range:72-80% and 77-87%, respectively). The oldest age group had the lowest 3-year age-specific survival (20-34%), and women aged 65-74 exhibited the widest variation across countries (3-year NS range: 40-60%). Differences in survival between countries were particularly stark for the oldest age group with 'distant' stage (3-year NS range: 12% in Ireland to 24% in Norway). CONCLUSIONS: International variations in ovarian cancer survival by stage exist with the largest differences observed in the oldest age group with advanced disease. This finding endorses further research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease.

Pacientes sob cuidados paliativos em fase final de vida: vivência de uma equipe multiprofissional / Patients at the end of life receiving palliative care: experiences of a multiprofessional team / Pacientes sob cuidados paliativos em fase final de vida: vivência de uma equipe multiprofissional

Objetivo: Investigar a vivência de uma equipe multiprofissional no que concerne a assistência aos pacientes sob cuidados paliativos em fase final de vida. Método: Trata-se de uma pesquisa exploratória com abordagem qualitativa. O estudo foi realizado em um hospital filantrópico, localizado na cidade de João Pessoa-Paraíba- Brasil, com 15 profissionais de uma equipe multiprofissional. Os depoimentos foram obtidos por meio de entrevista semiestruturada e organizados em categorias temáticas. Resultados: Da análise do material empírico emergiram duas categorias: I ­ cuidados paliativos na fase final de vida: ações e condutas da equipe multiprofissional e categoria II ­ desafios da equipe multiprofissional na promoção dos cuidados paliativos na fase final de vida: integração e capacitação. Conclusão: A equipe multiprofissional reconhece que uma maior integração facilite o processo de cuidado e a necessidade de se especializar para o desenvolvimento de competências com vistas à melhoria da qualidade da assistência paliativa

Objective: This study investigated the attitudes of multiprofessional team members toward palliative care in the final phase of life. Methods: This exploratory study with a qualitative approach was carried out with 15 multiprofessional team members in a philanthropic hospital located in João Pessoa city, Paraíba State, Brazil. Data were obtained through semi-structured interviews and organized into thematic categories. Results: Two categories emerged: "Palliative care in the final phase of life: actions and behaviors of the multiprofessional team members" and "Challenges faced by the multiprofessional team while promoting palliative care in the final phase of life: integration and training". Conclusion: The study participants recognized that greater integration and training facilitate palliative care and improve its quality

Objetivo: Investigar la experiencia de un equipo multiprofesional con respecto a la asistencia a pacientes bajo cuidados paliativos en la fase final de la vida. Método: esta es una investigación exploratoria con un enfoque cualitativo. El estudio se realizó en un hospital filantrópico ubicado en la ciudad de João Pessoa-Paraíba-Brasil, con 15 profesionales de un equipo multiprofesional. Las declaraciones fueron obtenidas a través de entrevistas semiestructuradas y organizadas en categorías temáticas. Resultados: del análisis del material empírico surgieron dos categorías: I - cuidados paliativos en la fase final de la vida: acciones y conducta del equipo multiprofesional y categoría II - desafíos del equipo multiprofesional para promover los cuidados paliativos en la fase final de la vida: integración y capacitación. Conclusión: el equipo multiprofesional reconoce que una mayor integración facilita el proceso de atención y la necesidad de especializarse en el desarrollo de competencias para mejorar la calidad de los cuidados paliativos

Epirubicin chemotherapy in women with breast cancer: Alternating arms for intravenous administration to reduce chemical phlebitis.

OBJECTIVE: To establish whether using alternating arms for peripheral intravenous epirubicin administration affects the severity or duration of epirubicin-induced phlebitis. METHODS: An observational study of women with breast cancer (n = 237) in a UK Cancer Centre. Data were analysed after receiving three treatment cycles according to the arm used for epirubicin administration: same, alternating or mixed arm (two consecutive cycles in one arm and one in the alternate arm). Phlebitis severity was graded by clinical staff after each treatment; participants also self-reported symptoms during treatment and for up to 6 months after. RESULTS: The alternating arm group experienced significantly less severe symptoms than the other arm use groups, 6% (4 of 64) compared with 34% (p < 0.001, odds ratio: 0.13 (95% CI: 0.043-0.38) alternating arm compared with same arm group). The alternating arm group reported less pain (p = 0.013), lower overall impact (p = 0.009), lower effect on function (p = 0.032) and shorter duration of symptoms (p = 0.001) than the other arm use groups. CONCLUSION: Using alternating arms for peripheral administration of epirubicin significantly reduces the severity and duration of chemical phlebitis and is recommended to improve patient experience and reduce the need for central venous access devices.

A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy.

BACKGROUND: Advanced pelvic radiotherapy techniques aim to reduce late bowel toxicity which can severely impact the lives of pelvic cancer survivors. Although advanced techniques have been largely adopted worldwide, to achieve their aim, knowledge of which dose-volume parameters of which components of bowel predict late bowel toxicity is crucial to make best use of these techniques. The rectum is an extensively studied organ at risk (OAR), and dose-volume predictors of late toxicity for the rectum are established. However, for other components of bowel, there is a significant paucity of knowledge. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) reviews recommend dose-volume constraints for acute bowel toxicity for peritoneal cavity and bowel loops, although no constraints are recommended for late toxicity, despite its relevance to our increasing number of survivors. This systematic review aims to examine the published literature to seek dose-volume predictors and constraints of late bowel toxicity for OARs (apart from the rectum) for use in clinical practice. METHODS: A systematic literature search was performed using Medline, Embase, Cochrane Library, Web of Science, Cinahl and Pubmed. Studies were screened and included according to specific pre-defined criteria. Included studies were assessed for quality against QUANTEC-defined assessment criteria. RESULTS: 101 studies were screened to find 30 relevant studies. Eight studies related to whole bowel, 11 to small bowel, and 21 to large bowel (including 16 of the anal canal). The anal canal is an important OAR for the development of late toxicity, and we recommend an anal canal Dmean <40Gy as a constraint to reduce late incontinence. For other components of bowel (sigmoid, large bowel, intestinal cavity, bowel loops), although individual studies found statistically significant parameters and constraints these findings were not corroborated in other studies. CONCLUSIONS: The anal canal is an important OAR for the development of late bowel toxicity symptoms. Further validation of the constraints found for other components of bowel is needed. Studies that were more conclusive included those with patient-reported data, where individual symptom scores were assessed rather than an overall score, and those that followed statistical and endpoint criteria as defined by QUANTEC.

Fatores de risco que favorecem a pneumonia associada à ventilação mecânica / Risk factors favoring pneumonia associated with mechanical ventilation

Objetivo: analisar os principais fatores de risco que favorecem à pneumonia associada à ventilação mecânica. Método: trata-se de estudo bibliográfico, tipo revisão integrativa, em que os artigos consultados foram nas Bases de Dados Lilacs, Medline a Biblioteca Virtual Scielo. Informam-se que a busca foi realizada em janeiro de 2018 e amostra final de 20 artigos, apresentando-se os resultados em figura. Resultados: observou-se a importância da atenção do enfermeiro com pacientes que se encontrem em ambiente de terapia intensiva e necessitem da ventilação mecânica a fim de prevenir, diagnosticar e tratar uma pneumonia associada à ventilação mecânica. Conclusão: revela-se que, em meio aos principais fatores de risco para a ocorrência do problema, os mais relevantes são as práticas incorretas de higiene realizadas pela equipe de saúde tendo em vista a existência de muitos patógenos oportunistas e que facilmente poderiam ser eliminados por meio de uma higiene eficaz.(AU)

Histone deacetylase inhibitor trichostatin A sensitises cisplatin-resistant ovarian cancer cells to oncolytic adenovirus.

Ovarian cancer is often termed a silent killer due to the late onset of symptoms. Whilst patients initially respond to chemotherapy, they rapidly develop chemo-resistance. Oncolytic adenoviruses (OAds) are promising anti-cancer agents engineered to "hijack" the unique molecular machinery of cancer cells enabling tumour-selective viral replication. This allows spread to adjacent cells and amplification of oncolysis within the tumour. OAds represent an excellent opportunity for ovarian cancer therapy via intra-peritoneal delivery, however the efficacy of OAds thus far is limited. Here, we evaluate chromatin (histone) modification in chemo-resistant cells and its relationship to Ad efficacy (wild-type or oncolytic Ad). In contrast to cisplatin-sensitive A2780 cells that show an efficient reduction of cell viability by Ad in the presence of cisplatin, cisplatin-resistant A2780/cp70 cells show diminishing Ad-mediated reduction of cell viability with escalating doses of cisplatin. Histone deacetylase (HDAC)-2 and to a lesser extent HDAC1 were up-regulated in cisplatin-resistant but not cisplatin-sensitive cells. Cisplatin-resistant cells treated with a pan-HDAC inhibitor trichostatin A (TsA) significantly enhanced Ad-mediated reduction of cell viability in the presence of cisplatin. Cells treated with TsA alone did not reduce cell viability suggesting these findings are Ad-dependent. Thus, we identify HDAC inhibition as a potential means to sensitise cisplatin-resistant ovarian cancer cells to virotherapies, an observation that may offer improved outcomes for patients with late stage, chemotherapy-resistant ovarian cancer.

Ad5NULL-A20: A Tropism-Modified, αvß6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies.

Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvß6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues.Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvß6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed.Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvß3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvß6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non-tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20-treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5.Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvß6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. Clin Cancer Res; 24(17); 4215-24. ©2018 AACR.

Pseudotyped αvß6 integrin-targeted adenovirus vectors for ovarian cancer therapies.

Encouraging results from recent clinical trials are revitalizing the field of oncolytic virotherapies. Human adenovirus type 5 (HAdV-C5/Ad5) is a common vector for its ease of manipulation, high production titers and capacity to transduce multiple cell types. However, effective clinical applications are hindered by poor tumor-selectivity and vector neutralization. We generated Ad5/kn48 by pseudotyping Ad5 with the fiber knob domain from the less seroprevalent HAdV-D48 (Ad48). The vector was shown to utilize coxsackie and adenovirus receptor (CAR) but not CD46 for cell entry. A 20-amino acid peptide NAVPNLRGDLQVLAQKVART (A20) was inserted into the Ad5. Luc HI loop (Ad5.HI.A20) and Ad5/kn48 DG loop (Ad5/kn48.DG.A20) to target a prognostic cancer cell marker, αvß6 integrin. Relative to the Ad5.Luc parent vector, Ad5.HI.A20, Ad5.KO1.HI.A20 (KO1, ablated CAR-binding) and Ad5/kn48.DG.A20 showed ~ 160-, 270- and 180-fold increased transduction in BT-20 breast carcinoma cells (αvß6high). Primary human epithelial ovarian cancer (EOC) cultures derived from clinical ascites provided a useful ex vivo model for intraperitoneal virotherapy. Ad5.HI.A20, Ad5.KO1.HI.A20 and Ad5/kn48.DG.A20 transduction was ~ 70-, 60- and 16-fold increased relative to Ad5.Luc in EOC cells (αvß6high), respectively. A20 vectors transduced EOC cells at up to ~ 950-fold higher efficiency in the presence of neutralizing ovarian ascites, as compared to Ad5.Luc. Efficient transduction and enhanced cancer-selectivity via a non-native αvß6-mediated route was demonstrated, even in the presence of pre-existing anti-Ad5 immunity. Consequently, αvß6-targeted Ad vectors may represent a promising platform for local intraperitoneal treatment of ovarian cancer metastases.

Breath analysis: translation into clinical practice.

Breath analysis in respiratory disease is a non-invasive technique which has the potential to complement or replace current screening and diagnostic techniques without inconvenience or harm to the patient. Recent advances in ion mobility spectrometry (IMS) have allowed exhaled breath to be analysed rapidly, reliably and robustly thereby facilitating larger studies of exhaled breath profiles in clinical environments. Preliminary studies have demonstrated that volatile organic compound (VOC) breath profiles of people with respiratory disease can be distinguished from healthy control groups but there is a need to validate, standardise and ensure comparability between laboratories before real-time breath analysis becomes a clinical reality. It is also important that breath sampling procedures and methodologies are developed in conjunction with clinicians and the practicalities of working within the clinical setting are considered to allow the full diagnostic potential of these techniques to be realised. A protocol is presented, which has been developed over three years and successfully deployed for quickly and accurately collecting breath samples from 323 respiratory patients recruited from 10 different secondary health care clinics.

Incorporation of Peptides Targeting EGFR and FGFR1 into the Adenoviral Fiber Knob Domain and Their Evaluation as Targeted Cancer Therapies.

Oncolytic virotherapies based on adenovirus 5 (Ad5) hold promise as adjunctive cancer therapies; however, their efficacy when delivered systemically is hampered by poor target cell specificity and preexisting anti-Ad5 immunity. Ovarian cancer represents a promising target for virotherapy, since the virus can be delivered locally into the peritoneal cavity. Both epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor 1 (FGFR1) are overexpressed in the majority of human tumors, including ovarian cancer. To generate adenoviral vectors with improved tumor specificity, we generated a panel of Ad5 vectors with altered tropism for EGFR and FGFR, rather than the natural Ad5 receptor, hCAR. We have included mutations within AB loop of the viral fiber knob (KO1 mutation) to preclude interaction with hCAR, combined with insertions in the HI loop to incorporate peptides that bind either EGFR (peptide YHWYGYTPQNVI, GE11) or FGFR1 (peptides MQLPLAT, M*, and LSPPRYP, LS). Viruses were produced to high titers, and the integrity of the fiber protein was validated by Western blotting. The KO1 mutation efficiently ablated hCAR interactions, and significantly increased transduction was observed in hCAR(low)/EGFR(high) cell lines using Ad5.GE11, while transduction levels using Ad5.M* or Ad5.LS were not increased. In the presence of physiological concentrations of human blood clotting factor X (hFX), significantly increased levels of transduction via the hFX-mediated pathway were observed in cell lines, but not in primary tumor cells derived from epithelial ovarian cancer (EOC) ascites samples. Ad5-mediated transduction of EOC cells was completely abolished by the presence of 2.5% serum from patients, while, surprisingly, incorporation of the GE11 peptide resulted in significant evasion of neutralization in the same samples. We thus speculate that incorporation of the YHWYGYTPQNVI dodecapeptide within the fiber knob domain may provide a novel means of circumventing preexisting Ad5 immunity that warrants further investigation.

Lung cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK: a population-based study, 2004-2007.

BACKGROUND: The authors consider whether differences in stage at diagnosis could explain the variation in lung cancer survival between six developed countries in 2004-2007. METHODS: Routinely collected population-based data were obtained on all adults (15-99 years) diagnosed with lung cancer in 2004-2007 and registered in regional and national cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Stage data for 57 352 patients were consolidated from various classification systems. Flexible parametric hazard models on the log cumulative scale were used to estimate net survival at 1 year and the excess hazard up to 18 months after diagnosis. RESULTS: Age-standardised 1-year net survival from non-small cell lung cancer ranged from 30% (UK) to 46% (Sweden). Patients in the UK and Denmark had lower survival than elsewhere, partly because of a more adverse stage distribution. However, there were also wide international differences in stage-specific survival. Net survival from TNM stage I non-small cell lung cancer was 16% lower in the UK than in Sweden, and for TNM stage IV disease survival was 10% lower. Similar patterns were found for small cell lung cancer. CONCLUSIONS: There are comparability issues when using population-based data but, even given these constraints, this study shows that, while differences in stage at diagnosis explain some of the international variation in overall lung cancer survival, wide disparities in stage-specific survival exist, suggesting that other factors are also important such as differences in treatment. Stage should be included in international cancer survival studies and the comparability of population-based data should be improved.

Stage at diagnosis and ovarian cancer survival: evidence from the International Cancer Benchmarking Partnership.

OBJECTIVE: We investigate what role stage at diagnosis bears in international differences in ovarian cancer survival. METHODS: Data from population-based cancer registries in Australia, Canada, Denmark, Norway, and the UK were analysed for 20,073 women diagnosed with ovarian cancer during 2004-07. We compare the stage distribution between countries and estimate stage-specific one-year net survival and the excess hazard up to 18 months after diagnosis, using flexible parametric models on the log cumulative excess hazard scale. RESULTS: One-year survival was 69% in the UK, 72% in Denmark and 74-75% elsewhere. In Denmark, 74% of patients were diagnosed with FIGO stages III-IV disease, compared to 60-70% elsewhere. International differences in survival were evident at each stage of disease; women in the UK had lower survival than in the other four countries for patients with FIGO stages III-IV disease (61.4% vs. 65.8-74.4%). International differences were widest for older women and for those with advanced stage or with no stage data. CONCLUSION: Differences in stage at diagnosis partly explain international variation in ovarian cancer survival, and a more adverse stage distribution contributes to comparatively low survival in Denmark. This could arise because of differences in tumour biology, staging procedures or diagnostic delay. Differences in survival also exist within each stage, as illustrated by lower survival for advanced disease in the UK, suggesting unequal access to optimal treatment. Population-based data on cancer survival by stage are vital for cancer surveillance, and global consensus is needed to make stage data in cancer registries more consistent.

Five years' experience treating locally advanced cervical cancer with concurrent chemoradiotherapy and high-dose-rate brachytherapy: results from a single institution.

PURPOSE: To assess the clinical outcomes after concurrent cisplatin chemotherapy and radiotherapy (RT) followed by high-dose-rate brachytherapy for locally advanced carcinoma of the cervix and perform a multivariate analysis of the prognostic factors. METHODS AND MATERIALS: The outcomes were analyzed for all women treated between 1999 and 2004 with concurrent cisplatin chemotherapy and RT followed by high-dose-rate brachytherapy. Kaplan-Meier analysis was used for overall survival (OS), local control (LC), and distant control (DC). The Cox proportional hazards model was used to perform multivariate analysis of the prognostic variables. RESULTS: The standard regimen comprised whole pelvic external RT 45 Gy in 25 fractions with concurrent weekly cisplatin 40 mg/m(2), followed by four high-dose-rate brachytherapy insertions of 6 Gy. Patients with radiologically enlarged para-aortic lymph nodes underwent extended-field RT. Of 92 patients, the OS rate was 72% at 2 years and 55% at 5 years. The LC rate was 76% at 2 years and 67% at 5 years. The DC rate was 68% at 2 years and 48% at 5 years. The most important prognostic factor for OS, LC, and DC was the pretreatment hemoglobin. For OS, the tumor size and the presence of enlarged lymph nodes were also important. For LC, the number of brachytherapy insertions was important; and for DC, the number of chemotherapy treatments was important. Of the patients, 4% experienced late Grade 3 or 4 toxicity. CONCLUSION: The results of our study have shown that the regimen is effective, with acceptable long-term side effects. In this cohort, the most important prognostic factor was the pretreatment hemoglobin level, a disease-related factor. However, more effective systemic treatments are needed.