RESUMEN
During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential 'salvage' measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.
Asunto(s)
COVID-19/epidemiología , Neoplasias de los Genitales Femeninos/epidemiología , Neoplasias de los Genitales Femeninos/terapia , Femenino , Ginecología , Humanos , Pandemias , SARS-CoV-2/aislamiento & purificación , Reino Unido/epidemiologíaRESUMEN
The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to BRCA germline and tumor testing in patients with ovarian cancer in routine clinical practice. In particular, the group explored models of consent, quality standards identified at pathology laboratories, and experience and data from pioneering cancer centers. The group liaised with representatives from ovarian cancer charities to also identify patient perspectives that would be important to implementation. Recommendations from these consensus group deliberations are presented in this manuscript.
Asunto(s)
Proteína BRCA1 , Proteína BRCA2 , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/genética , Consenso , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/normas , Mutación de Línea Germinal , Humanos , Reino UnidoRESUMEN
BACKGROUND: There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. METHODS: Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. RESULTS: We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. CONCLUSIONS: The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness.
Asunto(s)
Próstata , Neoplasias de la Próstata/metabolismo , Células del Estroma/metabolismo , Sindecano-1 , Anciano , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Movimiento Celular/fisiología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor/métodos , Pronóstico , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , Células del Estroma/patología , Sindecano-1/inmunología , Sindecano-1/metabolismoRESUMEN
The kinetic and thermodynamic consequences of intrinsic disorder in protein-protein recognition are controversial. We address this by inducing one partner of the high-affinity colicin E3 rRNase domain-Im3 complex (K(d) ≈ 10(-12) M) to become an intrinsically disordered protein (IDP). Through a variety of biophysical measurements, we show that a single alanine mutation at Tyr507 within the hydrophobic core of the isolated colicin E3 rRNase domain causes the enzyme to become an IDP (E3 rRNase(IDP)). E3 rRNase(IDP) binds stoichiometrically to Im3 and forms a structure that is essentially identical to the wild-type complex. However, binding of E3 rRNase(IDP) to Im3 is 4 orders of magnitude weaker than that of the folded rRNase, with thermodynamic parameters reflecting the disorder-to-order transition on forming the complex. Critically, pre-steady-state kinetic analysis of the E3 rRNase(IDP)-Im3 complex demonstrates that the decrease in affinity is mostly accounted for by a drop in the electrostatically steered association rate. Our study shows that, notwithstanding the advantages intrinsic disorder brings to biological systems, this can come at severe kinetic and thermodynamic cost.
Asunto(s)
Colicinas/metabolismo , Escherichia coli/metabolismo , Proteínas Intrínsecamente Desordenadas/metabolismo , Mapas de Interacción de Proteínas , Ribonucleasas/metabolismo , Colicinas/química , Colicinas/genética , Escherichia coli/química , Escherichia coli/genética , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/genética , Modelos Moleculares , Mutación Puntual , Unión Proteica , Conformación Proteica , Pliegue de Proteína , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Ribonucleasas/química , Ribonucleasas/genética , Proteínas Ribosómicas/química , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , TermodinámicaRESUMEN
Gynaecological cancers are a major global health concern due to the lack of effective screening programmes for ovarian and endometrial cancer, for example, and variable access to vaccination and screening tests for cervical cancer in many countries. Recent research on portable and cost-effective lab-on-a-chip (LoC) technologies show promise for mass screening and diagnostic procedures for gynaecological cancers. However, most LoCs for gynaecological cancer are still in development, with a need to establish and clinically validate factors such as the type of biomarker, sample and method of detection, before patient use. Multiplex approaches, detecting a panel of gynaecological biomarkers in a single LoC, offer potential for more reliable diagnosis. This review highlights the current research on LoCs for gynaecological cancer screening and diagnosis, emphasizing the need for further research and validation prior to their widespread adoption in clinical practice.
Asunto(s)
Neoplasias Endometriales , Neoplasias del Cuello Uterino , Femenino , Humanos , Detección Precoz del Cáncer , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations.
RESUMEN
BACKGROUND: Cognitive-communication impairments following acquired brain injury (ABI) can have devastating effects on a person's ability to participate in community, social, vocational, and academic preinjury roles and responsibilities. Guidelines for evidence-based practices are needed to assist speech-language pathologists (SLPs) and other rehabilitation specialists in the delivery of cognitive rehabilitation for the adult population. PURPOSE: The American Speech-Language-Hearing Association, in conjunction with a multidisciplinary panel of subject matter experts, developed this guideline to identify best practice recommendations for the delivery of cognitive rehabilitation to adults with cognitive dysfunction associated with ABI. METHOD: A multidisciplinary panel identified 19 critical questions to be addressed in the guideline. Literature published between 1980 and 2020 was identified based on a set of a priori inclusion/exclusion criteria, and main findings were pooled and organized into summary of findings tables. Following the principles of the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision Framework, the panel drafted recommendations, when appropriate, based on the findings, overall quality of the evidence, balance of benefits and harms, patient preferences, resource implications, and the feasibility and acceptability of cognitive rehabilitation. RECOMMENDATIONS: This guideline includes one overarching evidence-based recommendation that addresses the management of cognitive dysfunction following ABI and 11 subsequent recommendations focusing on cognitive rehabilitation treatment approaches, methods, and manner of delivery. In addition, this guideline includes an overarching consensus-based recommendation and seven additional consensus recommendations highlighting the role of the SLP in the screening, assessment, and treatment of adults with cognitive dysfunction associated with ABI. Future research considerations are also discussed.
Asunto(s)
Lesiones Encefálicas , Disfunción Cognitiva , Estados Unidos , Adulto , Humanos , American Speech-Language-Hearing Association , Consenso , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , CogniciónRESUMEN
PURPOSE: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. PATIENTS AND METHODS: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. RESULTS: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44-23.87); fulvestrant: 13.7% (7/51; 5.70-26.26); risk difference -1.96% (95% CI, -16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61-1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. CONCLUSIONS: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
Asunto(s)
Neoplasias de la Mama , Inhibidores de Proteínas Quinasas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Compuestos Bicíclicos Heterocíclicos con Puentes , Fosfatidilinositol 3-Quinasa Clase I/genética , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Femenino , Fulvestrant/uso terapéutico , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2 , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , SulfonamidasRESUMEN
BACKGROUND: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5-53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. PATIENTS AND METHODS: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). RESULTS: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70-1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69-1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68-1.75, P = 0.7). Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel. Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. CONCLUSIONS: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.
Asunto(s)
Neoplasias de la Mama , Neutropenia , Humanos , Femenino , Neoplasias de la Mama/patología , Paclitaxel , Calidad de Vida , Receptor ErbB-2 , Neutropenia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
Older women with ovarian cancer have disproportionately poorer survival outcomes than their younger counterparts and receive less treatment. In order to understand where the gaps lie in the treatment of older patients, studies incorporating more detailed assessment of baseline characteristics and treatment delivery beyond the scope of most cancer registries are required. We aimed to assess the proportion of women over the age of 65 who are offered and receive standard of care for first-line ovarian cancer at two UK NHS Cancer Centres over a 5-year period (December 2009 to August 2015). Standard of care treatment was defined as a combination of cytoreductive surgery and if indicated platinum-based chemotherapy (combination or single-agent). Sixty-five percent of patients aged 65 and above received standard of care treatment. Increasing age was associated with lower rates of receiving standard of care (35% > 80 years old versus 78% of 65-69-year-olds, p = 0.000). Older women were less likely to complete the planned chemotherapy course (p = 0.034). The oldest women continue to receive lower rates of standard care compared to younger women. Once adjusted for Federation of Gynaecology and Obstetrics (FIGO) stage, Eastern Cooperative Oncology Group (ECOG) performance status and first-line treatment received, age was no longer an independent risk factor for poorer overall survival. Optimisation of vulnerable patients utilising a comprehensive geriatric assessment and directed interventions to facilitate the delivery of standard of care treatment could help narrow the survival discrepancy between the oldest patients and their younger counterparts.
RESUMEN
Blood films are an easy tool to aid the diagnosis and management of unwell patients and should be prepared in this setting. Green-blue neutrophil inclusion bodies could be an ominous sign of poor prognosis in critically ill patients.
RESUMEN
Despite recent improvements in sequencing methods, there remains a need for assays that provide high sequencing depth and comprehensive variant detection. Current methods1-4 are limited by the loss of native modifications, short read length, high input requirements, low yield or long protocols. In the present study, we describe nanopore Cas9-targeted sequencing (nCATS), an enrichment strategy that uses targeted cleavage of chromosomal DNA with Cas9 to ligate adapters for nanopore sequencing. We show that nCATS can simultaneously assess haplotype-resolved single-nucleotide variants, structural variations and CpG methylation. We apply nCATS to four cell lines, to a cell-line-derived xenograft, and to normal and paired tumor/normal primary human breast tissue. Median sequencing coverage was 675× using a MinION flow cell and 34× using the smaller Flongle flow cell. The nCATS sequencing requires only ~3 µg of genomic DNA and can target a large number of loci in a single reaction. The method will facilitate the use of long-read sequencing in research and in the clinic.
Asunto(s)
Proteína 9 Asociada a CRISPR/metabolismo , Secuenciación de Nanoporos/métodos , ARN Guía de Kinetoplastida/metabolismo , Animales , Células Cultivadas , Cromosomas Humanos/genética , Sitios Genéticos/genética , Variación Genética , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Recurrent epithelial ovarian cancer (EOC) remains difficult to treat, with an urgent need for more therapy options. Androgens bind to the androgen receptor (AR), commonly expressed in EOC. CYP17 inhibitor abiraterone irreversibly inhibits androgen biosynthesis. The Cancer of the Ovary Abiraterone (CORAL) trial was designed to evaluate the clinical activity of abiraterone in EOC. PATIENTS & METHODS: CORAL was a multi-centre, open-label, non-randomised, 2-stage phase II clinical trial. Eligible patients had progression within 12 months of last systemic therapy and no prior hormonal anti-cancer agents. Patients received abiraterone 1000 mg daily plus 5 mg prednisone until progression. The primary endpoint was objective response rate (ORR) according to combined Response Evaluation Criteria in Solid Tumours/Gynaecological Cancer Intergroup (RECIST/GCIG) criteria at 12 weeks. Secondary endpoints included clinical benefit rate (CBR) at 12 weeks. RESULTS: A total of 42 patients were recruited; median age 65 (range 34-85) years; 37 (88.1%) had high-grade serous tumours; 20 (48%) had at least three prior lines of therapy; 29/40 (72.5%) were AR+. In stage 1, 1/26 response was observed (in an AR+, low-grade serous EOC); response lasted 47 weeks. Overall, 12 week ORR was 1/42 (2%), CBR was 11/42 (26%) (8/29 (28%) in AR+ patients). Disease control was ⩾6 months for 4/29 (14%). One patient (AR+, low-grade serous) had a RECIST response at 82 weeks. Four (10%) had grade ⩾3 hypokalaemia; 11 (26%) had dose delays. CONCLUSIONS: CORAL represents the first trial of an AR targeted agent in ovarian cancer. While responses were rare, a subset of patients achieved sustained clinical benefit. Targeting AR in EOC including low-grade serous cancer warrants further investigation. TRIAL REGISTRATION: CORAL is registered on the ISRCTN registry: ISRCTN63407050; http://www.isrctn.com/ISRCTN63407050.
RESUMEN
Expansions of short tandem repeats are genetic variants that have been implicated in several neuropsychiatric and other disorders, but their assessment remains challenging with current polymerase-based methods1-4. Here we introduce a CRISPR-Cas-based enrichment strategy for nanopore sequencing combined with an algorithm for raw signal analysis. Our method, termed STRique for short tandem repeat identification, quantification and evaluation, integrates conventional sequence mapping of nanopore reads with raw signal alignment for the localization of repeat boundaries and a hidden Markov model-based repeat counting mechanism. We demonstrate the precise quantification of repeat numbers in conjunction with the determination of CpG methylation states in the repeat expansion and in adjacent regions at the single-molecule level without amplification. Our method enables the study of previously inaccessible genomic regions and their epigenetic marks.
Asunto(s)
Metilación de ADN/genética , Genómica/métodos , Repeticiones de Microsatélite/genética , Secuenciación de Nanoporos/métodos , Algoritmos , Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Sistemas CRISPR-Cas/genética , Células Cultivadas , Humanos , NanoporosAsunto(s)
Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Neoplasias Peritoneales , Humanos , Femenino , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/diagnóstico , Neoplasias Ováricas/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias de las Trompas Uterinas/terapia , Neoplasias de las Trompas Uterinas/diagnóstico , Reino Unido , Sociedades MédicasRESUMEN
PURPOSE: Polymorphisms within the promoter region of several matrix metalloproteinase (MMP) genes have been linked to alterations in the level of transcription. We hypothesized that an individual's MMP genotype and haplotype will influence breast tumor progression and help predict prognosis. EXPERIMENTAL DESIGN: This study has evaluated the association between single-nucleotide polymorphisms (SNP) in the promoter regions of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 and metastatic spread of breast cancer in 128 lymph node-negative and 93 lymph node-positive patients. The study cohort was of mixed ethnicity, with Caucasian patients comprising 65%. Associations between genotype and lymph node status were estimated by logistic regression and with overall survival using the method of Kaplan-Meier and log-rank test. Associations between haplotype and lymph node status were also investigated. RESULTS: The data show a significant and independent association of the C/T genotype for MMP-9 [mixed ethnicities odds ratio 3.6, 95% confidence interval (95% CI) 1.2-11.1; Caucasian odds ratio 9.1, 95% CI 1.7-48.4] and the 2G/2G genotype for MMP-1 (mixed ethnicities odds ratio 3.9, 95% CI 1.7-9.4; Caucasian odds ratio 2.6, 95% CI 1.0-6.9) with lymph node-positive disease. MMP-1 2G/2G was associated with reduced survival (hazard ratio 3.1, 95% CI 1.1-8.7), although this is dependent on lymph node status. Two haplotypes, driven by the MMP-1 2G allele, were significantly associated with lymph node-positive disease and survival. CONCLUSIONS: These results suggest that MMP single-nucleotide polymorphisms influence breast cancer behavior and that the MMP-1 2G/2G genotype increases the risk of lymph node metastasis and predicts poor prognosis.
Asunto(s)
Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Metaloproteinasas de la Matriz/genética , Polimorfismo de Nucleótido Simple , Adulto , Progresión de la Enfermedad , Femenino , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To determine whether social skills deficits including unskilled, inappropriate behavior, problems reading social cues (social perception), and mood disturbances (such as depression and anxiety) could be remediated after severe traumatic brain injuries. DESIGN: Randomized controlled trial comparing a social skills program with social activity alone or with waitlist control. Several participants were reassigned after randomization. SETTING: Hospital outpatient and community facilities. PARTICIPANTS: Fifty-one outpatients from 3 brain injury units in Sydney, Australia, with severe, chronic acquired brain injuries were recruited. A total of 39 people (13 in skills training, 13 in social activity, 13 in waitlist) completed all phases of the study. INTERVENTION: Twelve-week social skills treatment program encompassing weekly 3-hour group sessions focused on shaping social behavior and remediating social perception and 1-hour individual sessions to address psychologic issues with mood, self-esteem, etc. MAIN OUTCOME MEASURES: Primary outcomes were: (1) social behavior during encounters with a confederate as rated on the Behaviorally Referenced Rating System of Intermediary Social Skills-Revised (BRISS-R), (2) social perception as measured by The Awareness of Social Inference Test, and (3) depression and anxiety as measured by the Depression, Anxiety and Stress Scale. Secondary outcomes were: relative report on social behavior and participation using: the Katz Adjustment Scale-R1; the Social Performance Survey Schedule; the La Trobe Communication Questionnaire; and the Sydney Psychosocial Reintegration Scale (both relative and self-report). RESULTS: Repeated-measures analysis of variance indicated that social activity alone did not lead to improved performance relative to waitlist (placebo effect) on any outcome variable. On the other hand, the skills training group improved differentially on the Partner Directed Behavior Scale of the BRISS-R, specifically the self-centered behavior and partner involvement behavior subscales. No treatment effects were found for the remaining primary outcomes (social perception, emotional adjustment) or for secondary outcome variables (relative and self-report measures of social function). CONCLUSIONS: This study suggested that treatment effects after social skills training in people with severe, chronic brain injuries are modest and are limited to direct measures of social behavior.
Asunto(s)
Terapia Conductista/métodos , Lesión Encefálica Crónica/rehabilitación , Conducta Social , Adulto , Análisis de Varianza , Australia , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Pronóstico , Reproducibilidad de los Resultados , Percepción Social , Resultado del TratamientoRESUMEN
Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.
Asunto(s)
Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Endometrioide/tratamiento farmacológico , Carcinosarcoma/tratamiento farmacológico , Ensayos Clínicos Fase I como Asunto , Tumor de Células de la Granulosa/tratamiento farmacológico , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Adulto , Anciano , Antígeno Ca-125/metabolismo , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patología , Carcinosarcoma/genética , Carcinosarcoma/metabolismo , Carcinosarcoma/patología , Descubrimiento de Drogas , Inglaterra , Femenino , Genes BRCA1 , Genes BRCA2 , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/metabolismo , Tumor de Células de la Granulosa/patología , Hemoglobinas/metabolismo , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Humanos , Recuento de Leucocitos , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/metabolismo , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Pronóstico , Estudios Retrospectivos , Albúmina Sérica/metabolismo , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
To determine whether the EP4 receptor for prostaglandin E2 (PGE2) contributes to the tumor promoting activity of PGs in murine skin, EP4 over-expressing mice (BK5.EP4) were generated and subjected carcinogenesis protocols. An initiation/promotion protocol resulted in 25-fold more squamous cell carcinomas (SCCs) in the BK5.EP4 mice than wild type (WT) mice. An increase in SCCs also occurred following treatment with initiator alone or UV irradiation. The initiator dimethylbenz[a]anthracene caused cytotoxicity in BK5.EP4, but not WT mice, characterized by sloughing of the interfollicular epidermis, regeneration and subsequent SCC development. A comparison of transcriptomes between BK5.EP4 and WT mice treated with PGE2 showed a significant upregulation of a number of genes known to be associated with tumor development, supporting a pro-tumorigenic role for the EP4 receptor.
Asunto(s)
Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Animales , Interleucinas/metabolismo , Ratones , Ratones Transgénicos , Subtipo EP4 de Receptores de Prostaglandina E/genética , Neoplasias Cutáneas/genética , Cicatrización de Heridas/fisiologíaRESUMEN
BACKGROUND: Integrin αvß6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of αvß6 has yet to be elucidated in breast cancer. METHODS: Protein expression of integrin subunit beta6 (ß6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ß6 in breast cell lines, the role of αvß6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ≥ 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided. RESULTS: High expression of either the mRNA or protein for the integrin subunit ß6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ß6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts. CONCLUSIONS: Targeting αvß6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.