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BACKGROUND/AIMS: Contact lens-associated keratitis (CLAK) is a common sight-threatening complication of contact lens use. Current management protocols in the UK are based on historical practice and necessitate a review for every patient within 48 hours regardless of severity, increasing the treatment burden on a resource-limited healthcare service. Our study aims to identify the different risk factors associated with CLAK, categorise CLAK using a novel grading system and recommend modifications to current management protocols based on the outcomes in the individual subgroups. METHODS: The retrospective cohort study identified 161 eyes from 153 patients with CLAK from the electronic patient records of a tertiary eye centre between 1 July 2021 and 28 February 2022. Patients were categorised based on epithelial defect size (grade 1: <1.0 mm, grade 2: 1.0-2.0 mm, grade 3: >2.0 mm) and their risk factors, clinical features, treatments and outcomes were analysed. RESULTS: The most significant risk factors for CLAK include extended-wear contact lens, poor hygiene and prolonged duration of wear. Grades 1 and 2 CLAKs have excellent outcomes following an empirical treatment regime with topical moxifloxacin with 96% discharged within 48 hours and 94.1% discharged in 2 weeks, respectively. Grade 3 CLAKs require prolonged average duration of treatment. CONCLUSION: We recommend typical grade 1 and 2 CLAKs can be discharged with empirical fluoroquinolone treatment. Grade 3 and all CLAKs with atypical features require monitoring for resolution, further diagnostics or treatment. We provide an evidence-based approach to reduce unnecessary patient visits and optimise resource allocation in an urban setting.
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The backbone 1H, 13C and 15N resonance assignment of Ubiquitin Specific Protease 7 catalytic domain (residues 208-554) was performed in its complex with a small molecule ligand and in its apo form as a reference. The amide 1H-15N signal intensities were boosted by an amide hydrogen exchange protocol, where expressed 2H, 13C, 15N-labeled protein was unfolded and re-folded to ensure exchange of amide deuterons to protons. The resonance assignments were used to determine chemical shift perturbations on ligand binding, which are consistent with the binding site observed by crystallography.
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Dominio Catalítico , Resonancia Magnética Nuclear Biomolecular , Humanos , Ligandos , Isótopos de NitrógenoRESUMEN
Acanthamoeba keratitis (AK) is a rare but severe eye disease. A research engagement event, "The Cornea Day," in London, UK in 2013, identified the lack of credible information about AK and a need for practical day to day management strategies. Experiences of 15 AK patients attending The Cornea Day were distilled into a survey that was administered to a wider group of 76 patients, carers, researchers, and clinicians. A Patient Information Leaflet was cocreated and then represented to additional patients for final modification. The AK Patient Leaflet (revised 2019) is available in several languages and used globally.
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PURPOSE: Moorfields Eye Hospital sits as a major tertiary centre for ophthalmic care in the United Kingdom and became a central hub to provide safe and effective ophthalmic care across London and surrounding regions during the COVID-19 pandemic. We explore the impact on both the acute and elective corneal services during the first wave of this pandemic. METHODS: A retrospective review of the proportion of corneal transplants and anterior segment trauma repairs was performed during the period of March 23rd to July 1st 2020 compared with an identical period in 2019. Data were acquired from our in-house electronic patient records. RESULTS: A 92% reduction in corneal elective work was observed during the lockdown period compared with an identical period in 2019, with only 10 elective cases in total being performed. In addition, 91 corneal cross-linking and 76 therapeutic lasers were cancelled. There were 15 cases of primary repair for anterior segment trauma compared with 6 cases pre-COVID-19. A similar scenario occurs with removal of foreign body (4 cases during COVID-19 period versus no cases during pre-COVID-19 era) and with traumatic lens aspirations (6 cases during COVID-19 compared with 2 pre-COVID-19). Interestingly, a statistical difference (p=0.03) was found in the time interval from presentation of symptoms to emergency corneal surgery. During the COVID-19 period, a delay of 1.5 days ± 2.29 (range 0-10 days) occurred compared with 0.8 days ± 1.54 (range 0-6 days) pre-COVID-19. CONCLUSION: Stringent risk stratification reduced elective corneal surgery capacity during the lockdown thereby preserving social distancing requirements. However, an apparent increase in emergency corneal surgery seen is likely attributed to centralisation of ophthalmic services during the pandemic crisis, alongside increased domestic injuries. Despite the challenges posed, successful delivery of corneal surgery occurred whilst helping to identify lessons in preparations for future pandemics and current inefficiencies in healthcare delivery.
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Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphological and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated (1) enhanced Wnt/ß-catenin signaling, (2) a broad spectrum of degrees of epithelial to mesenchymal transition (EMT) activation including hybrid E/M states (partial EMT) with highly plastic features, and (3) high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and ß-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically distinct cellular states and to underlie the phenotypic plasticity of colon cancer cells.
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Movimiento Celular , Plasticidad de la Célula , Neoplasias del Colon/patología , Animales , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/mortalidad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Molécula de Adhesión Celular Epitelial/genética , Molécula de Adhesión Celular Epitelial/metabolismo , Transición Epitelial-Mesenquimal , Femenino , Células HCT116 , Humanos , Masculino , Ratones Endogámicos NOD , Invasividad Neoplásica , Metástasis de la Neoplasia , Osteonectina/genética , Osteonectina/metabolismo , Fenotipo , Vía de Señalización Wnt , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
We describe a case of bilateral spontaneous corneal perforation secondary to pellucid marginal degeneration and present the associated swept-source anterior segment optical coherence tomography (SS-ASOCT) findings and management principles used. A 47-year-old woman presented with ocular pain, redness, foreign body sensation and clear discharge in the right eye in 2017 and with very similar symptoms in 2019 in the left eye. Clinically she had a corneal perforation at the inferior cornea with associated loss of anterior chamber volume. Corneal topography demonstrated peripheral thinning and steepening in the contralateral eye. ASOCT images revealed full-thickness perforation, iridocorneal touch and iris stranding. The patient was managed with a combination of contact bandaging and corneal gluing. SS-ASOCT is a useful adjunctive tool in the clinical assessment and evaluation of spontaneous corneal perforation. Alongside the clinical evaluation, it can be used to monitor the clinical response.
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BACKGROUND: In colon cancer, the location and density of tumor-infiltrating lymphocytes (TILs) can classify patients into low and high-risk groups for prognostication. While a commercially available 'Immunoscore®' exists, the incurred expenses and copyrights may prevent universal use. The aim of this study was to develop a robust and objective quantification method of TILs in colon cancer. METHODS: A consecutive, unselected series of specimens from patients with colon cancer were available for immunohistochemistry and assessment of TILs by automated digital pathology. CD3 + and CD8 + cells at the invasive margin and in tumor center were assessed on consecutive sections using automated digital pathology and image analysis software (Visiopharm®). An algorithm template for whole slide assessment, generated cell counts per square millimeters (cells/mm2), from which the immune score was calculated using distribution volumes. Furthermore, immune score was compared with clinical and histopathological characteristics to confirm its relevance. RESULTS: Based on the quantified TILs numbers by digital image analyses, patients were classified into low (n = 83, 69.7%), intermediate (n = 14, 11.8%) and high (n = 22, 18.5%) immune score groups. High immune score was associated with stage I-II tumors (p = 0.017) and a higher prevalence of microsatellite instable (MSI) tumors (p = 0.030). MSI tumors had a significantly higher numbers of CD3 + TILs in the invasive margin and CD8 + TILs in both tumor center and invasive margin, compared to microsatellite stable (MSS) tumors. CONCLUSION: A digital template to quantify an easy-to-use immune score corresponds with clinicopathological features and MSI in colon cancer.
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Complejo CD3/metabolismo , Linfocitos T CD8-positivos/inmunología , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Linfocitos Infiltrantes de Tumor/inmunología , Inestabilidad de Microsatélites , Neoplasias del Colon/metabolismo , Estudios de Seguimiento , Humanos , Pronóstico , Estudios ProspectivosRESUMEN
INTRODUCTION: Microsatellite instability (MSI) predict response to anti-PD1 immunotherapy in colorectal cancer (CRC). CRCs with MSI have higher infiltration of immune cells related to a better survival. Elevated Microsatellite Alterations at Tetranucleotides (EMAST) is a form of MSI but its association with PD-L1 expression and immune-cell infiltration is not known. METHODS: A consecutive, observational cohort of patients undergoing surgery for CRC. EMAST and clinicopathological characteristics were investigated against PD-L1, as well as CD3 and CD8 expression in the invasive margin or tumour centre (Immunoscore). Difference in survival between groups was assessed by log rank test. RESULTS: A total of 149 stage I-III CRCs patients, with a median follow up of 60.1 months. Patients with PD-L1+ tumours (7%) were older (median 79 vs 71 years, p = 0.045) and had EMAST+ cancers (OR 10.7, 95% CI 2.2-51.4, p = 0.001). Recurrence-free survival was longer in cancers with PD-L1+ immune cells (HR 0.35, 95% CI 0.16-0.76, p = 0.008, independent of EMAST) and high Immunoscore (HR 0.10, 95% CI 0.01-0.72, p = 0.022). Patients expressing PD-L1 in immune cells had longer disease-specific survival (HR 0.28, 95% CI 0.10-0.77, p = 0.014). CONCLUSIONS: Higher Immunoscore (CD3/CD8 cells) and expression of tumour PD-L1 is found in CRCs with EMAST. Lymphocytic infiltrate and peritumoral PD-L1 expression have prognostic value in CRC.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/mortalidad , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia/mortalidad , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
Purpose: The purpose of this qualitative study was to explore how stroke patients with unilateral spatial neglect experience; (a) performance in activities of daily living; (b) alterations in bodily perceptions; and (c) personal hopes and expectations, looking at the period between stroke onset and discharge from inpatient rehabilitation.Materials and methods: We conducted individual semi-structured interviews with 7 (5 men, 2 women, mean age 69 years) consecutively sampled participants. All interviews were transcribed verbatim and analyzed using thematic analysis.Findings: Participants' experiences were captured in three over-arching themes: "unawareness of neglect," "emergent awareness for neglect-related difficulties," and "comparing the new life with the old one." Findings showed that participants progressed from initial unawareness to emergent awareness for their neglect-related difficulties over the course of rehabilitation. Comparing their current life situation with the one before their stroke triggered feelings of uncertainty and regret, with associated decreased pleasure in meaningful activities.Conclusions: This study informs health professionals regarding personal experiences of orientation in and reorganization of life of stroke patients with unilateral spatial neglect. The findings highlight that being aware of neglect-related deficits is a prerequisite for using coping strategies and incorporating them in daily life. Possible therapeutic strategies that fit the current stage of recovery and level of awareness are discussed.IMPLICATIONS FOR REHABILITATIONSymptoms of unilateral spatial neglect and anosognosia are most common after right hemispheric stroke, both being predictors of poorer functional outcome during rehabilitation.Patients' regaining some awareness of their impairments is a prerequisite for successful treatment and for engagement in neglect-specific interventions.Health care providers should carefully examine the "state of awareness" of the patient and adapt their therapeutic approach accordingly.This check should frequently be repeated over the course of rehabilitation, as awareness changes at different paces for each patient.
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Agnosia , Trastornos de la Percepción , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Actividades Cotidianas , Anciano , Femenino , Humanos , Pacientes Internos , Masculino , Alta del Paciente , Trastornos de la Percepción/etiología , Accidente Cerebrovascular/complicacionesRESUMEN
BACKGROUND: Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a poorly investigated form of microsatellite instability (MSI) in colorectal cancer (CRC). OBJECTIVE: The aim of this study was to investigate the clinicopathological features of EMAST in CRC and its relation to outcome. METHODS: A population-based, consecutive cohort of surgically treated stage I-III CRC patients investigated for high-frequency MSI (MSI-H) and EMAST. Clinicopathological differences were reported as odds ratios (OR) and survival was presented as hazard ratios (HR) with 95% confidence intervals (CIs). RESULTS: Of 161 patients included, 25% were aged > 79 years. There was a large overlap in the prevalence of EMAST (31.7%) and MSI-H (27.3%) [82.4% of EMAST were also MSI-H]. EMAST had the highest prevalence in the proximal colon (OR 15.9, 95% CI 5.6-45.1; p < 0.001) and in women (OR 4.1, 95% CI 1.9-8.6; p < 0.001), and were poorly differentiated (OR 5.0, 95% CI 2.3-10.7; p < 0.001). Compared with EMAST-negative patients, EMAST-positive patients were older (median age 77 vs. 69 years; p < 0.001), leaner (median weight 67.5 vs. 77 kg; p = 0.001), had significantly higher rates of hypoalbuminemia (24% vs. 6%; OR 2.3, 95% CI 1.5-3.6; p = 0.002) and anemia (45% vs. 20%; OR 3.3, 95% CI 1.6-6.8; p = 0.001), and had elevated preoperative C-reactive protein (CRP) levels (51% vs. 34%; OR 1.9, 95% CI 1.0-3.9; p = 0.046). Improved recurrence-free survival was found in both MSI-H and EMAST subtypes. In multivariable analysis, node status (pN +), together with elevated CRP and MSI-positive, were the strongest prognostic factors for recurrence-free survival. CONCLUSIONS: EMAST in CRC is associated with an older, leaner, and frailer phenotype with a lower risk of recurrence. The relevance of, and putative mechanisms to, EMAST warrants further investigation.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Anciano Frágil , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Noruega/epidemiología , Fenotipo , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
INTRODUCTION: EMAST is a poorly understood form of microsatellite instability (MSI) in colorectal cancer (CRC) for which loss of MSH3 has been proposed as the underlying mechanism, based on experimental studies. We aimed to evaluate whether MSH3 loss is associated with EMAST in CRC. METHODS: A consecutive cohort of patients with stage I-III CRC. Digital image analysis using heatmap-derived hot spots investigated MSH3 expression by immunohistochemistry. Fragment analysis of multiplex PCR was used to assess MSI and EMAST, and results cross-examined with MSH3 protein expression. RESULTS: Of 152 patients, EMAST was found in 50 (33%) and exclusively in the colon. Most EMAST-positive cancers had instability at all 5 markers, and EMAST overlapped with MSI-H in 42/50 cases (84%). The most frequently altered tetranucleotide markers were D8S321 (38.2% of tumors) and D20S82 (34.4%). Subjective evaluation of MSH3 expression by IHC in tumor found ≤10% negative tumor cells in all samples, most being ≤5% negative. Digital analysis improved the detection but showed a similar spread of MSH3 loss (range 0.1-15.7%, mean 2.2%). Hotspot MSH3 negativity ranged between 0.1 to 95.0%, (mean 8.6%) with significant correlation with the whole slide analysis (Spearman's rho=0.677 P<.001). Loss of MSH3 expression did not correlate with EMAST. CONCLUSIONS: In a well-defined cohort of patients with CRC, loss of MSH3 was not associated with EMAST. Further investigation into the mechanisms leading to EMAST in CRC is needed.
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CONTEXT: Discussing end-of-life issues with patients is an essential role for chaplains. Few tools are available to help chaplains-in-training develop end-of-life communication skills. OBJECTIVE: This study aimed to determine whether playing an end-of-life conversation game increases the confidence for chaplain-in-trainings to discuss end-of-life issues with patients. METHODS: We used a convergent mixed methods design. Chaplains-in-training played the end-of-life conversation game twice over 2 weeks. For each game, pre- and postgame questionnaires measured confidence discussing end-of-life issues with patients and emotional affect. Between games, chaplains-in-training discussed end-of-life issues with an inpatient. One week after game 2, chaplains-in-training were individually interviewed. Quantitative data were analyzed using descriptive statistics and Wilcoxon rank-sum t tests. Content analysis identified interview themes. Quantitative and qualitative data sets were then integrated using a joint display. RESULTS: Twenty-three chaplains-in-training (52% female; 87% Caucasian; 70% were in year 1 of training) completed the study. Confidence scores (scale: 15-75; 75 = very confident) increased significantly after each game, increasing by 10.0 points from pregame 1 to postgame 2 ( P < .001). Positive affect subscale scores also increased significantly after each game, and shyness subscale scores decreased significantly after each game. Content analysis found that chaplains-in-training found the game to be a positive, useful experience and reported that playing twice was beneficial (not redundant). CONCLUSION: Mixed methods analysis suggest that an end-of-life conversation game is a useful tool that can increase chaplain-in-trainings' confidence for initiating end-of-life discussions with patients. A larger sample size is needed to confirm these findings.
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Servicio de Capellanía en Hospital/métodos , Clero/educación , Juegos Experimentales , Cuidados Paliativos al Final de la Vida/métodos , Rol Profesional , Cuidado Terminal/métodos , Adulto , Planificación Anticipada de Atención , Actitud Frente a la Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Investigación CualitativaRESUMEN
AIM: To test the feasibility of conducting parallel analyses of circulating T-cells in blood and intratumoural T-cells in colorectal cancer. A pre-operative 'liquid biopsy' to determine immune status would facilitate clinical decision-making. MATERIALS AND METHODS: A total of 18 patients with stage I-III colorectal cancer (CRC) were included. Blood was analyzed for T-cell type (CD3+, CD4+ and CD8+) and count using flow cytometry. Intratumoural T-cells were stained using immunohistochemistry and quantified by digital pathology. Tumour location was defined as invasive front (IF) or tumour center (TC). RESULTS: The number of CD3+ and CD4+ T-cells in pre-surgical blood samples correlated with the number of CD3+ T-cells found in the IF (Spearman ϱ=0.558, p<0.05 and 0.598, p<0.01 respectively) and CD3+ in the TC (ϱ=0.496, p<0.05, and ϱ=0.637, p<0.01, respectively). A strong correlation was found between CD4+ cells in blood and CD8+ T-cells found in the TC and IF (ϱ=0.602 and ϱ=0.591, p<0.01). CONCLUSION: There is a correlation between blood CD3+ and CD4+ T-cells and the T-cells found at the TC and IF.
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Complejo CD3/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/inmunología , Subgrupos de Linfocitos T/inmunología , Anciano , Anciano de 80 o más Años , Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Colon/inmunología , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/metabolismo , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Periodo Preoperatorio , Recto/inmunología , Recto/metabolismo , Recto/patología , Subgrupos de Linfocitos T/metabolismoRESUMEN
BACKGROUND: More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis. METHODS: An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases. Long-term outcomes will be cancer-specific survival, recurrence-free survival and overall survival at 5 years from diagnosis. Beyond routine clinicopathological and anthropometric characteristics and laboratory and biochemistry results, the project allows for additional blood samples and fresh-frozen tumour and normal tissue for investigation of circulating tumour cells (CTCs) and novel biomarkers (e.g. immune cells, microRNAs etc.). Tumour specimens will be investigated by immunohistochemistry in full slides. Extracted DNA/RNA will be analysed for genomic markers using specific PCR techniques and next-generation sequencing (NGS) panels. Flow cytometry will be used to characterise biomarkers in blood. Collaboration is open and welcomed, with particular interest in mutual opportunities for validation studies. STATUS AND PERSPECTIVES: The project is ongoing and recruiting at an expected rate of 120-150 patients per year, since January 2013. A project on circulating tumour cells (CTCs) has commenced, with analysis being prepared. Investigating molecular classes beyond the TNM staging is under way, including characteristics of microsatellite instability (MSI) and elevated microsatellite alterations in selected tetranucleotides (EMAST). Hot spot panels for known mutations in CRC are being investigated using NGS. Immune-cell characteristics are being performed by IHC and flow cytometry in tumour and peripheral blood samples. The project has ethical approval (REK Helse Vest, #2012/742), is financially supported with a Ph.D.-Grant (EMAST project; Folke Hermansen Cancer Fund) and a CTC-project (Norwegian Research Council; O. Nordgård). The ACROBATICC clinical and molecular biobank repository will serve as a long-term source for novel exploratory analysis and invite collaborators for mutual validation of promising biomarker results. The project aims to generate results that can help better discern prognostic groups in stage II/III cancers; explore prognostic and predictive biomarkers, and help detail the biology of colorectal liver metastasis for better patient selection and tailored treatment. The project is registered at http://www.ClinicalTrials.gov NCT01762813.
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Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/cirugía , Neoplasias Hepáticas/secundario , Investigación Biomédica Traslacional , Estudios de Cohortes , Neoplasias Colorrectales/patología , Conducta Cooperativa , Determinación de Punto Final , Citometría de Flujo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Células Neoplásicas Circulantes/patología , Tamaño de la Muestra , Resultado del TratamientoRESUMEN
The TNM-system fails to accurately predict disease recurrence in a considerate number of patients. While node-negative (stage II) colon cancer is considered to have an overall good prognosis, the 5-year cancer-specific survival is reported at 81-83% in patients who did not have adjuvant chemotherapy. Thus, reliance on node-status alone has lead to under-treatment in a subgroup of stage II patients with an unfavorable prognosis. The search for new and better prognosticators in stage II colon cancer has suggested several proposed biomarkers of better prognostication and prediction. However, few such biomarkers have reached widespread clinical utility. For the clinician swimming in the sea of emerging biomarkers, it may be hard to recognize the true floating aid from the surrounding debris in the search for more precise decision-making. Proposed markers include microsatellite instability (MSI), KRAS mutations and BRAF mutations, but a number of gene panels and consensus molecular subtypes are proposed for clinical prediction and prognostication as well. While several studies suggest such biomarkers or panels to have a prognostic role in subgroups of patients, a number of studies are reported in heterogeneous groups with in part discordant findings, which again distorts the predictive and prognostic ability of each marker. Lack of homogeneous cohorts, underpowered studies in strict subgroups and challenges in analytical and clinical validity may hamper the progress towards widespread clinical utility. The harvest of prognostic biomarkers in colon cancer has yielded a huge number of candidates for which it is now time to separate the wheat from the chaff.
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Microsatellite instability (MSI) is associated with better prognosis in colorectal cancer (CRC). Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a less-understood form of MSI. Here, we aim to investigate the role of EMAST in CRC±MSI related to clinical and tumor-specific characteristics. A consecutive, population-based series of stage I-III colorectal cancers were investigated for MSI and EMAST using PCR primers for 10 microsatellite markers. Of 151 patients included, 33 (21.8%) had MSI and 35 (23.2%) were EMAST+, with an overlap of 77% for positivity, (odds ratio [OR] 61; P < 0.001), and 95% for both markers being negative. EMAST was more prevalent in colon versus rectum (86% vs. 14%, P = 0.004). EMAST+ cancers were significantly more frequent in proximal colon (77 vs. 23%, P = 0.004), had advanced t-stage (T3-4 vs. T1-2 in 94% vs. 6%, respectively; P = 0.008), were larger (≥5 cm vs. <5 cm in 63% and 37%, respectively; P = 0.022) and had poorly differentiated tumor grade (71 vs. 29%, P < 0.01). Furthermore, EMAST+ tumors had a higher median number of harvested lymph nodes than EMAST- (11 vs. 9 nodes; P = 0.03). No significant association was found between EMAST status and age, gender, presence of distant metastases or metastatic lymph nodes, and overall survival. A nonsignificant difference toward worse survival in node-negative colon cancers needs confirmation in larger cohorts. EMAST+ cancers overlap and share features with MSI+ in CRC. Overall, survival was not influenced by the presence of EMAST, but may be of importance in subgroups such as node-negative disease of the colon.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Inestabilidad de Microsatélites , Repeticiones de Microsatélite , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaAsunto(s)
Biomarcadores de Tumor/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 9 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Functional Strength Training (FST) could enhance recovery late after stroke. The aim of this study was to evaluate the feasibility of a subsequent fully powered, randomized controlled trial. METHODS: The study was designed as a randomized, observer-blind trial. Both interventions were provided for up to one hour a day, four days a week, for six weeks. Evaluation points were before randomization (baseline), after six weeks intervention (outcome), and six weeks thereafter (follow-up). The study took place in participants' own homes. Participants (n = 52) were a mean of 24.4 months after stroke with a mean age of 68.3 years with 67.3% male. All had difficulty using their paretic upper (UL) and lower limb (LL). Participants were allocated to FST-UL or FST-LL by an independent randomization service. The outcome measures were recruitment rate, attrition rate, practicality of recruitment strategies, occurrence of adverse reactions, acceptability of FST, and estimation of sample size for a subsequent trial. Primary clinical efficacy outcomes were the Action Research Arm Test (ARAT) and the Functional Ambulation Categories (FAC). Analysis was conducted using descriptive statistics and thematic analysis of participants' views of FST. A power calculation used estimates of clinical efficacy variance to estimate sample size for a subsequent trial. RESULTS: The screening process identified 1,127 stroke survivors of whom 52 (4.6%) were recruited. The recruitment rate was higher for referral from community therapists than for systematic identification of people discharged from an acute stroke unit. The attrition rate was 15.5% at the outcome and follow-up time-points. None of the participants experienced an adverse reaction. The participants who remained in the study at outcome had received 68% of the total possible amount of therapy. Participants reported that their experience of FST provided a sense of purpose and involvement and increased their confidence in performing activities. The power calculation provides estimation that 150 participants in each group will be required for a subsequent clinical trial. CONCLUSIONS: This study found that a subsequent clinical trial was feasible with modifications to the recruitment strategy to be used. TRIAL REGISTRATION: Controlled-trials.com ISCTN71632550, 30 January 2009.