Eosinophilic Esophagitis (EoE) is an antigen-triggered inflammatory condition of the esophageal lining characterized by eosinophilic infiltration. EoE is associated with significant remodeling, and ...although this remodeling is reversed by current treatment regimens, symptoms of EoE and associated remodeling reappear upon cessation of therapies. We hypothesized that structural remodeling of cell-cell adhesion is a key factor in the pathogenesis of EoE and that epithelial to mesenchymal transition (EMT) was a viable molecular process to lead to this remodeling. Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were evaluated by transmission electron microscopy to measure intercellular spaces (IS) between cells. Biopsy samples from all groups were analyzed for cellular levels of cell-cell adhesion proteins: E-cadherin, zonula occludens associated protein-1 (ZO-1), and N-cadherin. We also analyzed for cellular levels and localization two of transcription factors, Twist1 and β-catenin, that are associated with promoting EMT. The IS was significantly increased in the EoE group compared to the control. We observed a significant decrease in E-cadherin and ZO-1 levels and a concomitant increase in N-cadherin levels in EoE samples compared to control. Further, while there was no significant change in cellular levels of β-catenin, we observed an altered localization of the protein from the cell membrane in control tissue to a nuclear/perinuclear localization in EoE. We observed higher levels of the transcription factor Twist1 in the EoE group compared to normal which was localized mainly at the nucleus. Our results suggest that the integrity of normally sealed esophageal epithelia is compromised in the EoE patients compared to control subjects, and this is due to alterations in the expression of cell adhesion molecules at the esophageal epithelium. Our data also suggest that EMT, potentially regulated by transcription factors β-catenin and Twist1, may be responsible for the molecular alteration which leads to the remodeling of esophageal epithelia in EoE.
Retrospective cohort study.
To investigate the impact of long symptom duration (>24 mo) on patient self-reported outcomes for pain, function, and quality of life following anterior cervical ...discectomy and fusion (ACDF) for cervical radiculopathy.
ACDF is an effective treatment to relieve the symptoms of cervical radiculopathy. However, there is no consensus on whether prolonged preoperative length of symptoms negatively impacts postoperative outcomes.
This study included consecutive patients who underwent ACDF for cervical radiculopathy from May 1, 2012 to Dec 1, 2019 by a single surgeon. Patients were stratified by short (<24 mo) and long (>24 mo) duration of symptoms. Outcomes including visual analog scale (VAS) neck and arm, neck disability index (NDI), EuroQol-5D (EQ-5D), and overall state of health (EQ-VAS) were compared between cohort both for absolute values and percentage of patients achieving minimal clinically important difference.
A total of 111 consecutive patients were included in our study, including 59 patients in the short symptom duration group and 52 patients in the long symptom duration group. The mean age of the patients was 51.4±9.4 and 41 (36.9%) were female. The baseline VAS neck and arm, NDI, EQ-5D, and EQ-VAS were similar between groups. Patients in both long and short symptom duration groups had clinical improvement following surgery. However, patients with short symptom duration had better VAS Neck and EQ-5D outcomes, and were more likely to meet minimal clinically important difference for NDI, EQ-5D, or any outcome. Multivariate analysis confirmed symptom duration <24 months as an independent predictor for better patient-reported outcomes.
We appreciated better clinical outcomes in patients with shorter symptom duration who received ACDF for cervical radiculopathy. On the basis of this data, we advocate for prompt treatment of cervical radiculopathy to avoid the potential for long-term impairment.
Level 3.
To assess prostate magnetic resonance imaging (MRI) image quality and compliance with technical standards between centres in the South West region of the UK.
Fifteen imaging sites in the region ...submitted seven consecutive anonymised MRI studies. These were assessed by two experienced radiologists in consensus. Overall, subjective image quality for T2-weighted imaging (T2W), diffusion weighted imaging (DWI), and dynamic contrast enhancement (DCE) was scored on a five-point Likert scale. Five additional quality parameters were also assessed visually, including image noise, motion, artefact, and distortion. The degree of compliance by each site with 21 published technical standards was also assessed.
Ninety-four MRI examinations were reviewed from across all sites (mean 6.3 scans per site, range 5–7). Mean compliance with technical standards was 63% (range 38–86%). Forty-seven percent of sites did not perform DCE. One site used a 3 T scanner. The percentage of patients with overall quality scores of ≥3 (diagnostically acceptable) were 68% for T2W, 81% for DWI, and 60% for both T2W and DWI. Ninety-three percent of the 45 patients who underwent DCE had diagnostically acceptable studies. By scanner age, the percentage of patients with diagnostically acceptable T2W scores was 53% for scanners ≥7 years and 80% when <7 years (p=0.006). Comparing individual sites, the mean overall quality scores were 2.9 (range 2.2–4.2) for T2W, 3.2 (1.8–4.7) for DWI, and 3.4 (2.5–4.7) for DCE.
There is wide variation in compliance with recognised technical standards and image quality across sites. If MRI is to replace biopsy in selected low-risk patients, improvements in image quality may be required.
•There was a large variation in image quality and guideline compliance between sites.•40% of patients had non-diagnostic quality scans.•Scanner age inversely correlated with T2W image quality.•DCE scored highest for image quality, but was only used in 53% of sites.•Image quality needs optimization if MRI is used to rule out cancer or avoid biopsy.
The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the ...resistance to therapy could aid the development of more effective treatments.
The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel.
DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting.
The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel.
The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.
•The use of MFB DBS for depression can be efficacious even in those patients who fail DBS at a separate target.•Having both MFB and SCC DBS seems to augment the treatment response in terms of ...patient-reported HAM-D score.•The increased efficacy of both systems together is likely due to combinatorial targeting of underlying disease networks.
Clinically relevant prostate cancer (PCa) is more frequent in Westernised societies and increasingly men have co-morbidities associated with a Western lifestyle, primarily diabetes, characterised by ...hyperinsulinaemia and hyperglycaemia. IGFs and their binding proteins (IGFBPs) are important mediators of the effects of nutrition on growth and play a key role in the development of PCa. We used DU145, PC3 and LNCaP PCa cell lines to examine how hyperglycaemia altered their response to docetaxel. Trypan Blue dye-exclusion assay was used to determine the percentage of cell death. Protein abundance was determined using western immunoblotting. Levels of IGFBP2 were measured using an ELISA. IGFBP2 gene silencing was achieved using siRNA technology. DNA methylation was assessed using combined bisulphide restriction analysis. Acetylation status of histones H3 and H4 associated with IGFBP2 gene was assessed using chromatin immunoprecipitation assay. Hyperglycaemia reduced docetaxel-induced apoptosis by 40% for DU145 cells and by 88% for LNCaP cells. This reduced cell death was mediated by a glucose-induced up-regulation of IGFBP2, as silencing IGFBP2 negated the survival effect of high glucose. Glucose increased IGFBP2 via increasing the acetylation of histones associated with the IGFBP2 gene promoter. This finding could have important implications in relation to therapeutic strategies as epigenetic modulation could be reversible.
Prostate cancer is the second most common cancer in men worldwide, accounting for an estimated 1.1 million new cases diagnosed in 2012 (www.globocan.iarc.fr). Currently, there is a lack of specific ...guidance on supportive care for men with prostate cancer. This article describes a qualitative systematic review and synthesis examining men's experience of and need for supportive care. Seven databases were searched; 20 journal articles were identified and critically appraised. A thematic synthesis was conducted in which descriptive themes were drawn out of the data. These were peer support, support from partner, online support, cancer specialist nurse support, self‐care, communication with health professionals, unmet needs (emotional support, information needs, support for treatment‐induced side effects of incontinence and erectile dysfunction) and men's suggestions for improved delivery of supportive care. This was followed by the development of overarching analytic themes which were: uncertainty, reframing, and the timing of receiving treatment, information and support. Our results show that the most valued form of support men experienced following diagnosis was one‐to‐one peer support and support from partners. This review highlights the need for improved access to cancer specialist nurses throughout the care pathway, individually tailored supportive care and psychosexual support for treatment side effects.
The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with ...salvage RT for prostate-specific antigen (PSA) failure.
RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT (‘Adjuvant-RT’) or an observation policy with salvage RT for PSA failure (‘Salvage-RT’) defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT.
Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 95% confidence interval (CI) 0.43-1.07, P=0.095. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017).
Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy.
RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.
•1396 participants were randomised (2007 to 2016) from UK, Denmark, Canada & Ireland to 699 Salvage-RT or 697 Adjuvant-RT.•There was no evidence of improvement with Adjuvant-RT in FFDM or survival but more toxicity.•An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy.
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