Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why ...cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To determine how clinicians use data in contemporary prostate biopsy reports.
A survey was circulated to members of the British Association of Urological Surgeons and the British Uro-oncology Group.
...Responses were received from 114 respondents (88 urologists, 26 oncologists). Ninety-seven (94%) use the number of positive cores from each side and 43 (42%) use the % number of positive cores. When determining the number and percentage of positive cores, 72 (71%) would not differentiate between targeted and non-targeted samples. If multiple Gleason Scores (GS) were included in a report, 77 (78%) would use the worst GS even if present in a core with very little tumour, 12% would use the global GS and 10% the GS in the core most involved by tumour. Fifty-five (55%) either never or rarely used perineural invasion for patient management.
The number of positive cores is an important parameter for patient management but may be difficult to determine in the laboratory due to core fragmentation so the biopsy taker must indicate the number of biopsies obtained. Multiple biopsies taken from a single site are often interpreted by clinicians as separate cores when determining the number of positive cores so pathologists should also report the number of
positive. Clinicians have a non-uniform approach to the interpretation of multiple GS in prostate biopsy reports so we recommend that pathologists also include a single 'bottom-line' GS for each case to direct the clinician's treatment decision.
Aims: To describe the histopathological features of a series of patients with ketamine‐related cystitis.
Methods and results: Seventeen patients with ketamine‐related cystitis, who had undergone ...biopsy, were identified and reviewed. Twelve showed ulceration with significant urothelial atypia. In 10 of these, immunohistochemistry was performed; 9/10 had high p53 immunoreactivity and 7/10 had moderate to high levels of Ki67 reactivity, but all were negative for cytokeratin 20.
Conclusions: Ketamine can lead to reactive urothelial changes that can mimic carcinoma in situ, but the long‐term cancer risk remains unknown.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Robotic radical prostatectomy (RARP) is a first-line curative treatment option for localized prostate cancer. Postoperative erectile dysfunction and urinary incontinence are common associated adverse ...side effects that can negatively impact patients' quality of life. Preserving the lateral neurovascular bundles (NS) during RARP improves functional outcomes. However, selecting men for NS may be difficult when there is concern about incurring in positive surgical margin (PSM) which in turn risks adverse oncological outcomes. The NeuroSAFE technique (intra-operative frozen section examination of the neurovascular structure adjacent prostate margin) can provide real-time pathological consult to promote optimal NS whilst avoiding PSM.
NeuroSAFE PROOF is a single-blinded, multi-centre, randomised controlled trial (RCT) in which men are randomly allocated 1:1 to either NeuroSAFE RARP or standard RARP. Men electing for RARP as primary treatment, who are continent and have good baseline erectile function (EF), defined by International Index of Erectile Function (IIEF-5) score > 21, are eligible. NS in the intervention arm is guided by the NeuroSAFE technique. NS in the standard arm is based on standard of care, i.e. a pre-operative image-based planning meeting, patient-specific clinical information, and digital rectal examination. The primary outcome is assessment of EF at 12 months. The primary endpoint is the proportion of men who achieve IIEF-5 score ≥ 21. A sample size of 404 was calculated to give a power of 90% to detect a difference of 14% between groups based on a feasibility study. Oncological outcomes are continuously monitored by an independent Data Monitoring Committee. Key secondary outcomes include urinary continence at 3 months assessed by the international consultation on incontinence questionnaire, rate of biochemical recurrence, EF recovery at 24 months, and difference in quality of life.
NeuroSAFE PROOF is the first RCT of intra-operative frozen section during radical prostatectomy in the world. It is properly powered to evaluate a difference in the recovery of EF for men undergoing RARP assessed by patient-reported outcome measures. It will provide evidence to guide the use of the NeuroSAFE technique around the world.
NCT03317990 (23 October 2017). Regional Ethics Committee; reference 17/LO/1978.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Oxley J D & Sen C (2011) Histopathology
Error rates in reporting prostatic core biopsies
58, 759–765
Aims: To evaluate the false‐negative and false‐positive error rates both in a screening and a ...non‐screening population.
Methods and results: A total of 4192 prostatic biopsies were reported in a 6‐year period by 15 consultant histopathologists, two of whom had an interest in uropathology and were deemed to be specialists (J.O. and C.S.). All biopsies were reviewed prior to the multidisciplinary team (MDT) meeting. The overall false‐negative rate was 1.7% (screening 2.1%, non‐screening 1.5%). The overall false‐positive rate was 0.5% (screening 0.9%, non‐screening 0.4%). These error rates varied among pathologists, with the false‐negative rate ranging from 0% to 9.3%, and the false‐positive rate ranging from 0% to 3.8%.
Conclusion: The false‐negative rate was three times greater than the false‐positive rate, showing that detection of significant pathology is far greater in the negative biopsies. More errors occurred in the screening population than in the non‐screening population. The consultants making the most errors were non‐specialists, but the specialists also made false‐negative errors, suggesting that just using specialist reporting alone would not have eradicated errors.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Prostate cancer is the second major cause of male cancer deaths. Obesity, type 2 diabetes, and cancer risk are linked. Insulin-like growth factor II (IGF-II) is involved in numerous cellular events, ...including proliferation and survival. The IGF-II gene shares its locus with the lncRNA, H19. IGF-II/H19 was the first gene to be identified as being "imprinted"-where the paternal copy is not transcribed-a silencing phenomenon lost in many cancer types. We disrupted imprinting behaviour in vitro by altering metabolic conditions and quantified it using RFLP, qPCR and pyrosequencing; changes to peptide were measured using RIA. Prostate tissue samples were analysed using ddPCR, pyrosequencing and IHC. We compared with in silico data, provided by TGCA on the cBIO Portal. We observed disruption of imprinting behaviour, in vitro
with a significant increase in IGF-II and a reciprocal decrease in H19 mRNA; the increased mRNA was not translated into peptides. In vivo, most specimens retained imprinting status apart from a small subset which showed reduced imprinting. A positive correlation was seen between IGF-II and H19 mRNA expression, which concurred with findings of larger Cancer Genome Atlas (TGCA) cohorts. This positive correlation did not affect IGF-II peptide. Our findings show that type 2 diabetes and/or obesity, can directly affect regulation growth factors involved in carcinogenesis, indirectly suggesting a modification of lifestyle habits may reduce cancer risk.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Evidence from observational studies have shown that moderate intensity physical activity can reduce risk of progression and cancer-specific mortality in participants with prostate cancer. ...Epidemiological studies have also shown participants taking metformin to have a reduced risk of prostate cancer. However, data from randomised controlled trials supporting the use of these interventions are limited. The Prostate cancer-Exercise and Metformin Trial examines that feasibility of randomising participants diagnosed with localised or locally advanced prostate cancer to interventions that modify physical activity and blood glucose levels. The primary outcomes are randomisation rates and adherence to the interventions over 6 months. The secondary outcomes include intervention tolerability and retention rates, measures of insulin-like growth factor I, prostate-specific antigen, physical activity, symptom-reporting, and quality of life. Methods Participants are randomised in a 2 x 2 factorial design to both a physical activity (brisk walking or control) and a pharmacological (metformin or control) intervention. Participants perform the interventions for 6 months with final measures collected at 12 months follow-up. Discussion Our trial will determine whether participants diagnosed with localised or locally advanced prostate cancer, who are scheduled for radical treatments or being monitored for signs of cancer progression, can be randomised to a 6 months physical activity and metformin intervention. The findings from our trial will inform a larger trial powered to examine the clinical benefits of these interventions. Trial registration Prostate Cancer Exercise and Metformin Trial (Pre-EMpT) is registered on the ISRCTN registry, reference number ISRCTN13543667. Date of registration 2nd August 2018-retrospectively registered. First participant was recruited on 11th September 2018. Keywords: Prostate cancer, Metformin, Physical activity, Feasibility randomised controlled trial, Localised, Locally advanced, Radiotherapy, Prostatectomy, Active surveillance
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