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Haematogenous spread of circulating tumour cells (CTCs) is the principle mechanism for development of metastases. Research into the enumeration and characterisation of CTCs, particularly in the last decade, has allowed the introduction of semi-automated CTC assessment in the clinical setting. In breast cancer, CTC enumeration is being used as a prognostic biomarker, a predictive biomarker of treatment response and is being assessed to guide treatment in both the early and metastatic setting. CTC characterisation has the potential to direct targeted therapies, such as HER2 therapies in HER2 negative primary breast tumour patients. However, CTC assessment has considerable challenges. Capture and identification of these very rare cells is currently largely dependent on a presumed homogeneity of phenotype. In addition, high throughput assays are lacking. The clinical significance of CTCs is incompletely understood. A large proportion of CTC positive patients have no evidence of metastases, raising the issue of either inconsequential tumour dormancy or non-viable CTCs. CTCs may have additional clinical sequelae such as promoting venous thrombosis. However CTCs provide a real-time liquid biopsy of the tumour and represent an exciting, minimally invasive method of assessing disease status and also a novel therapeutic target for malignancy. [ABSTRACT FROM AUTHOR]

The incidence of breast cancer increases with age with approximately 1800 cases per year in the UK occuring in over 90-year olds. We sought to determine the incidence of new breast cancer diagnoses in this subgroup and examine our practice in the management of these women. A retrospective case-note review was performed on 32 patients aged 90 years and over, diagnosed with non-metastatic invasive breast cancer between 2007 and 2017. Clinicopathological data was collected on patients' cancers, co-morbidities, treatment, recurrence and survival. Median age at diagnosis was 90 years (range 90-99). Median number of comorbidities was 2 (range 0-6). Mean tumour size was 35mm (range 5-85). 11 cancers (34%) were ER negative and 2 (6%) HER2 positive. 12 cancers (38%) were grade 3 at presentation and 12 had positive axillary lymph node metastases. Twenty-seven (84%) patients underwent a mastectomy, including one bilateral, and five (16%) patients had wide local excision. No patients suffered significant complications in the immediate post-operative period. Twenty-one patients (66%) had adjuvant radiotherapy. No patients underwent adjuvant chemotherapy. Eight patients (25%) developed local or distant recurrence and twenty-one patients (66%) died by the end of the study collection period. Mean disease free survival was 46.4 months (95% CI 31.1-61.7 months) and mean overall survival was 45 months (95% CI 31.7-59.7 months). Optimal management for older patients is achieved by the co-evaluation of the life expectancy, co-morbidities, and the treatment benefit/risk ratio. Our data suggests that treating older patients with focused surgical and adjuvant treatment is appropriate, however further age-adjusted data is required to standardise care in this subgroup. Pennine Acute Hospitals NHS Trust. Has not received any funding. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

The objective of this study was to present the outcomes for redo hypospadias repair using lingual mucosal graft (LMG). Between June 2012 and February 2017, 47 patients underwent staged LMG urethroplasty for redo hypospadias repair. The inclusion criteria were previous failed hypospadias repair with a paucity of local skin that interferes with correction using skin flaps and demands graft urethroplasty. During the first stage, a well-vascularized bed on the tunica albuginea was created. Then, the harvested LMG was secured to the prepared bed. The second-stage urethroplasty was carried out after six months. In this stage, tubularization of the previously implanted LMG was performed. In four cases, tubularization was difficult owing to graft contracture. This difficulty was managed by using the dorsally degloved penile skin as the onlay island flap in three cases and the buccal mucosa onlay graft in the fourth case. In all cases, a second protective layer from the dartos or tunica vaginalis was developed to cover the neourethra. The median (interquartile range [IQR]) age of patients at the first stage was 5 (4–6) years, and the median (IQR) duration between both stages was 7 (6–8) months. The median (IQR) follow-up after the second stage was 15 (13–16) months. The median (IQR) number of previous operations was 2 (2–3). The median (IQR) length of the LMG was 3 (2.5–4) cm, and the median (IQR) width was 1 (1–2) cm. No donor-site major complications, but mild oral discomfort in the first week after graft harvesting, were reported in 39 (83%) patients. After the second stage, complications were reported in nine (19.2%) patients, meatal stenosis in five and fistula in four. The reported success rate was 80.9%. Reconstruction of previously failed hypospadias is a challenge owing to local tissue scarring and a paucity of adjacent healthy tissue. In this study, the LMG was used in two-stage redo hypospadias repair after previous repair failure. In the present study, a success rate of 80.9% was reported after the second stage. According to this study and the published series, harvesting the LMG is associated with minimal immediate donor-site complications and no long-term morbidity. Another advantage of the LMG is easy harvesting with effortlessly reachable tongue in comparison with the buccal mucosa that is deep and requires application of a mouth retractor. Two-stage LMG urethroplasty is a reliable procedure for salvage urethroplasty. Lingual mucosal graft harvesting is easy, with minor oral complications. Summary figure LMG harvesting. Summary figure [ABSTRACT FROM AUTHOR]

Summary Background Though pediatric urethral stricture is an uncommon urological problem, it is a challenging urological one. The causative factors are iatrogenic, traumatic, and inflammatory. In the current study, the authors report their experience of the treatment of pediatric long anterior urethral stricture using penile circular fasciocutaneous flap. Patients and methods The study included 23 pediatric patients who had long anterior urethral strictures, which were repaired using circular penile fasciocutaneous flap. The flap was elevated through a subcoronal circumferential incision and then it was split ventrally. The strictured portion of the urethra was sharply incised ventrally, extending to 1 cm into normal urethra. The flap was sutured to the urethral plate over silicone catheter of suitable size, which was removed after 3 weeks. The follow-up was scheduled every 3 months for the first year and then yearly thereafter. Results The urethroplasty was successful in 20 cases (86.96%). There were two cases complicated by stricture recurrence, which was managed by visual internal urethrotomy. Fistula formation was reported in one case and was repaired by simple excision and closure. Penile skin necrosis was reported in only one patient and was managed by frequent dressing. Discussion During the last five decades, there was a substantial advancement in the reconstruction of long or complex anterior strictures due to the use of grafts and flaps. During pediatric urethral stricture repair, particular attention must be paid to the differences between adults and children anatomy, e.g. the small urethral lumen and tissue delicateness. McAninch introduced the reconstruction of complex anterior urethral strictures utilizing circular penile fasciocutaneous flap. The technique of penile fasciocutaneous flap urethroplasty takes long time and requires meticulous dissection. Therefore, it should be restricted for long or complex anterior urethra strictures. Success rate in this study was 86.96%, which is in the same league as that reported in literature as regard adults penile fasciocutaneous flap urethroplasty. Whitson et al. reported success rates of 84% and 79% in the 5th and 10th years, respectively. In another study, Kim et al. revealed a success rate of 68.9%. In this study, complications incidence was 21.6%, which is consistent with reported incidence of complications of adults penile fasciocutaneous flap urethroplasty (8%–20%). Conclusion According to the outcomes of this study, penile fasciocutaneous flap urethroplasty is a reasonable modality for the reconstruction of long anterior urethral stricture in pediatric patients especially after circumcision. Summary figure The flap is elevated with its pedicle. Summary figure [ABSTRACT FROM AUTHOR]

Introduction Venous thromboembolism (VTE) is a major cause of death in patients undergoing colorectal cancer surgery and usually arise from Deep Vein Thrombosis’s (DVTs). In patients with cancer below knee and asymptomatic DVTs are at risk of propagating and result in a VTE. Retrospective, population based studies predating extended course venous thromboprophylaxis report an incidence of symptomatic VTE in colorectal cancer patients of approximately 5.5%. Clinical studies have suggested that pre-operative d-dimer may predict the development of post-operative DVTs. Aim We undertook a multicentre prospective study to screen colorectal cancer patients pre- and post-operatively for the presence of DVTs. The aim of the study was to determine the incidence of DVTs in patients undergoing elective, curative surgery for colorectal cancer. The study also aimed to identify histological and clinical factors that pre-dispose to development of a DVT. The role of pre-operative d-dimer in predicting the development of post-operative DVTs was also analysed. Materials and Methods Patients at four hospitals undergoing elective curative surgery for colorectal cancer were recruited pre-operatively. Exclusion criteria were: previous VTE, previous malignancy, anti-coagulants. Bilateral full leg venous duplex was performed pre-operatively and at six weeks post-surgery. Plasma D-dimer was measured pre-operatively. Results Of 60 patients undergoing pre-operative duplex, five (8.3%) had below knee, asymptomatic DVTs. These patients were then excluded from further analysis. Of the remaining 55, 48 had post-operative duplex examination. Three (6.3%) developed post-operative DVTs all of which were asymptomatic and below knee. There were no symptomatic DVTs. Two of these patients had received extended course venous thromboprophylaxis and the other received inpatient thromboprophylaxis. Development of post op DVT was associated with lymph node positivity (p = 0.02). There were no other histological, surgical or demographical factors that predicted the development of post-operative DVTs. Pre-operative D-dimer was higher in patients who developed a post-operative DVT compared to those who did not [1,275 ng/L (95%CI: 780 – 1770 ng/L) vs 805 ng/L (95% CI: 632 – 980 ng/L) p = 0.03]. Conclusions Of patients diagnosed with operable colorectal cancer, 8% have pre-operative asymptomatic DVT, and a further 6% develop DVT despite thromboprophylaxis. The subgroup of patients with lymph node involvement may benefit from more aggressive anticoagulation as they are at increased risk of DVT despite extended course anticoagulation. Pre-operative D-dimer may offer a predictive method to identify patients at risk of post-operative DVT. [ABSTRACT FROM AUTHOR]

Introduction Ductal carcinoma in-situ (DCIS) is a preinvasive breast cancer where cancer cells remain confined within the ductal basement membrane. However, genotypic changes have been identified in stroma surrounding DCIS, outside the basement membrane. Stromal fibroblasts undergo phenotypic change in cancer to promote tumour angiogenesis, proliferation, immunosuppression and metastasis and in vivo can induce invasion of DCIS. Phenotypic changes in DCIS stromal fibroblasts may potentially act as a precursor for invasion. Aim To determine if stromal fibroblasts in DCIS have procoagulant changes similar to those seen in cancer-associated fibroblasts in invasive breast cancer. Materials and Methods As part of the prospective cohort study CHAMPion (Cancer induced Hypercoagulabulity as a Marker of Prognosis), patients with DCIS (n = 72) and invasive breast cancer (n = 292) were recruited. Stromal fibroblasts in tumour and corresponding normal breast tissue (distant from the cancer) were quantified (percentage IHC stained) for tissue factor (TF), thrombin, PAR1 and PAR2. Fibroblasts were identified morphologically, at a minimum distance of 0.2 mm from ductal tissue, to avoid myoepithelial scoring. Scoring was performed in duplicate by two independent pathologists. Results Fibroblast TF expression was present in normal breast tissue (mean 43% ([SD 27%]) but markedly increased in DCIS (mean 62% [SD 27%], p = 0.002). Fibroblast TF expression was further increased in invasive breast cancer (mean 74% [SD 23%], normal vs invasion, p < 0.001; DCIS vs invasion, p = 0.03). Fibroblast thrombin and PAR2, but not PAR1, expression was increased in DCIS compared to normal (thrombin: 60% vs 42%, p < 0.001; PAR2: 58% vs 41%, p = 0.002), however no further significant increase was seen in invasive cancer (thrombin 63%, PAR2 61%). Fibroblast tissue factor correlated with fibroblast thrombin expression (p < 0.001, r = 0.4) and fibroblast PAR2 expression (p < 0.001, r = 0.5), with thrombin and PAR2 expression also correlating (p < 0.001, r = 0.4). Conclusions Procoagulant phenotypic changes, in terms of increased TF, thrombin and PAR2 expression, occur in stromal fibroblasts at the preinvasive stage. It needs to be determined if this change is functional and therefore a potential therapeutic target for preventing transition to invasion. [ABSTRACT FROM AUTHOR]

Introduction Tissue Factor (TF) promotes apoptosis-resistance and facilitates haematogenous metastasis. Cancer cells release TF-bearing microparticles (TF-MP) which have pro-coagulant activity. TF-MPs from cancer cells induce increase in TF expression and procoagulant activity of recipient endothelial cells. Drug resistance microparticles transfer between cancer cells, resulting in induction of recipient cell drug resistance, however transfer of TF-MPs between cancer cells has not been demonstrated. Aim To determine if microparticles isolated from TF expressing cancer cell lines can induced TF-mediated procoagulant activity in cell lines that do not express TF. Materials and Methods A7 cells (a melanoma cell line that does not express TF) were transformed to express TF with adenoviral transformation. In addition, the TF-expressing breast cancer cell line MDAMB231 was used. Media was collected from (1) wild-type A7 (A7-WT) cells, which acted as control (2) MDAMB231 cells, (3) A7 cells transformed with ‘low’ levels of TF-adenovirus and (4) A7 cells transformed with ‘high’ levels of TF-adenovirus. MPs were isolated from media by centrifugation using standard techniques. Isolated MPs were incubated with wild-type A7 (A7-WT) cells overnight. Pro-coagulant activity of A7-WT cells was assessed using a FXa generation assay. Results i) A7-WT cells incubated overnight with MDAMB231-derived MPs produced an almost 5 fold increase in procoagulant activity compared to control (Mean 3.5 mOD/min S.E 0.32 vs control 0.68 S.E. 0.05, p < 0.01). ii) MPs released from A7-TF cells induced a dose-dependant increase in cell based procoagulant activity when incubated with A7-WTs compared to control:A7-WT cells incubated with control MPs (Control): mean mOD 0.83, S.E. 0.07A7-WT cells incubated with A7-TF derived MPs (low levels of TF-adenovirus): mean mOD 1.27, S.E. 0.06 (p = 0.04 vs control)A7-WT cells incubated with A7-TF derived MPs (low levels of TF-adenovirus): mean mOD 2.77, S.E. 0.23 (p < 0.01 vs control). Conclusions These results demonstrate, for the first time, microparticle-mediated transfer of TF procoagulant activity between cancer cells. MPs shed by cancer cells in vivo have been implicated in cancer cell progression and hypercoagulability. The acquisition and spread of of MP-mediated TF activity has implications for cancer cell biology and cancer-induced hypercoagulability. [ABSTRACT FROM AUTHOR]

Introduction Up to 6% of patients develop venous thromboembolism (VTE) following elective colorectal cancer surgery despite thromboprophylaxis. Clinical practices for perioperative thromboprophylaxis remains variable, particularly the use and duration of extended thromboprophylaxis. Identification of factors associated with a prolonged postoperative hypercoagulable state may allow the development of algorithms that allow more targeted thromboprophylaxis. Aim To identify patient, tumour and surgical risk factors for prolonged (two and six weeks) hypercoagulability in colorectal cancer patients undergoing surgical resection. Materials and Methods In a prospective cohort study (Cancer-induced Hypercoagulability As a Marker of Prognosis [CHAMPion]), plasma d-dimer was measured at 2 and 6 weeks post-operatively in patients undergoing elective, curative resection for colorectal cancer. Hypercoagulability (raised D-dimer) at 2 and 6 weeks was correlated with patient, tumour and operative factors. Results Of the 62 patients recruited (median age 69 years [range 39-90]), 37 were male. D-dimer was increased in females compared to males at six weeks (geometric mean (GM) 1,287 ng/ml [95% CI 944 – 1,755 vs. 821 ng/ml (95% CI 633 – 1064) p = 0.03]. Age, smoking, hypertension, use of antiplatelet medication, BMI and WHO performance status were not associated with a prolonged hypercoagulable state. There were no tumour factors (including size/T stage/lymph node involvement/differentiation) associated with a prolonged hypercoagulable state. D-dimer was increased in patients undergoing open surgery (n = 39) compared to laparoscopic surgery (n = 23) at 2 weeks (GM 2,337 ng/ml [95% CI 1,806-3,023] vs. 1,212 ng/ml [95% CI 898-1,629], p = 0.001) and 6 weeks (GM 1,162 ng/ml [95% CI 818-1647] vs. 723 ng/ml [95% CI 533-982]p = 0.04). Operative time was not associated with prolonged hypercoagulability. D-dimer had a trend to be increased at 2 weeks in patients receiving perioperative blood transfusions (n = 8) compared to those that did not (n = 54) (GM 2,618 ng/ml [95% CI 1,525-4,536] vs. 1613 ng/ml [95% CI 1,236 – 2,100] p = 0.08). Conclusions Even in this relatively small cohort of patients female gender, open surgery and receiving a blood transfusion are associated with on-going hypercoagulability up to six weeks post operation. This may represent a group where thromboprophylaxis should be targeted. [ABSTRACT FROM AUTHOR]

Introduction Colorectal cancer expression of Tissue Factor (TF), PAR1 and PAR2 is associated with a poor prognosis. Their stromal, rather than epithelial, expression has prognostic significance in other cancers, this has not been explored in colorectal cancer. Aim We aimed to determine the expression patterns of Tissue Factor (TF), PAR1 and PAR2 and thrombin in colorectal cancer and normal tissue. Materials and Methods Cancer and distant normal tissue were sampled from 37 patients. Expression of TF, Thrombin, PAR1 and PAR2 were determined by immunohistochemistry. Two observers scored expression level (0–3) in individual cells. Percentage of cells having each level of expression was determined and an H-score calculated which are given with 95% CI. Results Normal epithelium did not express TF, but it was expressed by cancer epithelium (36.5 (95% CI 17.6 – 55.4) p < 0.001). Thrombin expression was increased in cancer vs normal epithelium (126.2 (95% CI 110.6 – 141.7) vs 101.6 (95% CI 92.5–110.8) p = 0.01) as was PAR2 (172.4 (95% CI 152.9–191.8) vs 123.4 (95% CI 107.8–139.0) p < 0.001). The increase in cancer epithelium PAR1 expression compared to normal (105.4 (95%CI 84.3–126.5) vs 89.0 (95% CI 80.4–97.6)) was not significant. Normal stroma did not express TF or thrombin however both were expressed by cancer stroma (TF 46.3 (95% CI 24.6–68.0) p < 0.001, thrombin 11.4 (95% CI 6.2–16.7) p < 0.001). PAR1 and PAR2 were both expressed in normal stroma but demonstrated increased expression in cancer stroma (cancer vs normal; PAR 1: 130.7 (95% CI 112.2–149.2) vs 19.5 (95% CI 11.24–27.7) p < 0.001; PAR2: 21.5 (95% CI 12.9–30.1) vs 2.21 (95% CI 0.49–3.92) p < 0.001). Conclusions Upregulated expression of tissue thrombin pathway proteins is seen in colorectal cancer in both epithelial and stromal cells. Procoagulant tumour cells and tumour microenvironment may provide a novel therapeutic target for treatment in colorecal cancer. [ABSTRACT FROM AUTHOR]