Clinical and economic impact of the introduction of pre-biopsy MRI-based assessment on a large prostate cancer centre diagnostic population and activity: 10 years on.

INTRODUCTION: Prostate mpMRI was introduced in 2011 as a secondary test and subsequently integrated into a prostate cancer (PCa) diagnostics unit representing a population of approximately 550,000 people. The following represents an audit of its step-wise introduction between 2 index years, 2009 and 2018, focusing on the activity, patient outcomes and economic benefits. PATIENTS AND METHODS: The 2 distinct years were selected for relying on a transrectal ultrasound biopsy pathway in 2009 to an mpMRI-based pathway in 2018. All referrals were retrospectively screened and compared for age, PSA levels, DRE findings, biopsy history, biopsy and mpMRI allocation data. Cost analysis was determined using local unit procedure costs. RESULTS: Patients referred included 648 in 2009 and 714 in 2018. mpMRI seldomly informed decision to biopsy in 2009 (9.8%), while in 2018 it was performed in the pre-biopsy setting in 87.9% cases and enabled biopsy avoidance in 137 patients. In 2018, there was a 31.8% decrease in the number of biopsies in patients without previous PCa diagnosis, coupled with an increase in diagnostic rates of csPCa, from 28.6 to 49.0% (p < 0.0001) and a reduction in negative biopsy rates from 52.3 to 33.8%. mpMRI had a positive impact on the system with reduced patient morbidity and post-procedural complications. The estimated overall cost savings amount to approximately £75,000/year for PCa diagnosis and £11,000/year due to reduced complications. CONCLUSION: Our evaluation shows the mpMRI-based pathway has improved early detection of csPCa and reduction of repeat biopsies, resulting in significant financial benefits for the local healthcare system.

Continence-Sparing Techniques in Radical Prostatectomy: A Systematic Review of Randomized Controlled Trials.

Background: Numerous continence-sparing radical prostatectomy techniques have been developed to enhance postoperative early continence (EC) recovery; however, evidence regarding the best approach remains controversial. The objectives are to provide a critical appraisal of various prostatectomy techniques, based on the evidence of quality-assessed randomized control trials (RCTs); to summarize the immediate continence and the EC reported; and to propose a new standardization for continence outcomes reporting. Methods: Data acquired from five medical registries were reported to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Evidence from published, English, full-text RCTs reporting postoperative urinary continence outcomes within 6 months from surgery was included. The heterogeneity of surgical techniques and continence definitions did not allow a meta-analysis. All RCTs were critically appraised, and quality assessed. Results: In total, 39 RCTs were included: 19 of 39 studies were low-quality RCTs, presenting small cohort, monocentric, or single-surgeon data. The best RCT-supported evidence is in favor of robot-assisted radical prostatectomy (RARP) compared with laparoscopic radical prostatectomy (LRP) and of the Retzius-sparing (RS) technique over the traditional prostatectomy. Other techniques such as bladder neck and puboprostatic ligament (PPL) preservation, posterior reconstruction with or without combination of anterior suspension technique, and nerve-sparing (NS) approach seem to enhance EC. Oppositely, the endopelvic fascia preservation, bladder neck mucosa eversion/plication/slings, and the selective ligature of dorsal venous complex (DVC) were not significantly associated with EC improvements. RCTs are lacking on pubovesical complex-sparing, seminal vesicle preservation, anterior reconstruction of the puboprostatic collar, musculofascial reconstruction, and DVC suspension to the periosteum of the pubic bone techniques. Conclusions: RARP and RS have high-quality evidence supporting their ability to enhance postoperative EC recovery. NS, bladder neck, and PPL preservation may contribute to better EC recovery, although the evidence level is low. Further multicenter RCTs are needed to establish the optimal combination of standard surgical techniques. A new continence outcome-reporting standardization was proposed.

Vector Prostate Biopsy: A Novel Magnetic Resonance Imaging/Ultrasound Image Fusion Transperineal Biopsy Technique Using Electromagnetic Needle Tracking Under Local Anaesthesia.

BACKGROUND: Prostate magnetic resonance imaging (MRI) is now standard for assessment of suspected prostate cancer (PCa). A variety of approaches to MRI-based targeting has revolutionised prostate biopsies. OBJECTIVE: To describe the procedure and show the accuracy and tolerability of a novel Vector MRI/ultrasound fusion transperineal (TP) biopsy technique that uses electromagnetic (EM) needle tracking under local anaesthesia (LA). DESIGN, SETTING, AND PARTICIPANTS: Vector prostate biopsy using BiopSee fusion software, EM tracking technology, and transrectal ultrasound was performed in 69 patients meeting the biopsy criteria in two UK centres between September 2020 and August 2022. SURGICAL PROCEDURE: Stepper-mounted rectal ultrasound images were fused with MRI scans. LA was applied into two defined perineal tracks and a needle sheath with an EM sensor was inserted. The biopsy needle was directed precisely through the sheath to MRI targets under EM tracking. Biopsies were taken without antibiotic prophylaxis. MEASUREMENTS: Cancer detection (any PCa; grade group ≥2), side effects, and patient experience measures were recorded. RESULTS AND LIMITATIONS: Cancer detection in patients with Likert 4-5 lesions was 98% for any PCa and 83% for grade group ≥2. According to the 50 questionnaires returned, 42 patients (84%) reported no or minimal pain, while 40 (80%) reported no or minimal discomfort. No episodes of postoperative urinary retention occurred, and only one patient required treatment for infection. Limitations include the low patient number and incomplete responses to questionnaires. CONCLUSIONS: This novel Vector technique provides a feasible and tolerable procedure for MRI/ultrasound fusion TP biopsy under LA, with high cancer detection rates. This is achieved while maintaining patient comfort and with minimal rates of complications. PATIENT SUMMARY: We report a novel technique that uses electromagnetic needle tracking to perform highly accurate and comfortable prostate biopsies through the perineum under local anaesthetic.

Natural History of Patients with Prostate MRI Likert 1-3 and Development of RosCaP: a Multivariate Risk Score for Clinically Significant Cancer.

INTRODUCTION: Clinically significant prostate cancer (csCaP) with Gleason ≥3 + 4 is found in 10% negative prebiopsy multiparametric (mp) MRI cases and varies widely for equivocal mpMRI cases. The objective of this study was to investigate long-term outcomes of patients with negative and equivocal mpMRIs and to develop a predictive score for csCaP risk stratification in this group. PATIENTS AND METHODS: Patients who underwent an upfront mpMRI between May 2015 and March 2018 with an MRI score Likert 1 to 3 were included in the study. Patients had either a CaP diagnosis at MRI-targeted biopsy or were not diagnosed and attended follow-up in the community. Outcomes were analysed through the Kaplan-Meier estimator and Cox Model. Regression coefficients of significant variables were used to develop a Risk of significant Cancer of the Prostate score (RosCaP). RESULTS: At first assessment 281/469 patients had mpMRI only and 188/469 mpMRI and biopsy, 26 csCaP were found at biopsy, including 10/26 in Likert 3 patients. 12/371 patients discharged without CaP after first assessment were diagnosed with csCaP during a median of 34.2 months' follow-up, 11/12 diagnosis occurred in patients omitting initial biopsy. csCaP diagnosis-free survival was 95.7% in the MRI group and 99.1% in the biopsy group. From these outcomes, a continuous RosCaP score was developed: RosCaP = 0.083 x Age - 0.202 x (1/PSA Density) + 0.786 (if Likert 3), and 4 risk classes were proposed. Limitations include retrospective design and absence of external validation. CONCLUSION: Age, PSA Density and MRI Likert score were significantly associated to the risk of csCaP and utilised to devise the novel RosCap predictive score focused to support risk assessment in patients with negative or equivocal mpMRI results.

Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study.

PURPOSE: The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS: This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS: Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION: This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.

Optimal biopsy approach for detection of clinically significant prostate cancer.

Prostate cancer (PCa) diagnostic and therapeutic work-up has evolved significantly in the last decade, with pre-biopsy multiparametric MRI now widely endorsed within international guidelines. There is potential to move away from the widespread use of systematic biopsy cores and towards an individualised risk-stratified approach. However, the evidence on the optimal biopsy approach remains heterogeneous, and the aim of this review is to highlight the most relevant features following a critical assessment of the literature. The commonest biopsy approaches are via the transperineal (TP) or transrectal (TR) routes. The former is considered more advantageous due to its negligible risk of post-procedural sepsis and reduced need for antimicrobial prophylaxis; the more recent development of local anaesthetic (LA) methods now makes this approach feasible in the clinic. Beyond this, several techniques are available, including cognitive registration, MRI-Ultrasound fusion imaging and direct MRI in-bore guided biopsy. Evidence shows that performing targeted biopsies reduces the number of cores required and can achieve acceptable rates of detection whilst helping to minimise complications and reducing pathologist workloads and costs to health-care facilities. Pre-biopsy MRI has revolutionised the diagnostic pathway for PCa, and optimising the biopsy process is now a focus. Combining MR imaging, TP biopsy and a more widespread use of LA in an outpatient setting seems a reasonable solution to balance health-care costs and benefits, however, local choices are likely to depend on the expertise and experience of clinicians and on the technology available.

The potential of PIVKA-II as a treatment response biomarker in hepatocellular carcinoma: a prospective United Kingdom cohort study.

Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.

Association of Gastric Acid Suppression and Sorafenib Efficacy in Advanced Hepatocellular Carcinoma.

BACKGROUND: Recent studies have revealed that coadministration of gastric acid suppressants reduces the efficacy of the tyrosine kinase inhibitors erlotinib and sunitinib in patients with non-small cell lung cancer and renal cell carcinoma, respectively. The authors have therefore assessed if the concurrent use of gastric acid suppressants and sorafenib impairs outcomes in patients with advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on all patients treated with sorafenib for advanced HCC at a single tertiary referral unit in the United Kingdom, between January 2008 and January 2014. A multivariate Cox proportional hazard model was used to assess the effect of the concomitant use of gastric acid suppression and sorafenib on progression-free survival (PFS) and overall survival (OS). RESULTS: Data were collected from 197 patients, of which 182 could be assessed for this study; 77 (42%) were on concurrent gastric acid suppression therapy. After adjusting for imbalances between the groups, a Cox regression analysis gave an adjusted hazard ratio for the concurrent acid suppression group compared with the no acid suppression group of 5.4 (95% confidence interval, 3.6-7.9) for PFS and 1.85 (95% confidence interval, 1.3-2.6) for OS. CONCLUSIONS: This single-center experience shows that patients with advanced HCC taking sorafenib and concomitant gastric acid suppression therapy have significantly inferior PFS and OS. This is the first time that this negative interaction has been reported and further prospective validation is warranted.

Publisher Correction: The National Lung Matrix Trial of personalized therapy in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The National Lung Matrix Trial of personalized therapy in lung cancer.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

Non-secretion of AFP and neutrophil lymphocyte ratio as predictors for survival in hepatocellular carcinoma patients treated with sorafenib: a large UK cohort.

BACKGROUND: Sorafenib is the current standard of care for patients with advanced or metastatic hepatocellular carcinoma. Currently no universally agreed model exists correlating the Neutrophil Lymphocyte ratio (NLR) and non-secretion of AFP with the survival of HCC patients treated with sorafenib. PATIENTS AND METHODS: We retrospectively analysed patient records with a confirmed diagnosis of HCC treated with sorafenib between April 2009 and March 2014. Survival analysis was performed using the Kaplan-Meier method and Cox regression. RESULTS: Patients separated into groups based on NLR (≤3 or >3), or AFP secretion profile (<7 ng/ml or ≥7 ng/ml) derived diverging Kaplan-Meier curves for overall survival (OS). The median OS in those with NLR ≤3.0 was 9.0 months (95% CI: 7.7-11.1 months) and in those with NLR >3.0 it was 6.0 months (95% CI: 4.9-8.2 months) [HR 1.32 (95% CI: 0.96-1.80)]. The median overall survival post sorafenib was higher in the "non-secretor" AFP group. OS for AFP <7 ng/ml was 10.0 months (95% CI: 7.7-19.3 months) compared to AFP ≥7ng/ml: 6.6 months (95% CI: 5.3-8.4 months) [HR 1.64 (95% CI: 1.15-2.33)]. CONCLUSION: NLR and AFP non - secretion at diagnosis are potential significant prognosticators for overall survival from initiation of sorafenib.

Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.

RATIONALE: Positive signals, such as vascular endothelial growth factor, direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, "neuronal guidance cues" have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. OBJECTIVE: To identify signals that guide and pattern the first mammalian blood vessels. METHODS AND RESULTS: Using genetic mouse models, we show that blood vessels are sculpted through the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired dorsal aortae in mouse, as sema3E(-/-) embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant neuronal guidance cues. Mouse embryos that lack notochords fail to form cohesive aortic vessels because of loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm, a critical source of Sema3E. CONCLUSIONS: These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning and are the first to identify a repulsive role for the lateral plate mesoderm. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.

Primary aortoenteric fistula

One hundred and thirty-eight patients with abdominal aortic aneurysms were treated by aneurysmorrhaphy over an eleven-year period. Six patients, all male and aged 60 - 74 years, were found to have developed primary aorteonteric fistulae. Four patients presented with bleeding into the gastrointestinal tract in association with a tender abdominal swelling. In the other two cases, the aneurysm was discovered at emergency laparatomy for gastrointestinal haemorrhage. The presence of the fistula was confirmed at operation in five patients and at autopsy in one. Two patients died, one from a massive gastrointestinal haemorrhage to surgery, the other from sepsis complicated by adult respiratory distress syndrome and renal failure following operation

Benign colovesical fistulae

Two successfully treated cases of benign colovesical fistula are presented. The condition should be suspected whenever patients with colorectal disease develop urinary symptoms. Fllexible colonoscopy and lateral abdominal X-ray should be the initial investigations; but barium enema, cystoscopy and, rarely, CT scan may be necessary to confirm the presence of a colovesical fistula. Patients should be managed conservatively during the acute phase, and then be treated definitively by a single-stage bowel resection. Simple closure or resection and closure is used for the bladder defect.

Burn sepsis: the environment

Discusses a number of measures available to limit contamination of the burn wound - aseptic and antiseptic methods

Nutrition in burn patients: the principles of therapy

Discusses the provision of adequate nutritional support to the victim of a major burn