Mutations in SARS-CoV-2 spike protein impair epitope-specific CD4+ T cell recognition.

CD4+ T cells are essential for protection against viruses, including SARS-CoV-2. The sensitivity of CD4+ T cells to mutations in SARS-CoV-2 variants of concern (VOCs) is poorly understood. Here, we isolated 159 SARS-CoV-2-specific CD4+ T cell clones from healthcare workers previously infected with wild-type SARS-CoV-2 (D614G) and defined 21 epitopes in spike, membrane and nucleoprotein. Lack of CD4+ T cell cross-reactivity between SARS-CoV-2 and endemic beta-coronaviruses suggested these responses arose from naïve rather than pre-existing cross-reactive coronavirus-specific T cells. Of the 17 epitopes located in the spike protein, 10 were mutated in VOCs and CD4+ T cell clone recognition of 7 of them was impaired, including 3 of the 4 epitopes mutated in omicron. Our results indicated that broad targeting of epitopes by CD4+ T cells likely limits evasion by current VOCs. However, continued genomic surveillance is vital to identify new mutations able to evade CD4+ T cell immunity.

The risk of subsequent surgery following bowel resection for Crohn's disease in a national cohort of 19 207 patients.

AIM: Surgery is required for most patients with Crohn's disease (CD) and further surgery may be necessary if medical treatment fails to control disease activity. The aim of this study was to characterize the risk of, and factors associated with, further surgery following a first resection for Crohn's disease. METHODS: Hospital Episode Statistics from England were examined to identify patients with CD and a first recorded bowel resection between 2007 and 2016. Multivariable logistic regression was used to examine risk factors for further resectional surgery within 5 years. Prevalence-adjusted surgical rates for index CD surgery over the study period were calculated. RESULTS: In total, 19 207 patients (median age 39 years, interquartile range 27-53 years; 55% women) with CD underwent a first recorded resection during the study period. 3141 (16%) underwent a further operation during the study period. The median time to further surgery was 2.4 (interquartile range 1.2-4.6) years. 3% of CD patients had further surgery within 1 year, 14% by 5 years and 23% by 10 years. Older age (≥58), index laparoscopic surgery and index elective surgery (adjusted OR 0.65, 95% CI 0.54-0.77; 0.77, 0.67-0.88; and 0.77, 0.69-0.85; respectively) were associated with a reduced risk of further surgery by 5 years. Prior surgery for perianal disease (1.60, 1.37-1.87), an extraintestinal manifestation of CD (1.51, 1.22-1.86) and index surgery in a high-volume centre for CD surgery (1.20, 1.02-1.40) were associated with an increased risk of further surgery by 5 years. A 25% relative and 0.3% absolute reduction in prevalence-adjusted index surgery rates for CD was observed over the study period. CONCLUSIONS: Further surgery following an index operation is common in CD. This risk was particularly seen in patients with perianal disease, extraintestinal manifestations and those who underwent index surgery in a high-volume centre.

Rate of pancreatic cancer following a negative endoscopic ultrasound and associated factors.

BACKGROUND : Data are limited regarding pancreatic cancer diagnosed following a pancreaticobiliary endoscopic ultrasound (EUS) that does not diagnose pancreatic cancer. We have studied the frequency of, and factors associated with, post-EUS pancreatic cancer (PEPC) and 1-year mortality. METHODS : Between 2010 and 2017, patients with pancreatic cancer and a preceding pancreaticobiliary EUS were identified in a national cohort using Hospital Episode Statistics. Patients with a pancreaticobiliary EUS 6-18 months before a later pancreatic cancer diagnosis were the PEPC cases; controls were those with pancreatic cancer diagnosed within 6 months of pancreaticobiliary EUS. Multivariable logistic regression models examined the factors associated with PEPC and a Cox regression model examined factors associated with 1-year cumulative mortality. RESULTS : 9363 pancreatic cancer patients were studied; 93.5 % identified as controls (men 53.2 %; median age 68 [interquartile range (IQR) 61-75]); 6.5 % as PEPC cases (men 58.2 %; median age 69 [IQR 61-77]). PEPC was associated with older age (≥ 75 years compared with < 65 years, odds ratio [OR] 1.42, 95 %CI 1.15-1.76), increasing co-morbidity (Charlson co-morbidity score > 5, OR 1.90, 95 %CI 1.49-2.43), chronic pancreatitis (OR 3.13, 95 %CI 2.50-3.92), and diabetes mellitus (OR 1.58, 95 %CI 1.31-1.90). Metal biliary stents (OR 0.57, 95 %CI 0.38-0.86) and EUS-FNA (OR 0.49, 95 %CI 0.41-0.58) were inversely associated with PEPC. PEPC was associated with a higher cumulative mortality at 1 year (hazard ratio 1.12, 95 %CI 1.02-1.24), with only 14 % of PEPC patients (95 %CI 12 %-17 %) having a surgical resection, compared with 21 % (95 %CI 20 %-22 %) of controls. CONCLUSIONS : PEPC occurred in 6.5 % of patients and was associated with chronic pancreatitis, older age, more co-morbidities, and specifically diabetes mellitus. PEPC was associated with a worse prognosis and lower surgical resection rates.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

The outcomes of emergency hospital admissions with non-malignant upper gastrointestinal bleeding in England between 2003 and 2015.

BACKGROUND: Upper gastrointestinal bleeding (UGIB) is a common medical emergency with significant mortality. Despite developments in endoscopic and clinical management, only minor improvements in outcomes have been reported. METHODS: This was a retrospective cohort study of patients with non-malignant UGIB emergency admissions in England between 2003 and 2015, using Hospital Episode Statistics. Multilevel logistic regression analysis examined the associations with mortality. RESULTS: 242 796 patients with an UGIB admission were identified (58.8 % men; median age 70 [interquartile range (IQR) 53 - 81]). Between 2003 and 2015, falls occurred in both 30-day mortality (7.5 % to 7.0 %; P < 0.001) and age-standardized mortality (odds ratio (OR) 0.74, 95 % confidence interval [CI] 0.69 - 0.80; P < 0.001), including from variceal bleeding (OR 0.63, 95 %CI 0.45 - 0.87; P < 0.005). Increasing co-morbidity (Charlson score > 5, OR 2.94, 95 %CI 2.85 - 3.04; P < 0.001), older age (> 83 years, OR 6.50, 95 %CI 6.09 - 6.94; P < 0.001), variceal bleeding (OR 2.03, 95 %CI 1.89 - 2.18; P < 0.001), and a weekend admission (Sunday, OR 1.18, 95 %CI 1.12 - 1.23; P < 0.001) were associated with 30-day mortality. Of deaths at 30 days, 8.9 % were from ischemic heart disease (IHD) and the cardiovascular age-standardized mortality rate following UGIB was high (IHD deaths within 1 year, 1188.4 [95 %CI 1036.8 - 1353.8] per 100 000 men in 2003). CONCLUSIONS: Between 2003 and 2015, 30-day mortality among emergency admissions with non-malignant UGIB fell by 0.5 % to 7.0 %. Mortality was higher among UGIB admissions at the weekend, with important implications for service provision. Patients with UGIB had a much greater risk of subsequently dying from cardiovascular disease and addressing this risk is a key management step in UGIB.

A national study of artificial urinary sphincter and male sling implantation after radical prostatectomy in England.

OBJECTIVES: To consider the provision of post-radical prostatectomy (RP) continence surgery in England. MATERIALS AND METHODS: Patients with an Office of Population Census and Surveys Classification of Interventions and Procedures, version 4 code for an artificial urinary sphincter (AUS) or male sling between 1 January 2010 and 31 March 2018 were searched for within the Hospital Episode Statistics (HES) dataset. Those without previous RP were excluded. Multivariable logistic regressions for repeat AUS and sling procedures were built in stata. Further descriptive analysis of provision of procedures was performed. RESULTS: A total of 1414 patients had received index AUS, 10.3% of whom had undergone prior radiotherapy; their median follow-up was 3.55 years. The sling cohort contained 816 patients; 6.7% of these had received prior radiotherapy and the median follow-up was 3.23 years. Whilst the number of AUS devices implanted had increased each year, male slings peaked in 2014/2015. AUS redo/removal was performed in 11.2% of patients. Patients in low-volume centres were more likely to require redo/removal (odds ratio [OR] 2.23 95% confidence interval [CI] 1.02-4.86; P = 0.045). A total of 12.0% patients with a sling progressed to AUS implantation and 1.3% had a second sling. Patients with previous radiotherapy were more likely to require a second operation (OR 2.03 95% CI 1.01-4.06; P = 0.046). Emergency re-admissions within 30 days of index operation were 3.9% and 3.6% fewer in high-volume centres, for AUS and slings respectively. The median time to initial continence surgery from RP was 2.8 years. Increased time from RP conferred no reduced risk of redo surgery for either procedure. CONCLUSION: There is a volume effect for outcomes of AUS procedures, suggesting that they should only be performed in high-volume centres. Given the known impact of incontinence on quality of life, patients should be referred sooner for post-prostatectomy continence surgery.

Outcomes of pneumatic dilatation and Heller's myotomy for achalasia in England between 2005 and 2016.

INTRODUCTION: Achalasia is a disorder characterised by failed relaxation of the lower oesophageal sphincter. The aim of this study was to examine, at a national level, the long-term outcomes of achalasia therapies. METHODS: Hospital Episode Statistics include diagnostic and procedural data for all English National Health Service-funded hospital admissions. Subjects with a code for achalasia who had their initial treatment between January 2006 and December 2015 were grouped by treatment; pneumatic dilatation (PD) or surgical Heller's myotomy (HM). Procedural failure was defined as time to a further episode of the same therapy or a change to a different therapy. Up to three PDs were permitted without being considered a therapy failure. RESULTS: 6938 subjects were included; 3619 (52.2%) were men and median age at diagnosis was 59 (IQR 43-75) years. 4748 (68.4%) initially received PD and 2190 (31.6%) HM. The perforation rate following PD was 1.6%. Mortality at 30 days was 0.0% for HM and 1.9% for PD, and <8% after perforation following PD. Factors associated with increased mortality after PD included age quintile 66-77 (OR 4.55 (95% CI 2.00 to 10.38), p<0.001), >77 (9.78 (4.33 to 22.06), p<0.001); Charlson comorbidity score >4 (2.87 (2.08 to 3.95), p<0.001); previous HM (2.47 (1.33 to 4.62), p<0.001); and repeat PD 1-3 (1.58 (1.15 to 2.16), p=0.005), >3 (1.97 (1.21 to 3.19), p=0.006). Durability of up to 3 PD and HM over 10 years of follow-up was 86.2% and 81.9%, respectively (p<0.001). DISCUSSION: The efficacy of PD for achalasia appears to be greater than HM over 10 years. There was no mortality associated with HM, but 1.9% of subjects died within 30 days of PD. Mortality was associated with increasing age, comorbidity, previous HM and repeat PD.

Incidence, morbidity and mortality of patients with achalasia in England: findings from a study of nationwide hospital and primary care data.

BACKGROUND: Achalasia is an uncommon condition characterised by failed lower oesophageal sphincter relaxation. Data regarding its incidence, prevalence, disease associations and long-term outcomes are very limited. METHODS: Hospital Episode Statistics (HES) include demographic and diagnostic data for all English hospital attendances. The Health Improvement Network (THIN) includes the primary care records of 4.5 million UK subjects, representative of national demographics. Both were searched for incident cases between 2006 and 2016 and THIN for prevalent cases. Subjects with achalasia in THIN were compared with age, sex, deprivation tand smoking status matched controls for important comorbidities and mortality. RESULTS: There were 10 509 and 711 new achalasia diagnoses identified in HES and THIN, respectively. The mean incidence per 100 000 people in HES was 1.99 (95% CI 1.87 to 2.11) and 1.53 (1.42 to 1.64) per 100 000 person-years in THIN. The prevalence in THIN was 27.1 (25.4 to 28.9) per 100 000 population. Incidence rate ratios (IRRs) were significantly higher in subjects with achalasia (n=2369) compared with controls (n=3865) for: oesophageal cancer (IRR 5.22 (95% CI: 1.88 to 14.45), p<0.001), aspiration pneumonia (13.38 (1.66 to 107.79), p=0.015), lower respiratory tract infection (1.33 (1.05 to 1.70), p=0.02) and mortality (1.33 (1.17 to 1.51), p<0.001). The median time from achalasia diagnosis to oesophageal cancer diagnosis was 15.5 (IQR 20.4) years. CONCLUSION: The incidence of achalasia is 1.99 per 100 000 population in secondary care data and 1.53 per 100 000 person-years in primary care data. Subjects with achalasia have an increased incidence of oesophageal cancer, aspiration pneumonia, lower respiratory tract infections and higher mortality. Clinicians treating patients with achalasia should be made aware of these associated morbidities and its increased mortality.

Outcomes of colorectal stents when used as a bridge to curative resection in obstruction secondary to colorectal cancer.

BACKGROUND: Up to 25% of colorectal cancers present with bowel obstruction. Metal stents (MS) can provide a bridge to surgery by relieving obstruction and allowing the subject's condition to improve pre-operatively. METHODS: Hospital Episode Statistics (HES) is a database of all NHS funded secondary care episodes in England. Subjects admitted with bowel obstruction secondary to colorectal cancer without metastases were identified and subdivided into two groups: MS insertion prior to surgery and surgery only. Due to demographic differences between the groups, propensity score matching was used to analyse procedural outcomes, mortality and readmission within 30 days in left-sided cancers based upon age, sex and Charlson co-morbidity score. RESULTS: Over 10 years, 4571 subjects were identified; 401 received a MS and 4170 underwent surgery only. Median age of MS subjects was 71 (IQR 62-79) years; 226 (56.4%) were male. Median age of surgery-only subjects was 73 (64-81); 2165 (51.9%) were male. Following propensity matching 375 MS and 375 surgery-only subjects remained; MS had fewer readmissions within 30 days (28 (7.5%) versus 44 (11.7%), p = 0.047), fewer respiratory complications (< 6 (< 1.5%) versus 28 (7.5%), p < 0.001), lower stoma rates (49 (13.1%) versus 159 (42.4%), p < 0.001) and higher rates of laparoscopic surgery (154 (41.1%) versus 25 (6.7%), p < 0.001). Mortality was lower in the MS group at 30 days (7 (1.9%) versus 33 (8.8%), p < 0.001) and 1 year (37 (9.9%) versus 71 (19.0%), p < 0.001). CONCLUSIONS: In subjects presenting with obstructing colorectal cancer outcomes including respiratory complications, readmission and mortality appear to be better in subjects undergoing MS as a bridge to surgery compared to surgery alone.

Spontaneous CD4+ and CD8+ T-cell responses directed against cancer testis antigens are present in the peripheral blood of testicular cancer patients.

Cancer/testis antigen (CTAg) expression is restricted to spermatogenic cells in an immune-privileged site within the testis. However, these proteins are expressed aberrantly by malignant cells and T-cell responses against CTAgs develop in many cancer patients. We investigated the prevalence, magnitude and phenotype of CTAg-specific T cells in the blood of patients with testicular germ cell tumors (TGCTs). CD8+ and CD4+ T-cell responses against MAGE-A family antigens were present in 44% (20/45) of patients' samples assayed by ex vivo IFN-γ ELISPOT. The presence of MAGE-specific CD8+ T cells was further determined following short-term in vitro expansion through the use of pMHC-I multimers containing known immunogenic peptides. Longitudinal analysis revealed that the frequency of MAGE-specific T cells decreased by 89% following orchidectomy suggesting that persistence of tumor antigen is required to sustain CTAg-specific T-cell immunity. Notably, this decrease correlated with a decline in the global effector/memory T-cell pool following treatment. Spontaneous T-cell immunity against CTAg proteins therefore develops in many patients with testicular cancer and may play an important role in the excellent clinical outcome of patients with this tumor subtype.

Centralisation of radical cystectomies for bladder cancer in England, a decade on from the 'Improving Outcomes Guidance': the case for super centralisation.

OBJECTIVE: To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re-intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the 'Improving Outcomes Guidance' (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high-output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation. PATIENTS AND METHODS: RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30-day, 90-day, and 1-year all-cause postoperative mortality; median LoS; complication and re-intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers' annual case volume and mortality. RESULTS: In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30-day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30-day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1-year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re- intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977-0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988-0.993), and significantly reduced rates of re-intervention. CONCLUSION: Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re-intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive.

Post Roux-en-Y gastric bypass complications: A comparative study assessing the clinical effectiveness of oesophagogastroduodenoscopy and oral-contrast swallow.

INTRODUCTION: Anastomotic strictures at the gastrojejunal anastomosis have been reported to occur in 3-20% of patients following a Roux-en-Y gastric bypass (RYGB). Patients commonly present with dysphagia, vomiting and post-prandial pain. Clearly using the appropriate investigations to diagnose the potential complications have both clinical and economical benefits. The reported study compared whether Oesophagogastroduodenoscopy (OGD) or oral-contrast swallow should be employed in patient presenting with post-operative complications following RYGB. METHODS: A retrospective study was conducted on 112 patients between 2008 and 2012; at a level 4 bariatric surgery hospital. Patients who had ≥1 OGD to investigate a post-operative complication were included for analysis. Oral-contrast swallow radiology reports performed <28 days prior to an OGD were included for analysis. Patient demographics, OGD, oral-contrast swallow and additional interventions reports were collated from electronic records, pathology and radiology results. RESULTS: 112 patients underwent 1 or more OGD. 75% (n = 67) of patients were diagnosed with a post-operative complication with the most common, 51% (n = 57) being a gastrojejunal anastomotic stricture. 82% (n = 47) of patients presented with dysphagia + - vomiting prior to the diagnosis of gastrojejunal anastomotic strictures. 96% (n = 55) of patients with gastrojejunal anastomotic strictures were successfully treated with balloon dilation. 48% (n = 54) of patients had an oral-contrast swallow as a first line investigation for post-operative symptoms prior to the OGD. 15% (n = 8) of oral-contrast swallow were reported with a significant pathology, with only 1 stricture identified. 70% (n = 38) of oral-contrast swallows reported as normal had a pathology identified at OGD, including 28 strictures. CONCLUSION: We recommend that an OGD should be performed in patients presenting with symptoms consistent with a stricture following RYGB. The urgency of the OGD will be dictated by clinical correlation. The use of a water-soluble contrast swallow should be reserved for a suspected anastomotic leak.

Factors associated with colorectal cancer occurrence after colonoscopy that did not diagnose colorectal cancer.

BACKGROUND AND AIMS: Up to 6% of colorectal cancers (CRCs) are diagnosed within 5 years of a colonoscopy that did not diagnose CRC (post-colonoscopy colorectal cancer, PCCRC). PCCRC and associated risk factors were examined within a national hospital episode database. METHODS: A retrospective case-control study of all colonoscopies performed on adults recorded in Hospital Episode Statistics (HES) between 2003 and 2009 in England. PCCRC cases underwent colonoscopy 6 to 60 months before diagnosis; controls had not undergone colonoscopy 6 to 60 months before diagnosis. Multivariate logistic regression analysis examined associations with PCCRC. RESULTS: A total of 1,439,684 colonoscopies were analyzed, including 67,202 cases of CRC and 8147 cases of PCCRC (12.1%). Multivariate analysis revealed that female sex (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.08-1.19; P < .001), older age (70-74 years) (OR, 1.09; 95% CI, 1.00-1.18; P = .039), increased comorbidity (Charlson index 5+) (OR, 1.16; 95% CI, 1.05-1.28; P < .003), and CRC of the right side of the colon (OR, 1.17; 95% CI, 1.11-1.23; P < .0001) were associated with PCCRC. Emergency colonoscopy (OR, 0.54; 95% CI, 0.59-0.69; P < .0001) was negatively associated with PCCRC. More individuals with PCCRC developed metastases within 12 months and fewer underwent surgery (OR, 0.33; 95% CI, 0.32-0.35; P < .0001) or chemotherapy (OR, 0.66; 95% CI, 0.62-0.69), P < .0001). PCCRC rates varied 2-fold between providers and PCCRC was associated with medium-volume providers compared with high-volume providers (OR, 1.13; 95% CI, 1.01-1.27; P = .035). The PCCRC rate fell from 13.8% in 2003 to 11.9% in 2009. CONCLUSIONS: PCCRC occurred in 12.1% of patients with CRC between 2003 and 2009. PCCRC was associated with female sex, older age, increased comorbidity, CRC of the right side of the colon, elective procedures, and colonoscopy volume. PCCRC was associated with worse outcomes.

Cytokines as effectors and predictors of responses in the treatment of bladder cancer by bacillus Calmette-Guérin.

The most effective intravesical treatment of non-muscle-invasive bladder cancer is instillation of live Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG stimulates the release of cytokines, contributing directly or indirectly to its effectiveness. However, the function of specific cytokines is not well understood. We have undertaken a nonsystematic review of primary evidence regarding cytokine detection, activation and response in BCG patients. Cytokines IL-2, IL-8 and TNF-α appear to be essential for effective BCG therapy and nonrecurrence, while IL-10 may have an inhibitory effect on BCG responses. IL-2, IL-8, TRAIL and TNF-α are potentially predictive of response to BCG. Alterations in genes encoding cytokines may also affect responses. There are significant data showing the association of certain cytokines with successful BCG treatment, and which may be useful predictive markers. Isolating those cytokines mediating efficacy may hold the key to ameliorating BCG's side effects and improving efficacy and patient compliance.

High early mortality following percutaneous nephrostomy in metastatic cancer: a national analysis of outcomes.

OBJECTIVES: To assess the outcomes of percutaneous nephrostomy in England for renal decompression, in the context of metastatic cancer. METHODS: Retrospective observational study of all patients undergoing nephrostomy with a diagnosis of metastatic cancer from 2010 to 2019 in England, identified and followed up within Hospital Episode Statistics.The primary outcome measure was mortality (14-day and 30-day postprocedure). Secondary outcomes included subsequent chemotherapy or surgery and direct complications of nephrostomy. RESULTS: 10 932 patients were identified: 58.0% were male, 51.0% were >70 years old and 57.7% had no relevant comorbidities (according to Charlson's criteria, other than cancer).1 in 15 patients died within 14 days of nephrostomy and 1 in 6 died within 30 days. Factors associated with higher 30-day mortality were the presence of comorbidities (Charlson score 1-4 (OR 1.27, 95% CI 1.08 to 1.50, p=0.003), score 5+ (OR 1.29, 95% CI 1.14 to 1.45), p<0.001)); inpatient nephrostomy (OR 3.76, 95% CI 2.75 to 5.14, p<0.001) and admitted under the care of specialities of internal medicine (OR 2.10, 95% CI 1.84 to 2.40, p<0.001), oncology (OR 1.80, 95% CI 1.51 to 2.15, p<0.001), gynaecology/gynaeoncology (OR 1.66, 95% CI 1.21 to 2.28, p=0.002) or general surgery (OR 1.62, 95% CI 1.32 to 1.98, p<0.001)), compared with urology.25.4% received subsequent chemotherapy. Receiving chemotherapy was associated with younger patients (eg, age 18-29 (OR 4.04, 95% CI 2.66 to 6.12, p<0.001) and age 30-39 (OR 3.07, 95% CI 2.37 to 3.97, p<0.001)) and under the care of oncology (OR 1.60, 95% CI 1.40 to 1.83, p<0.001) or gynaecology/gynaeoncology (OR 1.64, 95%CI 1.28 to 2.10, p<0.001) compared with urology.43.8% had subsequent abdominopelvic surgery. Not receiving surgery was associated with inpatient nephrostomy (OR 0.82, 95%CI 0.72 to 0.95,p=0.007): non-genitourinary cancers (eg, gynaecology/gynaeoncology cancer (OR 0.86, 95% CI 0.74 to 0.99, p=0.037)); and under the care of a non-surgical specialty (medicine (OR 0.69, 95% CI 0.63 to 0.77, p<0.001), oncology (OR 0.58, 95% CI 0.51 to 0.66, p<0.001)).24.5% of patients had at least one direct complication of nephrostomy: 12.5% required early exchange of nephrostomy, 8.1% had bleeding and 6.7% had pyelonephritis. CONCLUSIONS: The decision to undertake nephrostomy in patients with poor prognosis cancer is complex and should be undertaken in a multidisciplinary team setting. Complication rates are high and minimal survival benefit is derived in many patients, especially in the context of emergency inpatient care.

High early mortality after percutaneous liver biopsy in metastatic cancer: national analysis.

OBJECTIVE: The study aimed to assess outcomes in patients undergoing liver biopsy for metastatic cancer, focusing on mortality rates and chemotherapy following their biopsy. METHODS: Hospital Episode Statistics data from 2010 to 2019 identified 30 992 patients with metastatic cancer who underwent percutaneous liver biopsy. Primary outcomes included 14-day and 30-day mortality rates, as well as the proportion receiving chemotherapy within 6 months. RESULTS: 30 992 patients were studied (median age of 69 (IQR 59-74) years, 52% female). 28% underwent inpatient biopsy with 8% dying within 14 days and 26% within 30 days. Outpatient biopsies had lower mortality rates: 2.2% at 14 days and 8.6% at 30 days.30-day mortality was associated with: inpatient biopsy (OR 3.5 (95% CI 3.26 to 3.76)) and increasing comorbidity (Charlson score 1-4: 1.21 (95% CI 1.11 to 1.32)); but negatively with all ages under 70 (eg, for 18-29 years 0.35 (95% CI 0.20 to 0.63)) and biopsy at a radiotherapy centre (0.88 (95% CI 0.82 to 0.95)).46% of patients received chemotherapy within 6 months of biopsy (53% with outpatient biopsies but only 33% with inpatient biopsies). Receiving chemotherapy was associated with: all ages under 70 (eg, 18-29 years 3.3 (95% CI 2.62 to 5.30)), female sex (1.06 (95% CI 1.01 to 1.11)) and medium (1.13 (95% CI 1.04 to 1.22) and high (1.49 (95% CI 1.38 to 1.62)) volume liver biopsy providers; but negatively with inpatient biopsy (0.45 (95% CI 0.43 to 0.48)) and increasing comorbidity (Charlson score 1-4: 0.85 (95% CI 0.79 to 0.91)). CONCLUSIONS: Mortality rates following liver biopsy for metastatic cancer are notably higher among patients undergoing emergency inpatient procedures. Clinicians should carefully weigh the risks and benefits of biopsy in elderly, comorbid or poor performance status patients. Multidisciplinary approaches involving palliative care may aid in decision-making for these patients.

Rapid achievement of low-density lipoprotein cholesterol goals within 1 month after acute coronary syndrome during combination therapy with rosuvastatin, ezetimibe and bempedoic acid: Initial experience from the LAI-REACT study.

Rapid reduction of low-density lipoprotein cholesterol (LDL-C) to target levels immediately following acute coronary syndrome (ACS) event is critical to prevent future events. High-dose statins alone often fail to achieve LDL-C goals. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-dose statins improves LDL-C goal attainment, but is unaffordable for many patients in India and worldwide. In a real-world open-label study, we demonstrated in a cohort of 122 patients with ACS, concurrent triple therapy with rosuvastatin 40 mg/d, ezetimibe 10 mg/d, and bempedoic acid 180 mg/d (REB) started at the time of hospital admission was associated with 57.7%, 61.7%, 61.9% and 60.6% reductions in LDL-C from 115.6 mg/dL at baseline to 48.9 mg/dL at week 1, 44.3 mg/dL at week 2, 44.1 mg/dL at week 4, and 45.6 mg/dL at week 6, respectively (each p < 0.001 compared to baseline; p < 0.001 across repeated measures). REB provided significant reductions in LDL-C within as early as one week and enabled 76.3% and 92.2% of patients to achieve the Lipid Association of India and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 2-weeks, respectively, which were sustained at 4-6 weeks. REB was generally well tolerated. Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen in India.

Image directed redesign of bladder cancer treatment pathways: the BladderPath RCT.

Background: Transurethral resection of bladder tumour has been the mainstay of bladder cancer staging for > 60 years. Staging inaccuracies are commonplace, leading to delayed treatment of muscle-invasive bladder cancer. Multiparametric magnetic resonance imaging offers rapid, accurate and non-invasive staging of muscle-invasive bladder cancer, potentially reducing delays to radical treatment. Objectives: To assess the feasibility and efficacy of the introducing multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour in the staging of suspected muscle-invasive bladder cancer. Design: Open-label, multistage randomised controlled study in three parts: feasibility, intermediate and final clinical stages. The COVID pandemic prevented completion of the final stage. Setting: Fifteen UK hospitals. Participants: Newly diagnosed bladder cancer patients of age ≥ 18 years. Interventions: Participants were randomised to Pathway 1 or 2 following visual assessment of the suspicion of non-muscle-invasive bladder cancer or muscle-invasive bladder cancer at the time of outpatient cystoscopy, based upon a 5-point Likert scale: Likert 1-2 tumours considered probable non-muscle-invasive bladder cancer; Likert 3-5 possible muscle-invasive bladder cancer. In Pathway 1, all participants underwent transurethral resection of bladder tumour. In Pathway 2, probable non-muscle-invasive bladder cancer participants underwent transurethral resection of bladder tumour, and possible muscle-invasive bladder cancer participants underwent initial multiparametric magnetic resonance imaging. Subsequent therapy was determined by the treating team and could include transurethral resection of bladder tumour. Main outcome measures: Feasibility stage: proportion with possible muscle-invasive bladder cancer randomised to Pathway 2 which correctly followed the protocol. Intermediate stage: time to correct treatment for muscle-invasive bladder cancer. Results: Between 31 May 2018 and 31 December 2021, of 638 patients approached, 143 participants were randomised; 52.1% were deemed as possible muscle-invasive bladder cancer and 47.9% probable non-muscle-invasive bladder cancer. Feasibility stage: 36/39 [92% (95% confidence interval 79 to 98%)] muscle-invasive bladder cancer participants followed the correct treatment by pathway. Intermediate stage: median time to correct treatment was 98 (95% confidence interval 72 to 125) days for Pathway 1 versus 53 (95% confidence interval 20 to 89) days for Pathway 2 [hazard ratio 2.9 (95% confidence interval 1.0 to 8.1)], p = 0.040. Median time to correct treatment for all participants was 37 days for Pathway 1 and 25 days for Pathway 2 [hazard ratio 1.4 (95% confidence interval 0.9 to 2.0)]. Limitations: For participants who underwent chemotherapy, radiotherapy or palliation for multiparametric magnetic resonance imaging-diagnosed stage T2 or higher disease, it was impossible to conclusively know whether these were correct treatments due to the absence of histopathologically confirmed muscle invasion, this being confirmed radiologically in these cases. All patients had histological confirmation of their cancers. Due to the COVID-19 pandemic, we were unable to realise the final stage. Conclusion: The multiparametric magnetic resonance imaging-directed pathway led to a substantial 45-day reduction in time to correct treatment for muscle-invasive bladder cancer, without detriment to non-muscle-invasive bladder cancer participants. Consideration should be given to the incorporation of multiparametric magnetic resonance imaging ahead of transurethral resection of bladder tumour into the standard pathway for all patients with suspected muscle-invasive bladder cancer. The improved decision-making accelerated time to treatment, even though many patients subsequently needed transurethral resection of bladder tumour. A proportion of patients can avoid transurethral resection of bladder tumour completely, reducing costs and morbidity, given the much lower cost of magnetic resonance imaging and biopsy compared to transurethral resection of bladder tumour. Future work: Further work to cross-correlate with the recently developed Vesical Imaging-Reporting and Data System will improve accuracy and aid dissemination. Longer follow-up to examine the effect of the pathway on outcomes is also required. Incorporation of liquid deoxyribonucleic acid-based biomarkers may further improve the quality of decision-making and should also be investigated further. Study registration: This study is registered as ISRCTN 35296862. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135775) and is published in full in Health Technology Assessment; Vol. 28, No. 42. See the NIHR Funding and Awards website for further award information.

The BladderPath trial explored how to accelerate diagnosis and avoid unnecessary surgery for patients with bladder cancer which had grown into the muscle wall of the bladder, referred to as muscle-invasive bladder cancer. Following initial outpatient diagnosis, bladder cancer patients currently undergo inpatient or day-case surgical tumour removal using a telescope (transurethral resection of bladder tumour). This surgery is fundamental to the treatment of early bladder cancer (non-muscle-invasive). However, for muscle-invasive disease, the main role of transurethral resection of bladder tumour is to confirm that the tumour has grown into the bladder muscle, and this is often inaccurate; the actual correct treatment for muscle-invasive bladder cancer patients should include chemotherapy, radiotherapy and/or bladder removal. For these patients, having transurethral resection of bladder tumour may delay this correct treatment and impact survival. Additionally, for patients determined to need palliative care due to advanced disease, the transurethral resection of bladder tumour may represent over-treatment. A magnetic resonance imaging scan with contrast agent (called multiparametric magnetic resonance imaging) gives a clearer picture of the bladder than normal scans, allowing distinction between invasive and non-invasive tumours. The BladderPath trial investigated adding multiparametric magnetic resonance imaging for patients with suspected muscle-invasive bladder cancer and the effect on treatment times. Subsequent therapy could include transurethral resection of bladder tumour if clinically determined as necessary by the treating team. Trial participants were randomly allocated either to the standard pathway (Pathway 1: all underwent transurethral resection of bladder tumour) or to a new pathway (Pathway 2). In Pathway 2, urologists conducting the initial outpatient diagnostic bladder inspections used a scale to assess whether tumours appeared to be either probably non-muscle-invasive or possibly muscle-invasive. Participants whose tumours appeared possibly muscle-invasive had initial multiparametric magnetic resonance imaging as their next investigation instead of transurethral resection of bladder tumour. We then compared the duration of time from initial diagnosis to receiving the correct treatment for participants in each pathway. Of the 143 participants, 75 (52.1%) were diagnosed as possibly muscle invasive. In Pathway 1, the duration for half of the participants in the group to have received their correct treatment for muscle-invasive bladder cancer was 98 days, which reduced to 53 days in Pathway 2. Furthermore, the duration for half of all the participants in the two groups to have received their correct treatment was 37 days for Pathway 1 and 31 days for Pathway 2. In summary, use of initial multiparametric magnetic resonance imaging in suspected muscle-invasive bladder cancer participants substantially reduced the time to correct treatment (surgery, radiotherapy, chemotherapy or instigation of palliative care) and avoided unnecessary surgery. There was no negative impact on participants with non-invasive disease. Adopting multiparametric magnetic resonance imaging into the pathway ahead of transurethral resection of bladder tumour for patients with suspected muscle-invasive bladder cancer is recommended.