Risks of second primary cancers among 584,965 female and male breast cancer survivors in England: a 25-year retrospective cohort study.

Background: Second primary cancers (SPCs) after breast cancer (BC) present an increasing public health burden, with little existing research on socio-demographic, tumour, and treatment effects. We addressed this in the largest BC survivor cohort to date, using a novel linkage of National Disease Registration Service datasets. Methods: The cohort included 581,403 female and 3562 male BC survivors diagnosed between 1995 and 2019. We estimated standardized incidence ratios (SIRs) for combined and site-specific SPCs using incidences for England, overall and by age at BC and socioeconomic status. We estimated incidences and Kaplan-Meier cumulative risks stratified by age at BC, and assessed risk variation by socio-demographic, tumour, and treatment characteristics using Cox regression. Findings: Both genders were at elevated contralateral breast (SIR: 2.02 (95% CI: 1.99-2.06) females; 55.4 (35.5-82.4) males) and non-breast (1.10 (1.09-1.11) females, 1.10 (1.00-1.20) males) SPC risks. Non-breast SPC risks were higher for females younger at BC diagnosis (SIR: 1.34 (1.31-1.38) <50 y, 1.07 (1.06-1.09) ≥50 y) and more socioeconomically deprived (SIR: 1.00 (0.98-1.02) least deprived quintile, 1.34 (1.30-1.37) most). Interpretation: Enhanced SPC surveillance may benefit BC survivors, although specific recommendations require more detailed multifactorial risk and cost-benefit analyses. The associations between deprivation and SPC risks could provide clinical management insights. Funding: CRUK Catalyst Award CanGene-CanVar (C61296/A27223). Cancer Research UK grant: PPRPGM-Nov 20∖100,002. This work was supported by core funding from the NIHR Cambridge Biomedical Research Centre (NIHR203312)]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Regional variation in routes to diagnosis of cholangiocarcinoma in England from 2006 to 2017.

BACKGROUND: Incidence of cholangiocarcinoma (CCA) is rising, with overall prognosis re-maining very poor. Reasons for the high mortality of CCA include its late presentation in most patients, when curative options are no longer feasible, and poor response to systemic therapies for advanced disease. Late presentation presents a large barrier to improving outcomes and is often associated with diagnosis via mergency presentation (EP). Earlier diagnoses may be made by Two Week Wait (TWW) referrals through General practitioner (GP). We hypothesise that TWW referrals and EP routes to diagnosis differ across regions in England. AIM: To investigate routes to diagnosis of CCA over time, regional variation and influencing factors. METHODS: We linked patient records from the National Cancer Registration Dataset to Hospital Episode Statistics, Cancer Waiting Times and Cancer Screening Programme datasets to define routes to diagnosis and certain patient characteristics for patients diagnosed 2006-2017 in England. We used linear probability models to investigate geographic variation by assessing the proportions of patients diagnosed via TWW referral or EP across Cancer Alliances in England, adjusting for potential confounders. Correlation between the proportion of people diagnosed by TWW referral and EP was investigated with Spearman's correlation coefficient. RESULTS: Of 23632 patients diagnosed between 2006-2017 in England, the most common route to diagnosis was EP (49.6%). Non-TWW GP referrals accounted for 20.5% of diagnosis routes, 13.8% were diagnosed by TWW referral, and the remainder 16.2% were diagnosed via an 'other' or Unknown route. The proportion diagnosed via a TWW referral doubled between 2006-2017 rising from 9.9% to 19.8%, conversely EP diagnosis route declined, falling from 51.3% to 46.0%. Statistically significant variation in both the TWW referral and EP proportions was found across Cancer Alliances. Age, presence of comorbidity and underlying liver disease were independently associated with both a lower proportion of patients diagnosed via TWW referral, and a higher proportion diagnosed by EP after adjusting for other potential confounders. CONCLUSION: There is significant geographic and socio-demographic variation in routes to diagnosis of CCA in England. Knowledge sharing of best practice may improve diagnostic pathways and reduce unwarranted variation.

Cohort study to assess geographical variation in cholangiocarcinoma treatment in England.

BACKGROUND: Outcomes for cholangiocarcinoma (CCA) are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous sub-types. Beyond curative surgery, which is only an option for a minority of patients diagnosed at an early stage, few systemic therapy options are currently recommended to relieve symptoms and prolong life. Stent insertion to manage disease complications requires highly specialised expertise. Evidence is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA patients. AIM: To assess geographic variation in treatments received amongst CCA patients in England. METHODS: Data used in this cohort study were drawn from the National Cancer Registration Dataset (NCRD), Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset. A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the NCRD. Potentially curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of interest. Linear probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis, and for socio-demographic and clinical characteristics at diagnosis. RESULTS: Of 8853 CCA patients, 1102 (12.4%) received potentially curative surgery. The mean [95% confidence interval (CI)] percentage-point difference from the population average ranged from -3.96 (-6.34 to -1.59)% to 3.77 (0.54 to 6.99)% across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics, showing statistically significant variation. Amongst 7751 who did not receive surgery, 1542 (19.9%) received systemic therapy, with mean [95%CI] percentage-point difference from the population average between -3.84 (-8.04 to 0.35)% to 9.28 (1.76 to 16.80)% across Cancer Alliances after adjustment, again showing the presence of statistically significant variation for some regions. Stent insertion was received by 2156 (27.8%), with mean [95%CI] percentage-point difference from the population average between -10.54 (-12.88 to -8.20)% to 13.64 (9.22 to 18.06)% across Cancer Alliances after adjustment, showing wide and statistically significant variation from the population average. Half of 8853 patients (n = 4468) received no treatment with either surgery, systemic therapy or stent insertion. CONCLUSION: Substantial regional variation in treatments received by CCA patients was observed in England. Such variation could be due to differences in case-mix, clinical practice or access to specialist expertise.

CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies.

BACKGROUND: A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH. METHODS: PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations. RESULTS: We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR] = 2.02 [95% confidence interval {CI } = 1.23-3.31]) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 [95% CI = 1.58-6.22]) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 [95% CI = 1.60-6.56] for KS; HR = 5.28 [95% CI = 2.17-12.83] for NHL). CONCLUSIONS: Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3.

2017 Cancer Prevalence Dashboard for London.

BACKGROUND: As cancer incidence increases and survival improves, the number of people living with a cancer diagnosis is increasing. People living with cancer have 50% more contact with GPs 15 months after diagnosis than a population of similar age, sex and locality; 70% have another long-term condition. AIM: To aid service providers' understanding of the cancer prevalent population by creating a publicly available visualisation tool that both describes patients' demographics and length of time lived with cancer, and compares counts of nationally registered cancer survivors to GP-maintained registers. METHOD: Using National Cancer Registration and Analysis Service (NCRAS) data, prevalence rates and counts were generated for London patients diagnosed 1995-2017 and alive 31 December 2017, overall and for lower-level geographies. GP-recorded Quality and Outcomes Framework (QOF) prevalence at Clinical Commissioning Group (CCG) level was compared to NCRAS counts for the same period. RESULTS: On 31 December 2017, 231 740 (2.6%) people were living with cancer in London; 33% were diagnosed 5-9 years prior and 31% were diagnosed ≥10 years prior. Prevalence was higher in women (P<0.001) and dramatically increased with age for London (P<0.001); >12% of >75 year olds were living with a cancer diagnosis in every lower-level geography. Completeness of GP QOF cancer registers against NCRAS prevalence counts ranged from 75-108% across CCGs. CONCLUSION: Local understanding of the cancer prevalent population is needed, with a concerted effort to interpret large discrepancies between QOF and NCRAS registers, which may arise from differences in coding practice. Ensuring patients are identified in primary care is a first key step to managing cancer as a long-term condition.

Incidence and outcome of colorectal cancer in liver transplant recipients: A national, multicentre analysis on 8115 patients.

BACKGROUND & AIMS: De novo malignancies after liver transplantation represent one of the leading causes of death in the long-term. It remains unclear whether liver transplant recipients have an increased risk of colorectal cancer and whether this negatively impacts on survival, particularly in those patients affected by primary sclerosing cholangitis and ulcerative colitis. METHODS: In this national multicentre cohort retrospective study, the incidence of colorectal cancer in 8115 evaluable adult patients undergoing a liver transplantation between 1 January 1990 and 31 December 2010 was compared to the incidence in the general population through standardised incidence ratios. RESULTS: Fifty-two (0.6%) cases of colorectal cancer were identified at a median of 5.6 years postliver transplantation, predominantly grade 2 (76.9%) and stage T3 (50%) at diagnosis. The incidence rate of colorectal cancer in the whole liver transplant population was similar to the general UK population (SIR: 0.92), but significantly higher (SIR: 7.0) in the group of patients affected by primary sclerosing cholangitis/ulcerative colitis. One-, five- and ten-year survival rates from colorectal cancer diagnosis were 71%, 48% and 31%, respectively, and the majority of colorectal cancer patients died of cancer-specific causes. CONCLUSIONS: Liver transplantation alone is not associated with an increased risk of colorectal cancer development. The primary sclerosing cholangitis/ulcerative colitis liver transplant population showed a significantly higher risk of colorectal cancer development than the general population, with a high proportion of advanced stage at diagnosis and a reduced patient survival.

Effect of immediate initiation of antiretroviral treatment on the risk of acquired HIV drug resistance.

OBJECTIVE: We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/µl and initiation with CD4 cell count less than 350 cells/µl. DESIGN: Cohort study based on routinely collected data from the HIV-CAUSAL collaboration. METHODS: For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics. RESULTS: In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/µl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/µl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/µl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2). CONCLUSION: Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

Acortamiento cervical y su relación con parto pretérmino / Cervical shortening and its relationship with preterm birth

El cérvix es la porción del útero que se encarga de mantener el embarazo hasta el momento del término. El acortamiento es un factor de riesgo de parto pretérmino, de hecho se considera que el riesgo de parto pretérmino es inversamente proporcional a la longitud cervical, siendo mayor el riesgo con un cérvix menor de 15mm. Objetivo: identificar los rangos de longitud cervical, con riesgo de parto pretérmino acorde a la edad gestacional. Material y Métodos: la información se obtuvo a través de una búsqueda por medio de Google Académico, PubMed y el programa HINARI, seleccionando 21 artículos. Conclusión: el acortamiento del cérvix se asocia a parto pretérmino inminente, sobre todo cuando la longitud cervical es menor de 15mm antes de las 20 semanas de gestación. La ecografía transvaginal es la mejor herramienta para determinar longitud cervical.

The Human Immunodeficiency Virus Continuum of Care in European Union Countries in 2013: Data and Challenges.

BACKGROUND.: The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a "90-90-90" target to curb the human immunodeficiency virus (HIV) epidemic by 2020, but methods used to assess whether countries have reached this target are not standardized, hindering comparisons. METHODS.: Through a collaboration formed by the European Centre for Disease Prevention and Control (ECDC) with European HIV cohorts and surveillance agencies, we constructed a standardized, 4-stage continuum of HIV care for 11 European Union countries for 2013. Stages were defined as (1) number of people living with HIV in the country by end of 2013; (2) proportion of stage 1 ever diagnosed; (3) proportion of stage 2 that ever initiated ART; and (4) proportion of stage 3 who became virally suppressed (≤200 copies/mL). Case surveillance data were used primarily to derive stages 1 (using back-calculation models) and 2, and cohort data for stages 3 and 4. RESULTS.: In 2013, 674500 people in the 11 countries were estimated to be living with HIV, ranging from 5500 to 153400 in each country. Overall HIV prevalence was 0.22% (range, 0.09%-0.36%). Overall proportions of each previous stage were 84% diagnosed, 84% on ART, and 85% virally suppressed (60% of people living with HIV). Two countries achieved ≥90% for all stages, and more than half had reached ≥90% for at least 1 stage. CONCLUSIONS.: European Union countries are nearing the 90-90-90 target. Reducing the proportion undiagnosed remains the greatest barrier to achieving this target, suggesting that further efforts are needed to improve HIV testing rates. Standardizing methods to derive comparable continuums of care remains a challenge.

Diabetes y embarazo / Diabetes and pregnancy

La diabetes mellitus gestacional es la intolerancia a la glucosa en el embarazo. Es una de las complicaciones médicas comunes y la complicación metabólica más frecuente. En el 90% de los casos la diabetes se manifiesta por primera vez durante el embarazo, y el restante 10% lo produce diabetes mellitus tipo 1 y 2 previo al embarazo. El objetivo de la revisión es plantear los criterios de diagnóstico para diabetes en el embarazo y las principales complicaciones asociadas. Actualmente se utiliza la curva de tolerancia oral a la glucosa como prueba diagnóstica. Debido a todas las alteraciones metabólicas de esta enfermedad, un mal control de la misma se asocia a resultados perinatales adversos. El tratamiento de primera línea es dieta y ejercicio, se inicia uso de insulina cuando estos no logran las metas de glicemia (menor de 90mg/dL en ayuno y menor de 120mg/dL postprandial). La diabetes gestacional como principal complicación metabólica del embarazo debe ser diagnosticada de manera precoz. El manejo adecuado permite la prevención de complicaciones fetales y maternas asociadas a esta patología. De igual manera el seguimiento postparto debe formar parte de la evaluación integral del puerperio de la paciente diabética...(AU)

Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study.

BACKGROUND: Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per µL, and initiation at a CD4 count less than 350 cells per µL. METHODS: We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55,826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders. FINDINGS: Median CD4 count at diagnosis of HIV infection was 376 cells per µL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per µL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per µL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per µL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per µL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per µL, and initiation at a CD4 count less than 350 cells per µL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9). INTERPRETATION: The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING: National Institutes of Health.

Renal tubular disease in the era of combination antiretroviral therapy.

OBJECTIVES: To describe the spectrum of renal tubular disease (RTD) in HIV-positive patients and its association with exposure to antiretroviral therapy (ART). DESIGN: Review of 265 consecutive renal biopsies from HIV-positive patients attending eight clinics in the United Kingdom between 2000 and 2012. METHODS: We described the clinical characteristics of patients with RTD and compared current/recent exposure (at the time of, or up to 3 months prior to the date of biopsy) to potentially nephrotoxic ART [tenofovir (TDF), atazanavir (ATV), indinavir (IDV) and lopinavir/ritonavir (LPV/r)]. We also analysed the incidence of RTD in the UK CHIC cohort. Kruskall-Wallis, analysis of variance and Fisher's exact tests were used to evaluate between-group differences. RESULTS: Of the 60 RTD cases, 54 (90%) were included in the analyses. RTD comprised of three distinct patterns: acute tubular injury (ATI, n = 22), tubulo-interstitial nephritis (TIN, n = 20) and interstitial fibrosis and tubular atrophy (IFTA, n = 12). Compared with TIN and IFTA, ATI cases were less likely to be of black ethnicity (10 vs. 42-55%; P = 0.006), more likely to be on ART (100 vs. 55-68%; P = 0.001), with HIV-RNA below 200 copies/ml (100 vs. 54-58%; P < 0.001), and more likely to have current/recent exposure to TDF (P < 0.001). We did not find evidence for an association between exposure to TDF, ATV/r or LPV/r and either TIN or IFTA. CONCLUSION: RTD was present in approximately 20% of renal biopsies and comprised three distinct injury patterns with considerable clinical overlap. ATI was associated with TDF exposure, although the overall incidence of biopsy-defined ATI was low.

Sexual and reproductive health in a UK cohort of young adults perinatally infected with HIV.

OBJECTIVES: To assess sexual health and behaviour outcomes of young adults with perinatally acquired HIV-1 (PaHIV), and audit sexual health interventions against published standards of care. METHODS: Retrospective case note audit of 16-25-year-olds with PaHIV attending a dedicated transition clinic from January 2005 to 2011. RESULTS: Fifty-two young adults, 31 women, median age 20 years. 41 were sexually active; median age of coitarche 16 years. Median number of lifetime partners was 3.5, and five reported non-consensual sex. All had a sexually transmitted infection (STI) screen; 6 were diagnosed with an STI, genital warts (human papilloma virus) most frequently. The median interval from coitarche to first STI screen was 2 years. The pregnancy incidence was 103 per 1000 person years. 18/25 (72%) sexually active women had a cervical smear, four had colposcopy. All patients had hepatitis B virus (HBV) serology. 47 had not been vaccinated against HBV prior to transition. 23 completed HBV vaccination of which 11 had surface antibody >100 IU/ml at 1 year. CONCLUSIONS: The majority of our cohort was sexually active while still under the care of paediatric health services. Cervical screening and hepatitis B vaccination rates fell short of audit standards. Vaccination for hepatitis B should be considered prior to transfer of care to adult HIV services.