Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic TP53 mutation carriers: a case-controlled study (SIGNIFY).

BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429.

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

Objectives: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Methods: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. Results: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Conclusions: Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.

Prostate Cancer Germline Variations and Implications for Screening and Treatment.

Prostate cancer (PCa) is a highly heritable disease, and rapid evolution of sequencing technologies has enabled marked progression of our understanding of its genetic inheritance. A complex polygenic model that involves common low-penetrance susceptibility alleles causing individually small but cumulatively significant risk and rarer genetic variants causing greater risk represent the current most accepted model. Through genome-wide association studies, more than 100 single-nucleotide polymorphisms (SNPs) associated with PCa risk have been identified. Consistent reports have identified germline mutations in the genes BRCA1, BRCA2, MMR, HOXB13, CHEK2, and NBS1 as conferring moderate risks, with some leading to a more aggressive disease behavior. Considering this knowledge, several research strategies have been developed to determine whether targeted prostate screening using genetic information can overcome the limitations of population-based prostate-specific antigen (PSA) screening. Germline DNA-repair mutations are more frequent in men with metastatic disease than previously thought, and these patients have a more favorable response to therapy with poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors. Genomic information is a practical tool that has the potential to enable the concept of precision medicine to become a reality in all steps of PCa patient care.

Impacto sobre la incidencia de la tuberculosis en Cuba, 1994-2015 / Impact on the incidence of tuberculosis in Cuba, 1994-2015

Introducción: La incidencia es fundamental para evaluar la carga de tuberculosis. Objetivo: Valorar el impacto del Programa Nacional de Control de la Tuberculosis en la incidencia de la tuberculosis en Cuba en el periodo 1994-2015. Métodos: Estudio de series temporales de la incidencia de tuberculosis en el periodo 1994-2015. Se estimó la tendencia exponencial y las variaciones de las tendencias de casos nuevos notificados en Cuba y sus provincias; los totales y medias anuales de los periodos 1994-1999, 1999-2015 y 1994-2015. Se calcularon las diferencias absolutas y relativas entre las provincias cubanas desde 1994-2015. Resultados: La tendencia general de la tasa fue descendente. El periodo de 1994-1999 visualizó una reducción de -0,33x100 000(-505 casos) y entre 1999 y 2015 fue de -0,42(-448 casos). La reducción media anual entre 1994-1999 fue de -0,07 y de 1999-2015 fue de -0,03. En 1994, 1999 y 2015 se notificaron 1616 casos (14,7), 1111(10,0) y 651(5,8), respectivamente. En 1994 la mayor tasa correspondió a la provincia de Cienfuegos (23,1) con riesgo atribuible poblacional porcentual del 65,8 por ciento. En 1999 y 2015 las mayores tasas se presentaron en Ciego de Ávila (18,3) y (9,5), respectivamente (riesgo atribuible poblacional porcentual del 60,7 por ciento en 1999 y del 75,8 por ciento en 2015). En 1994 y 1999 todas las provincias tuvieron tasas > 5,0. En 2015, ocho provincias mostraron tasas < 5,0. En 1999 la provincia con mayor variación de su tasa anual fue Cienfuegos (-0,65) y en 2015 Camagüey (-0,73). Conclusiones: El Programa Nacional de Control de la Tuberculosis en Cuba obtuvo hasta el 2015 una discreta disminución sostenida de la incidencia de la enfermedad en el país; pero no es suficiente para lograr su eliminación, por lo que se requieren nuevas intervenciones diferenciadas y priorizadas(AU)

Introduction: Incidence is critical to assess the burden of tuberculosis. Objective: Assess the impact of the National Program of Tuberculosis Control on the incidence of tuberculosis in Cuba in the period 1994-2015. Methods: Study of time series of tuberculosis incidence in the period 1994-2015. The exponential trend and variations in the trends of new cases reported in Cuba and its provinces were estimated; also the annual totals and averages for the periods 1994-1999, 1999-2015 and 1994-2015. The absolute and relative differences between the Cuban provinces from 1994-2015 were calculated. Results: The overall trend of the rate was downward. The period from 1994-1999 had a reduction of -0.33x100 000 (-505 cases) and between 1999 and 2015 it was -0.42 (-448 cases). The average annual reduction between 1994-1999 was -0.07 and from 1999-2015 it was -0.03. In 1994, 1999 and 2015, 1616 cases (14.7), 1111 (10.0) and 651 (5.8) were reported, respectively. In 1994 the highest rate corresponded to the province of Cienfuegos (23.1) with a percentage population attributable risk of 65.8percent. In 1999 and 2015, the highest rates occurred in Ciego de Ávila (18.3) and (9.5), respectively (percentage population attributable risk of 60.7percent in 1999 and 75.8percent in 2015). In 1994 and 1999 all provinces had rates > 5.0. In 2015, eight provinces showed rates < 5.0. In 1999 the province with the greatest variation in its annual rate was Cienfuegos (-0.65) and in 2015 Camagüey (-0.73). Conclusions: The National Program of Tuberculosis Control in Cuba obtained until 2015 a discreet sustained decrease in the incidence of the disease in the country; but it is not enough to achieve its elimination, so new differentiated and prioritized interventions are required(AU)

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.