Milestones of Lynch syndrome: 1895-2015 Lynch, Henry T; Snyder, Carrie L; Shaw, Trudy G ...
Nature reviews. Cancer,
03/2015, Letnik:
15, Številka:
3
Journal Article
Recenzirano
Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and ...endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
The lack of race/ethnic and gender diversity in grants funded by the National Institutes of Health (NIH) is a persistent challenge related to career advancement and the quality and relevance of ...health research. We describe pilot programs at nine institutions supported by the NIH-sponsored Building Infrastructure Leading to Diversity (BUILD) program aimed at increasing diversity in biomedical research.
We collected data from the 2016-2017 Higher Education Research Institute survey of faculty and NIH progress reports for the first four years of the program (2015-2018). We then conducted descriptive analyses of data from the nine BUILD institutions that had collected data and evaluated which activities were associated with research productivity. We used Poisson regression and rate ratios of the numbers of BUILD pilots funded, students included, abstracts, presentations, publications, and submitted and funded grant proposals.
Teaching workshops were associated with more abstracts (RR 4.04, 95% CI 2.21-8.09). Workshops on grant writing were associated with more publications (RR 2.64, 95% CI 1.64-4.34) and marginally with marginally more presentations. Incentives to develop courses were associated with more abstracts published (RR 4.33, 95% CI 2.56-7.75). Workshops on research skills and other incentives were not associated with any positive effects.
Pilot interventions show promise in supporting diversity in NIH-level research. Longitudinal modeling that considers time lags in career development in moving from project development to grants submissions can provide more direction for future diversity pilot interventions.
Background
Pediatric oncology patients with prolonged (≥96 hours) febrile neutropenia (absolute neutrophil count < 500/μL) often undergo an evaluation for invasive fungal disease (IFD) and other ...infections. Current literature suggests that beta‐D‐glucan (BDG), galactomannan, bronchoalveolar lavage (BAL), and computed tomography (CT) scans (sinus, chest, and abdomen/pelvis) may help determine a diagnosis in this population.
Methods
In a retrospective cohort study of all cancer/stem cell transplant patients (diagnosed 2005‐2019) from one pediatric hospital, all episodes with prolonged febrile neutropenia or IFD evaluations (defined as sending a fungal biomarker or performing a CT scan to assess for infection) were identified.
Results
In total, 503 episodes met inclusion criteria and 64% underwent IFD evaluations. In total, 36.4% of episodes documented an infection after initiation of prolonged febrile evaluation, most commonly Clostridioides difficile colitis (6.4%) followed by a true bacterial bloodstream infection (BSI) (5.2%), proven/probable IFD (4.8%), and positive respiratory pathogen panel (3.6%). There was no difference in sinus CTs showing sinusitis (74% vs 63%, p = 0.46), whereas 32% of abdomen/pelvis CTs led to a non‐IFD diagnosis, and 25% of chest CTs showed possible pneumonia. On chest CT, the positive predictive value (PPV) for IFD was 19% for nodules and 14% for tree and bud lesions. BDG had a PPV of 25% for IFD and GM 50%. BAL diagnosed IFD once and pneumocystis jirovecii pneumonia twice.
Conclusions
Chest CTs and abdomen/pelvis CTs provide clinically relevant information during the prolonged febrile neutropenia evaluation, whereas BDG, galactomannan, BAL, and sinus CTs have less certain utility.
This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) ...compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers.
Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery.
One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery.
Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers.
•Lynch syndrome (LS) mutation carriers at high risk for proximal first colorectal cancer (CRC).•Metachronous CRC diagnosed in 27% LS patients after proximal colectomy (PC) for proximal first CRC.•Compared with metachronous CRC diagnosed in 6% LS patients after total & subtotal colectomy (TC + STC).•No significant difference in estimated survival after PC compared with TC + STC through 25 years.•Extra-colonic abdominal-pelvic cancers diagnosed in 30% of LS patients after proximal first CRC.
Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian ...origin. The bulk of these hereditary cases fits the hereditary breast–ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of
BRCA1 and
BRCA2 gene mutations which predispose to the hereditary breast–ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are
MSH2 and
MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.
The Patient-Reported Outcomes Measurement Information System (PROMIS) item banks have been validated for general populations, but their application to high-functioning patient populations remains ...speculative.
To examine the measurement properties of the PROMIS physical function item bank, version 1.0, when applied to individuals representing high levels of physical ability.
Cross-sectional study.
National Collegiate Athletic Association Division I and III collegiate athletic training rooms and intramural events.
A heterogeneous sample of 215 adults from Division I or Division III collegiate or recreational sports volunteered for this study. Participants were divided into 4 groups depending on sport activity and injury status: healthy collegiate (HC; 33 men, 37 women; age = 19.7 ± 1.1 years), injured and currently active in sport (IP; 21 men, 29 women; age = 19.9 ± 1.2 years), injured and currently not active in sport (INP; 12 men, 18 women; age = 19.7 ± 1.3 years), and healthy recreational (HR; 47 men, 18 women; age = 20.1 ± 1.4 years).
Participants completed 2 assessments: (1) an injury-history questionnaire and (2) the PROMIS physical function item bank, version 1.0, in computer-adaptive form. Mean PROMIS physical function scores were determined for each group.
The PROMIS physical function score for the HC group (61.7 ± 6.0) was higher than for the IP (54.9 ± 7.5) and INP (44.1 ± 8.2) groups (P < .001). The IP group had a higher score than the INP group (P < .001). Mean PROMIS scores were not different between the HC and HR participants (mean difference = 1.9, P = .10).
The computer-adaptive PROMIS physical function item bank, version 1.0, accurately distinguished injury status in elite-level athletes on a physical function latent trait continuum. Although it was unable to distinguish HC athletes from HR athletes, exposing a possible ceiling effect, it offers potential for use as an outcome instrument for athletic trainers and other sports medicine clinicians.
The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families.
Our Hereditary Cancer Registry was searched for gynecologic ...and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified.
Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen.
The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.
Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated ...a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
PDF
