Accuracy of Sentinel Lymph Node Mapping After Previous Hysterectomy in Patients with Occult Cervical Cancer.

BACKGROUND In patients with a diagnosis of occult cervical cancer made on a hysterectomy specimen after surgery for a benign indication, lymph node assessment is crucial to determine treatment. We aimed to compare sentinel lymph node (SLN) mapping between patients with postoperative diagnosis of occult cervical carcinoma and patients with cervical cancer and uterus in situ. METHODS A retrospective analysis of cervical cancer patients International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIA disease undergoing laparoscopic SLN mapping was performed. Patients were divided into two groups: those with a diagnosis of occult cervical cancer made on a hysterectomy specimen (group 1) and those with a diagnosis of cervical cancer and uterus in situ (group 2). Tracers used for SLN mapping included technetium-99m ((99m)Tc), blue dye, and indocyanine green. After detection and excision, the SLN was sent for frozen section analysis, and the planned surgical procedure was aborted in case of metastatic disease in favor of a chemoradiotherapeutic treatment. RESULTS Groups 1 and 2 included 9 and 62 patients, respectively. Clinicopathologic characteristics were similar among the two groups. Overall and bilateral detection rates were 66.6 and 33.3 and 95.1 and 87 % in groups 1 and 2, respectively (p < 0.05). No false-negative SLNs were identified in either group, with a negative predictive value of 100 %. CONCLUSIONS SLN mapping in occult cervical cancer patients has lower detection rates compared to patients with uterus in situ. In these patients, proper management of their disease has already failed before diagnosis, and additional mistakes may definitely compromise attempts at cure

Fetal Cerebellar Vermis Circumference Measured by 2-Dimensional Ultrasound Scan: Reference Range, Feasibility and Reproducibility.

Purpose: To provide 2-dimensional ultrasonographic (2D-US) normograms of cerebellar vermis biometry, as well as to evaluate the feasibility and the reproducibility of these measurements in clinical practice. Materials and Methods: A prospective cross-sectional study of 328 normal singleton pregnancies between 18 and 33 weeks of gestation. Measurements of the fetal cerebellar vermis circumference (VC) in the mid-sagittal plane were performed by both a senior and a junior operator using 2D-US. VC as a function of gestational age (GA) was expressed by regression equations. In 24 fetuses 3-dimensional (3D) reconstructed planes were obtained in order to allow comparisons with 2D-US measurements. The agreement between 2D and 3D measurements and the interobserver variability were assessed by interclass correlation coefficients (ICC). Results: Satisfactory vermis measurements could be obtained in 89.9% of cases. The VC (constant= - 12.21; slope=2.447; r=0.887, p<0.0001) correlated linearly with GA. A high degree of consistency was observed between 2D and 3D ultrasound measurements (ICC=0.846 95% CI 679-0.930) as well as between measurements obtained by different examiners (ICC=0.890 95% CI 989-0.945). Conclusion: 2-dimensional ultrasonographic measurements of cerebellar vermis throughout gestation in the mid-sagittal view seem to be feasible and reproducible enough to be potentially used in clinical practice. Such measurements may supply a tool for accurate identification of posterior fossa anomalies, providing the basis for proper counseling and management and of these conditions

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Tailored treatment including radical prostatectomy and radiation therapy + androgen deprivation therapy versus exclusive radical prostatectomy in high-risk prostate cancer patients: results from a prospective study

Purpose To evaluate outcomes of patients with high risk prostate cancer (PCa) who underwent radical prostatectomy (RP) in a context of a multidisciplinary approach including adjuvant radiation (RT) + androgen deprivation therapy (ADT). Matherials and Methods 244 consecutive patients with high risk localized PCa underwent RP and bilateral extended pelvic lymph node dissection at our institution. Adjuvant RT + 24 months ADT was carried out in subjects with pathological stage ≥ T3N0 and/or positive surgical margins or in patients with local relapse. Results After a median follow-up was 54.17 months (range 5.4-117.16), 13 (5.3%) subjects had biochemical progression, 21 (8.6%) had clinical progression, 7 (2.9%) died due to prostate cancer and 15 (6.1%) died due to other causes. 136 (55.7%) patients did not receive any adjuvant treatment while 108 (44.3%) received respectively adjuvant or salvage RT+ADT. Multivariate Cox proportional hazard analysis showed that pre-operative PSA value at diagnosis is a significant predictive factor for BCR (HR: 1.04, p < 0.05) and that Gleason Score 8-10 (HR: 2.4; p<0.05) and PSMs (HR: 2.01; p < 0.01) were significant predictors for clinical progression. Radical prostatectomy group was associated with BPFS, CPFS, CSS and OS at 5-years of 97%, 90%, 95% and 86% respectively, while adjuvant radiation + androgen deprivation therapy group was associated with a BPFS, CPFS and CSS at 5-years of 91%, 83%, 95% and 88%, without any statistical difference. Conclusions Multimodality tailored treatment based on RP and adjuvant therapy with RT+ADT achieve similar results in terms of OS after 5-years of follow-up

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Peer reviewedPublisher PD

Genome-wide association study of germline variants and breast cancer-specific mortality.

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P &lt; 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.ConclusionsWe uncovered germline variants on chromosome 7 at BFDP &lt; 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies