Clinical management of atypical ductal hyperplasia on vacuum-assisted biopsy of microcalcifications: External validation study of a decision tree selecting patients eligible for surveillance.

BACKGROUND: Atypical lesions found on percutaneous breast biopsy raise specific management issues. The aim of this study was to validate the previous performance of a decision tree defined by Forgeard et al to select a subset of patients at low-risk of surgical diagnostic upgrade that would be eligible for surveillance. METHODS: A consecutive series of 211 patients diagnosed with ADH on vacuum-assisted biopsy (VAB) of clustered microcalcifications alone, then operated in our institution, was reviewed. Histological findings on percutaneous cores were compared with definitive diagnoses on surgical specimens. The rate of cancer underestimation on VAB was analyzed in the four arms and two management attitudes defined in the scheme, using size and quality of microcalcification removal and the number of ADH foci. RESULTS: Ninety-eight women with ADH met the inclusion criteria. Overall, 20 cancers were diagnosed at surgery, showing a malignancy rate of 44% (17/39 patients) in the surgery group and of 5% (3/59 patients) in the surveillance group, which was not significantly different from the 2% rate in the monitored reference group (p > 0.64). The malignancy rate increased significantly with the size of clustered microcalcifications (0% when < 6mm, 17% when between 6mm and 21 mm, 48% when > 21 mm, p < 0001) and the number of ADH foci on VAB (14% when ≤ 2, 45% when > 2, p < 0.005). CONCLUSION: Our results corroborate - within the limits of large confidence intervals - those obtained with the reference decision tree. Due to statistical uncertainty, however, they need to be prospectively validated in a broader series.

HPV DNA integration site as proof of the origin of ovarian metastasis from endocervical adenocarcinoma: three case reports.

BACKGROUND: Most endocervical adenocarcinomas are human papillomavirus (HPV)-related cancers associated with p16 immunostaining. Ovarian metastasis from cervical cancer is a rare phenomenon, the mechanism of dissemination remains unclear. The diagnosis of metastasis may be difficult to establish when the ovarian neoplasm presents features consistent with primary tumor. Immunohistochemical expression of p16 in ovarian tumors can guide the diagnosis of metastasis from HPV-related cervical cancer, but p16 positivity is nonspecific. Identical HPV genotype in the paired endocervical and ovarian tumors is a better marker for cervical origin, which may also be confirmed by identical HPV integration site. CASE PRESENTATION: Two women presented with HPV18 cervical adenocarcinoma. No signs of disease were visible on MRI after treatment. After several years of follow-up, mucinous ovarian tumors were discovered in both patients. Molecular analyses showed that the ovarian lesions were HPV18-positive; indicating a primary cervical origin. A third woman was diagnosed with grade 1 ovarian endometrioid carcinoma with no peritoneal carcinomatosis. Final histological examination and HPV genotyping revealed HPV18-related in situ endometrioid adenocarcinoma in the endocervix and HPV18-related invasive endometrioid adenocarcinoma in the endometrium and both ovaries. Additional molecular analyses performed in two patients identified the same HPV integration sites in both the ovarian and cervical tumors, confirming that the ovarian mass was a metastasis from the cervical adenocarcinoma. CONCLUSION: We report three new cases of ovarian neoplasia in which the diagnosis of metastasis from cervical cancer was supported by the same HPV genotype and the same integration site in the paired cervical and ovarian tumors. To our knowledge, this is the first report of molecular evidence of the cervical origin of an ovarian metastasis. HPV screening should be performed in ovarian tumors for all patients with history of cervical neoplasia.

Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma.

Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were PIK3CA (25%) followed by FBXW7 (15%), FAT1 (15%), and TRIP12 (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting PIK3CA) and losses of chromosome 11q (affecting ATM). The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy.

Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic MSH2 somatic mutations.

The invalidation of the Mismatch Repair (MMR) system is responsible for a so-called "deficient MMR" phenotype (dMMR) characterized by microsatellite instability and abnormal pattern of expression of MMR proteins in tumor tissue. This phenotype occurs in at least 20% of sporadic endometrial adenocarcinomas by epigenetic silencing of MLH1 gene. It is also observed in virtually all tumors occurring in patients with Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR-pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR-pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome. We report the case of a woman with an early-onset endometrial adenocarcinoma who was suspected to be affected with Lynch syndrome based on tumor dMMR phenotype (MSI associated with loss of expression of MSH2 and MSH6 proteins). After complete germline and somatic evaluations, this phenotype was eventually explained by two MSH2 somatic mutations and the diagnosis of Lynch-like syndrome due to an unidentified MSH2 germline mutation was ruled out. Somatic mosaicism at low mutation rate was unlikely as no mutation was detected by DNA analysis from various tissue samples. Nevertheless, the three patient's children were tested for the two mutations and these tests were negative. Biallelic somatic mutations of one MMR gene is a mechanism of invalidation of the MMR system in sporadic cases. Clinicians have to be aware of this mechanism because of the great clinical implication for the patients and their relatives.

HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report.

Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.

Knowledge, Practice and Self-Efficacy in Evidence-Based Practice among Midwives in East Iran.

OBJECTIVES: The successful implementation of evidence-based practice (EBP) can lead to appropriate and effective midwifery care during pregnancy, childbirth and in the postnatal period. However, levels of knowledge and confidence in one's ability to apply EBP are related to its effective implementation. This study aimed to investigate levels of knowledge, practice of and self-efficacy towards the use of EBP among midwives in East Iran. METHODS: This cross-sectional study took place between January and February 2016 and involved 98 midwives employed at two hospitals and all four urban health care centres in Torbat-e Heydariyeh, Iran. Two subscales of the Evidence-Based Practice Questionnaire were used to assess participants' knowledge and practice of EBP, respectively, while a modified version of a previously described scale was used to determine self-efficacy. RESULTS: A total of 76 midwives participated in the study (response rate: 77.6%). Mean knowledge, practice and self-efficacy scores were 4.48 ± 0.94, 3.53 ± 0.68 and 2.80 ± 0.81, respectively. Significant relationships were found between mean self-efficacy, practice and knowledge scores and proficiency in English language (P = 0.001 each) and statistical methods (P <0.050 each). Additionally, significant relationships were found between knowledge and practice of EBP and proficiency in the use of databases (P <0.050 each). Knowledge and self-efficacy scores were significantly correlated with practice (P = 0.001 each). CONCLUSION: These findings demonstrate a need for improvement in the self-efficacy, practice and knowledge of EBP among midwives in East Iran. Interventions that promote these factors may help increase the use of EBP in this population.

Mutational analysis of anal cancers demonstrates frequent PIK3CA mutations associated with poor outcome after salvage abdominoperineal resection.

BACKGROUND: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment. METHODS: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis. RESULTS: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025). CONCLUSIONS: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA-mutated patients.

Diffusion-weighted MRI for uveal melanoma liver metastasis detection.

OBJECTIVES: We aimed to assess the sensitivity of diffusion-weighted (DW) magnetic resonance (MR) imaging for the detection of pathologically confirmed uveal melanoma liver metastases (UMLM). METHODS: Twenty patients who underwent complete surgical resection of their UMLM (N = 83) were included. Pre-surgery liver MR imaging included T2-weighted, T1-weighted, DW and dynamic-gadolinium-enhanced MR sequences. Two radiologists independently reviewed three sets of images (DW / morphologic-dynamic / combined) for each patient using intraoperative and pathological findings as a standard of reference. RESULTS: The sensitivities of the morphologic-dynamic and DW images for UMLM detection were 63 % and 59 %, respectively, for reader #1 (R1) and 64 % and 53 %, for reader #2 (R2). Sensitivity of the combined set was higher than sensitivity in the two other sets (R1:69 %, R2:67 %), but was only significantly different than the sensitivity of the DW images (McNemar test). For the three sets and the two readers, the sensitivity for UMLM smaller than 5 mm (37-46 %) was significantly lower than that for UMLM larger than 5 mm (67-90 %). The sensitivity for UMLM located in the subcapsular area (41-54 %) was significantly lower than that for intraparenchymal UMLM (68-86 %) (Chi-square test). CONCLUSION: Our study shows that the addition of DW imaging to morphologic-dynamic images does not significantly increase MR sensitivities for UMLM detection. KEY POINTS: • The MR imaging sensitivity for uveal melanoma liver metastases (UMLM) was 69 %. • Addition of DW imaging to morphologic-dynamic images does not increase sensitivity significantly. • Sensitivity for subcapsular UMLM was significantly lower than sensitivity for intraparenchymal UMLM. • The T2 shortening effect does not appear to influence lesion detection in DWI.