Anal Cancer and Anal Intraepithelial Neoplasia Risk among Patients Treated for HPV-Related Gynecological Diseases-A Systematic Review.

BACKGROUND: The most important causative agent of neoplasms in the anogenital area is the human papillomavirus (HPV). Due to the anatomical proximity of the genital and anus area and the ease with which HPV infection is transmitted, it seems that patients after the treatment of HPV-related gynecological diseases may have an increased risk of developing a second HPV-related neoplasm anal cancer. The aim of this study was to determine the risk of anal intraepithelial neoplasia (AIN) and anal cancer (AC) among patients after the treatment of HPV-related gynecological diseases. METHODS: We conducted a comprehensive review of the available literature from multiple databases. The study was performed following Cochrane Reviewers' Handbook and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 guidelines. Moreover, we assessed the quality of each study using QUADAS-2. RESULTS: Twenty-five studies were included in the final analysis. Patients after the treatment of HPV-related gynecological diseases have a significantly higher risk of AC (mean standardized incidence ratio (SIR) = 5.387, mean incidence risk (IR) = 0.096%, mean IR per 100,000 person-years = 10.37) and AIN (mean IR = 23.683%) compared to the population risk. CONCLUSIONS: patients with HPV-related gynecological diseases should constitute a group for which an appropriate primary and secondary screening for AC should be introduced.

Analysis of BRCA1 and BRCA2 alternative splicing in predisposition to ovarian cancer.

BACKGROUND: The mRNA splicing is regulated on multiple levels, resulting in the proper distribution of genes' transcripts in each cell and maintaining cell homeostasis. At the same time, the expression of alternative transcripts can change in response to underlying genetic variants, often missed during routine diagnostics. AIM: The main aim of this study was to define the frequency of aberrant splicing in BRCA1 and BRCA2 genes in blood RNA extracted from ovarian cancer patients who were previously found negative for the presence of pathogenic alterations in the 25 most commonly analysed ovarian cancer genes, including BRCA1 and BRCA2. MATERIAL AND METHODS: Frequency and spectrum of splicing alterations in BRCA1 and BRCA2 genes were analysed in blood RNA from 101 ovarian cancer patients and healthy controls (80 healthy women) using PCR followed by gel electrophoresis and Sanger sequencing. The expression of splicing events was examined using RT-qPCR. RESULTS: We did not identify any novel, potentially pathogenic splicing alterations. Nevertheless, we detected six naturally occurring transcripts, named BRCA1ΔE9-10, BRCA1ΔE11, BRCA1ΔE11q, and BRCA2ΔE3, BRCA2ΔE12 and BRCA2ΔE17-18 of which three (BRCA1ΔE11q, BRCA1ΔE11 and BRCA2ΔE3) were significantly higher expressed in the ovarian cancer cohort than in healthy controls (p ≤ 0.0001). CONCLUSIONS: This observation indicates that the upregulation of selected naturally occurring transcripts can be stimulated by non-genetic mechanisms and be a potential systemic response to disease progression and/or treatment. However, this hypothesis requires further examination.

Recommendations of the Polish Society of Gynaecologists and Obstetricians, Polish Paediatric Society, Polish Society of Family Medicine, Polish Society of Vaccinology, Polish Society of Oncological Gynaecology and Polish Society of Colposcopy and Pathophysiology of the Uterine Cervix on prophylactic vaccinations against infections with human papillomaviruses in Poland.

Several hundred million people are infected with genital genotypes of the human papillomavirus (HPV) annually in the world. The infections transmitted mainly through sexual routes are usually asymptomatic, but can lead to the development of cervical, vulvar, vaginal, anal, penile cancers, some head and neck cancers and genital warts (condylomas). The fraction HPV-related cancers range from nearly 100% in the case of cervical cancer to several/over a dozen percent in the case of other cancers and diseases. There are no effective drugs against HPV, but prophylactic HPV vaccines are available free of charge in immunization programmes in many countries around the world. In Poland, HPV vaccinations have so far been executed out on the pocket or in free-of-charge, local-governmental prevention programs, but the vaccination coverage of the target population does not exceed 10%. From November 2021, one of the vaccines is available with a 50% reimbursement, work is underway to reimburse the next ones, and the National Oncology Strategy assumes the implementation of the HPV immunization programmes and vaccination of 60% of the teen population by 2028. Three prophylactic HPV vaccines are registered. All of them are safe and their effectiveness in the prevention of diseases caused by vaccine genotypes reaches almost 100%, provided that full post-vaccination immunity is obtained before the contact with the virus. Girls aged 11-13 are the priority target cohort for HPV vaccination in Poland. The implementation of routine, free-of-charge HPV immunization in the Preventive Immunization Program (PIP) for all adolescents should be pursued. Persons over the age of 13 may also benefit from HPV vaccination and should be vaccinated according to product specifications. In addition to free access under the PIP, the key element for the success of the implementation of HPV vaccinations in Poland will be the education of medical personnel and parents of adolescents to be vaccinated.

Ultrasound-Guided Trans-Uterine Cavity Core Needle Biopsy of Uterine Myometrial Tumors to Differentiate Sarcoma from a Benign Lesion-Description of the Method and Review of the Literature.

Uterine sarcomas are rare, aggressive tumors with poor prognosis that can be further negatively affected by inadequate surgical approaches such as morcellation. There are no clinical and radiologic criteria for differentiating leiomyoma from malignant uterine tumors. However, some ultrasonography and magnetic resonance imaging findings may be informative. We present a technique of ultrasound-guided trans-uterine cavity (UG-TUC) core needle biopsy for uterine lesions. As the procedure is an in-organ biopsy, there is no risk of needle canal contamination. The technique also enables the biopsy of lesions inaccessible by the transvaginal tru-cut biopsy. The core needle of the automatic biopsy system is inserted via the cervical canal into the uterine cavity and is directed and activated at the myometrial lesion under ultrasound control. The standard local treatment of localized uterine sarcomas is en bloc total hysterectomy; for fibroids, there are multiple options including conservative management or tumorectomy and tumor morcellation using minimally invasive techniques. Fragmentation of the sarcoma significantly worsens oncologic outcomes and should therefore be avoided. The UG-TUC core needle biopsy of uterine lesions can complement imaging to obtain sufficient material for histologic and molecular analyses of suspected or undetermined lesions, thus facilitating treatment planning and decreasing the risk of unsuspected sarcomas.

Total mesometrial resection (TMMR) for cervical cancer FIGO IB-IIA: first results from the multicentric TMMR register study.

OBJECTIVE: The surgical concept of total mesometrial resection (TMMR) and therapeutic lymphadenectomy (tLNE) for the treatment of early cervical cancer is based on the ontogenetic cancer field model. Unicentric data show excellent locoregional control rates without adjuvant chemoradiation. However, there are so far no prospective, multicentric data supporting the method. METHODS: The multicentric TMMR register study was designed to answer the question whether the concept of TMMR+tLNE could be transferred to different centers and surgeons without compromising the outstanding oncologic results described in a unicentric setting. RESULTS: In 116 patients with cervical cancer stages IB-IIA, (International Federation of Gynecology and Obstetrics [FIGO] 2018), who underwent TMMR/tLNE, 25.0% were lymph node-positive. pT stages were pT1a in 3 patients (2.6%), pT1b1 in 82 (70.7%), pT1b2 in 18 (15.5%), pT2a in 4 (3.5%) and pT2b in 9 (7.8%). The overall recurrence rate was 7.8% in a median follow-up time of 24 months (6-80). Locoregional recurrences occurred in 6.0% of patients. One patient (0.9%) died from the disease during the observation period. CONCLUSION: These are the first multicentric data on the surgical concept of TMMR and tLNE for the treatment of cervical cancer FIGO IB-IIA. We were able to reproduce the excellent oncologic data described for the method albeit with a relatively short median observation time. A randomized controlled trial seems warranted to definitely establish TMMR+tLNE as the method of choice for the treatment of early cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01819077.

Accuracy of Ultrasonography and Magnetic Resonance Imaging for Preoperative Staging of Cervical Cancer-Analysis of Patients from the Prospective Study on Total Mesometrial Resection.

We aimed to evaluate the accuracy of ultrasonography with gynecologic examination performed by a gynecological oncologist and magnetic resonance imaging (MRI) interpreted by a radiologist for the local and regional staging of patients with early-stage cervical cancer. The study was a single-site sub-analysis of the multi-institutional prospective, observational Total Mesometrial Resection (TMMR) Register Study, which included all consecutive study patients from Gdynia Oncology Center. Imaging results were compared with pathology findings. A total of 58 consecutive patients were enrolled, and 50 underwent both ultrasonography and MRI. The accuracy of tumor detection and measurement errors was comparable across ultrasonography and MRI. There were no significant differences between ultrasonography and MRI in the accuracy of detecting parametrial involvement (92%, confidence interval (CI) 84-100% vs. 76%, CI 64-88%, p = 0.3), uterine corpus infiltration (94%, CI 87-100% vs. 86%, CI 76-96%, p = 0.3), and vaginal fornix involvement (96%, CI 91-100% vs. 76%, CI 64-88%, p = 0.3). The importance of uterine corpus involvement for the first-line lymph node metastases was presented in few cases. The accuracy of ultrasonography was higher than MRI for correctly predicting tumor stage: International Federation of Gynecology and Obstetrics (FIGO)-2018: 69%, CI 57-81% vs. 42%, CI 28-56%, p = 0.002, T (from TNM system): 79%, CI 69-90% vs. 52%, CI 38-66%, p = 0.0005, and ontogenetic tumor staging: 88%, CI 80-96% vs. 70%, CI 57-83%, p = 0.005. For patients with cervical cancer who are eligible for TMMR and therapeutic lymphadenectomy, the accuracy of ultrasonography performed by gynecological oncologists is not inferior to that of MRI interpreted by a radiologist for assessing specific local parameters, and is more accurate for local staging of the disease and is thus more clinically useful for planning adequate surgical treatment.

Accuracy of Pretreatment Ultrasonography Assessment of Intra-Abdominal Spread in Epithelial Ovarian Cancer: A Prospective Study.

The aim of this study was to test the accuracy of ultrasonography performed by gynecological oncologists for the preoperative assessment of epithelial ovarian cancer (EOC) spread in the pelvis and abdominal cavity. A prospective, observational cohort study was performed at a single tertiary cancer care unit. Patients with suspected EOC were recruited and underwent comprehensive transvaginal and abdominal ultrasonography performed by a gynecological oncologist. Sixteen intra-abdominal localizations and parameters were assessed using ultrasonography and compared with surgical-pathological status (reference standard). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were calculated. Differences were analyzed using Fisher's exact and chi-square tests. Ultimately, we included 132 patients (median age 62 years), of whom 67% were in stage IIIC-IVB and 72% had serous cancer. Overall prediction accuracies for the involvement of the omentum, small bowel mesentery root, and frozen pelvis, and detecting ascites were >90%. Detecting the involvement of the pelvis peritoneum, liver and spleen hilum, and rectosigmoid colon, and predictions of disease stage and residual disease had overall accuracies of 80-90%. The lowest accuracy was for involvement of the abdominal peritoneum (69%) and diaphragm peritoneum (right 71%; left 75%) and surgical complexity prediction (77%). Stratification of results by presence or absence of ascites revealed significantly higher specificity of ultrasonography (clinically meaningful) for assessments of the abdominal/pelvic peritoneum, spleen hilum, and rectum wall, if there were ascites. A gynecological oncologist, experienced in surgery and sonology, performing comprehensive ultrasonography on patients with EOC can accurately detect intraperitoneal lesions and recognize critical disease manifestations and predict stage, surgical complexity, and residual disease, which allow accurate qualification of patients for primary debulking surgery or neoadjuvant chemotherapy.

BARD1 Autoantibody Blood Test for Early Detection of Ovarian Cancer.

BACKGROUND: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease. METHODS: Autoantibody reactivity to 20 epitopes of BARD1 and concentration of cancer antigen 125 (CA125) were assessed in 480 serum samples of OC patients and healthy controls. Autoantibody reactivity and CA125 were also tested for 261 plasma samples of OC with or without mutations in BRCA1/2, BARD1, or other predisposing genes, and healthy controls. Lasso statistic regression was applied to measurements to develop an algorithm for discrimination between OC and controls. Findings and interpretation: Measurement of autoantibody binding to a number of BARD1 epitopes combined with CA125 could distinguish OC from healthy controls with high accuracy. This BARD1-CA125 test was more accurate than measurements of BARD1 autoantibody or CA125 alone for all OC stages and menopausal status. A BARD1-CA125-based test is expected to work equally well for average-risk women and high-risk women with hereditary breast and ovarian cancer syndrome (HBOC). Although these results are promising, further data on well-characterised clinical samples shall be used to confirm the potential of the BARD1-CA125 test for ovarian cancer screening.

Lung and Intercostal Upper Abdomen Ultrasonography for Staging Patients with Ovarian Cancer: A Method Description and Feasibility Study.

A detailed transabdominal and transvaginal ultrasound examination, performed by an expert examiner, could render a similar diagnostic performance to computed tomography for assessing pelvic/abdominal tumor spread disease in women with epithelial ovarian cancer (EOC). This study aimed to describe and assess the feasibility of lung and intercostal upper abdomen ultrasonography as pretreatment imaging of EOC metastases of supradiaphragmatic and subdiaphragmatic areas. A preoperative ultrasound examination of consecutive patients suspected of having EOC was prospectively performed using transvaginal, transabdominal, and intercostal lung and upper abdomen ultrasonography. A surgical-pathological examination was the reference standard to ultrasonography. Among 77 patients with histologically proven EOC, supradiaphragmatic disease was detected in 13 cases: pleural effusions on the right (n = 12) and left (n = 8) sides, nodular lesions on diaphragmatic pleura (n = 9), focal lesion in lung parenchyma (n = 1), and enlarged cardiophrenic lymph nodes (n = 1). Performance (described with area under the curve) of combined transabdominal and intercostal upper abdomen ultrasonography for subdiaphragmatic areas (n = 77) included the right and left diaphragm peritoneum (0.754 and 0.575 respectively), spleen hilum (0.924), hepatic hilum (0.701), and liver and spleen parenchyma (0.993 and 1.0 respectively). It was not possible to evaluate the performance of lung ultrasonography for supradiaphragmatic disease because only some patients had this region surgically explored. Preoperative lung and intercostal upper abdomen ultrasonography performed in patients with EOC can add valuable information for supradiaphragmatic and subdiaphragmatic regions. A reliable reference standard to test method performance is an area of future research. A multidisciplinary approach to ovarian cancer utilizing lung ultrasonography may assist in clinical decision-making.

Performance of Selected Models for Predicting Malignancy in Ovarian Tumors in Relation to the Degree of Diagnostic Uncertainty by Subjective Assessment With Ultrasound.

OBJECTIVES: The study's main aim was to evaluate the relationship between the performance of predictive models for differential diagnoses of ovarian tumors and levels of diagnostic confidence in subjective assessment (SA) with ultrasound. The second aim was to identify the parameters that differentiate between malignant and benign tumors among tumors initially diagnosed as uncertain by SA. METHODS: The study included 250 (55%) benign ovarian masses and 201 (45%) malignant tumors. According to ultrasound findings, the tumors were divided into 6 groups: certainly benign, probably benign, uncertain but benign, uncertain but malignant, probably malignant, and certainly malignant. The performance of the risk of malignancy index, International Ovarian Tumor Analysis assessment of different neoplasias in the adnexa model, and International Ovarian Tumor Analysis logistic regression model 2 was analyzed in subgroups as follows: SA-certain tumors (including certainly benign and certainly malignant) versus SA-probable tumors (probably benign and probably malignant) versus SA-uncertain tumors (uncertain but benign and uncertain but malignant). RESULTS: We found a progressive decrease in the performance of all models in association with the increased uncertainty in SA. The areas under the receiver operating characteristic curve for the risk of malignancy index, logistic regression model 2, and assessment of different neoplasias in the adnexa model decreased between the SA-certain and SA-uncertain groups by 20%, 28%, and 20%, respectively. The presence of solid parts and a high color score were the discriminatory features between uncertain but benign and uncertain but malignant tumors. CONCLUSIONS: Studies are needed that focus on the subgroup of ovarian tumors that are difficult to classify by SA. In cases of uncertain tumors by SA, the presence of solid components or a high color score should prompt a gynecologic oncology clinic referral.

Ultrasound and Clinical Preoperative Characteristics for Discrimination Between Ovarian Metastatic Colorectal Cancer and Primary Ovarian Cancer: A Case-Control Study.

The aim of this study was to describe the clinical and sonographic features of ovarian metastases originating from colorectal cancer (mCRC), and to discriminate mCRC from primary ovarian cancer (OC). We conducted a multi-institutional, retrospective study of consecutive patients with ovarian mCRC who had undergone ultrasound examination using the International Ovarian Tumor Analysis (IOTA) terminology, with the addition of evaluating signs of necrosis and abdominal staging. A control group included patients with primary OC. Clinical and ultrasound data, subjective assessment (SA), and an assessment of different neoplasias in the adnexa (ADNEX) model were evaluated. Fisher's exact and Student's t-tests, the area under the receiver-operating characteristic curve (AUC), and classification and regression trees (CART) were used to conduct statistical analyses. In total, 162 patients (81 with OC and 81 with ovarian mCRC) were included. None of the patients with OC had undergone chemotherapy for CRC in the past, compared with 40% of patients with ovarian mCRC (p < 0.001). The ovarian mCRC tumors were significantly larger, a necrosis sign was more frequently present, and tumors had an irregular wall or were fixed less frequently; ascites, omental cake, and carcinomatosis were less common in mCRC than in primary OC. In a subgroup of patients with ovarian mCRC who had not undergone treatment for CRC in anamnesis, tumors were larger, and had fewer papillations and more locules compared with primary OC. The highest AUC for the discrimination of ovarian mCRC from primary OC was for CART (0.768), followed by SA (0.735) and ADNEX calculated with CA-125 (0.680). Ovarian mCRC and primary OC can be distinguished based on patient anamnesis, ultrasound pattern recognition, a proposed decision tree model, and an ADNEX model with CA-125 levels.

Bayesian multilevel model of micro RNA levels in ovarian-cancer and healthy subjects.

In transcriptomics, micro RNAs (miRNAs) has gained much interest especially as potential disease indicators. However, apart from holding a great promise related to their clinical application, a lot of inconsistent results have been published. Our aim was to compare the miRNA expression levels in ovarian cancer and healthy subjects using the Bayesian multilevel model and to assess their potential usefulness in diagnosis. We have analyzed a case-control observational data on expression profiling of 49 preselected miRNA-based ovarian cancer indicators in 119 controls and 59 patients. A Bayesian multilevel model was used to characterize the effect of disease on miRNA levels controlling for differences in age and body weight. The difference between the miRNA level and health status of the patient on the scale of the data variability were discussed in the context of their potential usefulness in diagnosis. Additionally, the cross-validated area under the ROC curve (AUC) was used to assess the expected out-of-sample discrimination index of a different sets of miRNAs. The proposed model allowed us to describe the set of miRNA levels in patients and controls. Three highly correlated miRNAs: miR-101-3p, miR-142-5p, miR-148a-3p rank the highest with almost identical effect sizes that ranges from 0.45 to 1.0. For those miRNAs the credible interval for AUC ranged from 0.63 to 0.67 indicating their limited discrimination potential. A little benefit in adding information from other miRNAs was observed. There were several miRNAs in the dataset (miR-604, hsa-miR-221-5p) for which inferences were uncertain. For those miRNAs more experimental effort is needed to fully assess their effect in the context of new hits discovery and usefulness as disease indicators. The proposed multilevel Bayesian model can be used to characterize the panel of miRNA profile and to assess the difference in expression levels between healthy and cancer individuals.

Development and validation of a model that includes two ultrasound parameters and the plasma D-dimer level for predicting malignancy in adnexal masses: an observational study.

BACKGROUND: Pre-operative discrimination of malignant from benign adnexal masses is crucial for planning additional imaging, preparation, surgery and postoperative care. This study aimed to define key ultrasound and clinical variables and develop a predictive model for calculating preoperative ovarian tumor malignancy risk in a gynecologic oncology referral center. We compared our model to a subjective ultrasound assessment (SUA) method and previously described models. METHODS: This prospective, single-center observational study included consecutive patients. We collected systematic ultrasound and clinical data, including cancer antigen 125, D-dimer (DD) levels and platelet count. Histological examinations served as the reference standard. We performed univariate and multivariate regressions, and Bayesian information criterion (BIC) to assess the optimal model. Data were split into 2 subsets: training, for model development (190 observations) and testing, for model validation (n = 100). RESULTS: Among 290 patients, 52% had malignant disease, including epithelial ovarian cancer (72.8%), metastatic disease (14.5%), borderline tumors (6.6%), and non-epithelial malignancies (4.6%). Significant variables were included into a multivariate analysis. The optimal model, included three independent factors: solid areas, the color score, and the DD level. Malignant and benign lesions had mean DD values of 2.837 and 0.354 µg/ml, respectively. We transformed established formulae into a web-based calculator ( http://gin-onc-calculators.com/gynonc.php ) for calculating the adnexal mass malignancy risk. The areas under the curve (AUCs) for models compared in the testing set were: our model (0.977), Simple Rules risk calculation (0.976), Assessment of Different NEoplasias in the adneXa (ADNEX) (0.972), Logistic Regression 2 (LR2) (0.969), Risk of Malignancy Index (RMI) 4 (0.932), SUA (0.930), and RMI3 (0.912). CONCLUSIONS: Two simple ultrasound predictors and the DD level (also included in a mathematical model), when used by gynecologist oncologist, discriminated malignant from benign ovarian lesions as well or better than other more complex models and the SUA method. These parameters (and the model) may be clinically useful for planning adequate management in the cancer center. The model needs substantial validation.

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients.

Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals.

Detection of BRCA1/2 mutations in circulating tumor DNA from patients with ovarian cancer.

Approximately 25% of patients with ovarian cancer harbor a pathogenic BRCA1/2 mutation that has been associated with favorable responses for targeted therapy with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type individuals. The overall frequency of germline and somatic BRCA1/2 alterations is estimated at 13-15% and 3-10%, respectively. A high incidence of BRCA1/2 somatic variants significantly increases the number of patients eligible for treatment with PARP1 inhibitors. Here, we assessed circulating tumor DNA (ctDNA) from 121 patients with ovarian cancer for BRCA1/2 mutational analysis by next generation sequencing. A total number of patients carrying the pathogenic BRCA1/2 variants was 30/121 (24.8%), including 22 and 7 individuals with exclusively germline or somatic mutations, respectively and one patient with variants of both origin. Among this cohort, more than one known pathogenic BRCA1 and/or BRCA2 alterations were identified in 7/30 individuals. The most recurrent mutations were detected in the BRCA1 gene: c.5266dupC (p.Gln1756Profs*74) with the frequency of ~18%, followed by c.3756_3759del (p.Ser1253Argfs*10) and c.181T>G (p.Cys61Gly). In seven (5.8%) patients, coincidence of two or more BRCA1/2 pathogenic mutations have been identified. Our results clearly demonstrate that the detection of both germline and somatic BRCA1/2 mutations in ctDNA from ovarian cancer patients is feasible and may be a valuable complementary tool for identification of somatic alterations when the standard diagnostic procedures are insufficient. Finally, ctDNA can potentially allow to monitor the efficacy of PARP1 inhibitors and to detect a secondary reversion BRCA1/2 mutations.

Drainage of malignant ascites: patient selection and perspectives.

Malignant ascites (MA) is a sign of advanced cancer and poor prognosis. MA can result in impairment in quality of life (QOL) and significant symptoms. As a supportive treatment, ascites can be drained by paracentesis (PC), percutaneously implanted catheters (tunneled, untunneled, central venous catheters), or peritoneal ports, or peritoneovenous shunts. The aim of this study was to evaluate the effectiveness, safety, and patient-reported outcomes (PRO) of different drainage methods for the management of MA. A systematic review of the literature was performed, and 32 original articles met the inclusion criteria. Patients selected for permanent drain insertion demonstrated symptoms related to MA and had undergone repeated PC. The primary focus of the reviewed articles was procedural safety issues. The rate of technical success of drainage device installation was 100%. Most patients experienced improvements in symptom control after ascites drainage. When analyzed together, 19.7% (255/1297) of patients experienced any complication and 6.2% (81/1297) experienced serious adverse events during MA drainage. Complications were reported for every drainage method; however, the least occurred after PC or central venous catheter, while the most serious occurred after peritoneovenous shunts. Adverse events were as follows: catheter obstruction: 4.4%, infection: 4.1%, leakage: 3.5%, catheter dislodgment: 2.3%, hypotension: 0.6%, injuries during device insertion: 0.6%, renal impairment: 0.5%, electrolyte imbalance: 0.2%, other: 3.6%. PRO and QOL endpoints were available for 12 studies. When PRO were measured using an interview, a significant improvement in symptom control and QOL was reported in almost all patients. Once standardized questionnaires were used, improvements in symptomatic scores and role functioning were observed. Deterioration was observed in cognitive and emotional subscales. MA drainage is a safe and effective method to control symptoms associated with ascites, and should be perceived as a supportive care, that can be applied for those who need it at any time of their cancer trajectory. Patient selection should be performed using a thorough assessment of symptoms and QOL, and should not be delayed.

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.

Analysis of large mutations in BARD1 in patients with breast and/or ovarian cancer: the Polish population as an example.

Only approximately 50% of all familial breast cancers can be explained by known genetic factors, including mutations in BRCA1 and BRCA2. One of the most extensively studied candidates for breast and/or ovarian cancer susceptibility is BARD1. Although it was suggested that large mutations may contribute substantially to the deleterious variants of BARD1, no systematic study of the large mutations in BARD1 has been performed. To further elucidate the role of large mutations in BARD1, we designed a multiplex ligation-dependent probe amplification (MLPA) assay and performed an analysis of 504 women with a familial breast and/or ovarian cancer and 313 patients with ovarian cancer. The investigation did not reveal any large mutations in the BARD1 gene. Although the analysis was not focused on identification of small mutations, we detected seven deleterious or potentially deleterious point mutations, which contribute substantially to the total number of BARD1 mutations detected so far. In conclusion, although we cannot exclude the presence of large mutations in BARD1, our study indicates that such mutations do not contribute substantially to the risk of breast and/or ovarian cancer. However, it has to be noted that our results may be specific to the Polish population.

Usefulness of diagnostic indices comprising clinical, sonographic, and biomarker data for discriminating benign from malignant ovarian masses.

The objective of this study was to review the accuracy of indices combining several diagnostic variables, in comparison to other models, sonography alone, and biomarker assays, for predicting benign or malignant ovarian lesions. Different single modalities were reviewed. The most useful complex models were International Ovarian Tumor Analysis (IOTA) sonographic logistic regression model 2 (area under the curve, 0.949), risk of malignancy index-cancer antigen 125-human epididymis protein 4 (0.950), risk of malignancy algorithm (0.953), pelvic mass score (0.960), non-IOTA logistic regression model (0.970), and histoscanning score logistic regression model (0.970). None of the indices was superior to an expert subjective sonographic assessment (0.968). For women with adnexal tumors, indices with high accuracy are available that are applicable in clinical practice and comparable to an expert subjective sonographic assessment for discriminating benign from malignant masses.