Vulvar sebaceous hyperplasia - a problematic dermatosis of the vulva.

Sebaceous glandular hyperplasia (SGH) is a benign form of skin pathology, occurring in approximately one percent of the population. Risk factors for the SGH include advanced age, male sex, exposure to UV radiation and immunosuppression. The pathogenesis of SGH involves hormonal changes, is also regulated by insulin levels, thyroid stimulating hormone (TSH) and cortisol. SGH manifests itself as solitary or multiple light-yellow lumps, 2-3 mm big, with a smooth surface and a central umbilical depression. The vulvar localization of lesions is extremely rare and presents with a polymorphous clinical picture, posing a major diagnostic problem. A 40-year-old patient presented to the clinic due to vulvar skin lesions, periodically with the swelling of the labia and itching, with the symptoms deteriorating for approximately two years. The patient has been consulted by several doctors; however, the diagnosis has not been established. She did not receive adequate treatment either. On physical examination, attention was drawn to the overgrown labia minora - especially on the right side - with a network of abnormal vessels and numerous small papular lesions. SGH was diagnosed, based on the samples collected from the vulva. The patient was recommended isotretinoin therapy and referred to a dermatologist for a consultation. The presented case of vulvar SGH is interesting and rare. It is a diagnostic challenge with no established treatment standards. Nonetheless, SGH should be considered in the differential diagnosis of vulvar skin lesions. The comprehensive and interdisciplinary care is needed to help patients struggling with this insidious condition.

Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma.

Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient-derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928-40. ©2018 AACR.

New directions in cervical cancer prophylaxis worldwide and in Poland - Case study of the Polish rural female population.

INTRODUCTION: Cervical cancer is one of the most frequent malignant neoplasms in females. Such neoplasms can be almost completely eliminated by means of adequate primary and secondary prophylaxis. The most developed countries focus their attention on the improvement of prophylaxis systems, test quality, and efficacy improvement, as well as on the expansion of the primary prophylaxis. In Poland, the discussions focus on the improvement of the malfunctioning population programme. OBJECTIVE: Drawing on recent research findings, the article presents current Polish and global recommendations with regard to screening tests for cervical cancer. The results of the Population Programme of Prophylaxis and Early Detection of Cervical Cancer are discussed in the context of current trends of healthy behaviour among women inhabiting rural areas. DESCRIPTION OF THE STATE OF KNOWLEDGE: In the future, it will be relevant to increase the number of human papillary virus (HPV) tests as part of the prophylaxis programme, especially among the high risk patient group. In particular, there is a necessity to increase the number of vaccinations among young women, especially before the beginning of their sexual activity, as well as to establish new strategies of secondary prophylaxis in this group. At present, women who had been vaccinated should undergo routine screening. In Poland, the report based on SIMP registry (IT System of Prophylaxis Monitoring), shows that only 27% of the 3.3 million of invited women participated in the cytology tests. The data analysis shows that women living in rural areas more often respond and participate in the tests, compared to women living in the cities (39.3% vs. 16.8%).

Photodynamic therapy in the treatment of vulvar lichen sclerosus.

BACKGROUND: Vulvar lichen sclerosus is a chronic and incurable disease that causes various unpleasant symptoms and serious consequences. OBJECTIVE: The purpose of the study was to assess the effectiveness of photodynamic therapy in the treatment of vulvar lichen sclerosus. METHODS: Participants in the study included 102 female patients aged 19-85 suffer from vulvar lichen sclerosus. The patients underwent photodynamic therapy (PDT). In the course of PDT the 5% 5- aminolevulinic acid was used in gel form. The affected areas were irradiated with a halogenic lamp PhotoDyn 501 (590-760nm) during a 10-min radiation treatment. The treatment was repeated weekly for 10 weeks. RESULT: PDT has brought about a good therapeutic effect (complete or partial clinical remission), with 87.25% improvement rate in patients suffering from lichen sclerosus. The greatest vulvoscopic response was observed in the reduction of subepithelial ecchymoses and teleangiectasia (78.95%), and the reduction of erosions and fissures (70.97%). A partial remission of lichenification with hyperkeratosis was observed in 51.61% of cases. The least response was observed in the atrophic lesions reduction (improvement in 37.36% of cases). CONCLUSION: Our patients suffering from vulvar lichen sclerosus demonstrated positive responses to photodynamic therapy and the treatment was well tolerated. Photodynamic therapy used to treat lichen sclerosus yields excellent cosmetic results.

The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome.

The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (p<0.001) and tumor response to the PC therapy (p=0.014). The rs34529039 SNP did not affect the risk of developing ovarian cancer. This is the first study providing evidence that the c.690G>T, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy.

The Evaluation of Risk Factors Associated With Relapse and Recurrence of Borderline Ovarian Tumors With Long-Term Follow-up.

OBJECTIVE: The goal was to analyze the risk factors of relapse and to compare the type of recurrence in patients with borderline tumors treated and followed up in Oncologic Center in Warsaw. MATERIALS AND METHODS: This is a retrospective-prospective cohort study of 307 patients with confirmed borderline ovarian tumors treated in the Maria Sklodowska-Curie Memorial Cancer Center in Warsaw between 1994 and 2010. Univariate and multivariate analysis as well as Kaplan-Meier estimates were used to explore the impact of different covariates on progression-free survival. The analysis included the following potential prognostic factors: age, CA 125 value, stage according to classification of the International Federation of Gynecology and Obstetrics (FIGO), methods and radicality of operation, staging, tumor capsule rupture, histopathology, implants, ascites, and microinvasion. The analysis of relapses was also performed. RESULTS: Univariate analysis showed the negative impact of 2 factors on progression-free survival: FIGO II/III (implants) (P = 0.011) and ascites (P = 0.027). The multivariate analyses showed the detrimental effect of FIGO Ic (HR, 2.63; 95% confidence interval [CI], 1.12-6.17, P = 0.027), FIGO II or III (implants) (HR, 3.67; 95% CI, 1.56-8.61, P = 0.003), and incomplete staging (HR, 3.63; 95% CI, 1.09-12.07, P = 0.035), but not ascites (P > 0.1). Relapse occurred in 32 (10%) patients: in 22 patients as borderline and in 10 patients as invasive tumor. Seven (70%) patients with invasive relapse died of disease. All patients with borderline relapses were successfully managed by second surgery, which in 80% was again conservative. CONCLUSIONS: Relapses in borderline ovarian tumor are uncommon, in 10% of patients. Invasive relapses are rare, only in 3% of patients, but often with fatal course irrespective of the treatment applied. The most important clinical risk factors of relapse are implants (FIGO II/III), FIGO Ic, and incomplete staging and this patients as well as patients with ascites should be closely followed. Relapses of borderline histology are easily detected and successfully managed by surgery.

Clinical value of human epididymis protein 4 and the Risk of Ovarian Malignancy Algorithm in differentiating borderline pelvic tumors from epithelial ovarian cancer in early stages.

OBJECTIVE: The clinical value of human epididymis protein 4 (HE4) and the possibility of its use in the differential diagnosis in patients with benign, borderline and epithelial ovarian cancer in early International Federation of Gynaecology and Obstetrics (FIGO) stages. STUDY DESIGN: The study group consisted of 205 women, including 60 with ovarian cancer, 18 with borderline tumors, 77 with benign lesions and 50 healthy subjects. In all the patients, before the treatment and in control groups, we determined CA 125 and HE4 in serum by electrochemiluminescence on the basis of the COBAS e601 system. For comparison of two independent groups, we used the U Mann-Whitney test. The analysis of the diagnostic power of the assessed parameters has been determined using the MedCalc statistical program. The probability of disease free survival (DFS) was evaluated using the log-rank test and Cox regression model. RESULTS: Concentrations of HE4, CA 125 and Risk of Ovarian Malignancy Algorithm (ROMA) value were significantly higher in early ovarian cancer than in patients with benign (P<0.0001) and borderline tumors (P<0.002), the receiver operating characteristics (ROC) curves, demonstrated the highest diagnostic sensitivity for the ROMA score, as well post (AUC=0.817) as pre-menopausal (AUC=0.806). HE4 concentrations (P<0.021) and the value of the ROMA score (P<0.004) were significantly higher in patients with relapse than in patients in remission. There was no connection between concentrations of the studied tumor markers and DFS. CONCLUSIONS: Determination of HE4 serum concentrations has a significant clinical value, especially in patients with benign lesions and elevated CA 125 levels. The combined assessment of HE4, CA 125 and the ROMA algorithm is helpful in differentiating benign tumors and borderline pelvic tumors from epithelial ovarian cancer in early FIGO stages. Determination of HE4, CA 125 and ROMA algorithm is not helpful in differentiating patients with borderline from benign lesions.

Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Does Metformin affect ER, PR, IGF-1R, ß-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer?

OBJECTIVE: Diabetes mellitus, as a risk factor for endometrial cancer (EC), causes an increase in insulin and IGF-1 concentrations in the blood serum. The increase in insulin and IGF-1 are considered mitogenic factors contributory to cancer development. Studies suggest that metformin has preventive activity, decreasing mortality and the risk of neoplasms. Since estrogen (ER), progesterone (PR) and IGF-1 (IGF-1R) receptor expression and ß-catenin and PAX-2 mutations are significant in the development of endometrial cancer, it was decided to study these factors in patients with endometrial cancer and type 2 diabetes mellitus (DM2), and to establish the effects of metformin on their expression. METHODS: The expression of ER, PR, IGF-1R, ß-catenin and PAX-2 have been immunohistochemically investigated in 86 type I endometrial cancer specimens. Patients were grouped according to the presence of DM2 and the type of hypoglycemic treatment administered. RESULTS: Comparing EC patients with DM2 and normal glycemic status, we found increased IGF-1R expression in women with DM2. A decrease in ER expression was noted in women with EC and DM2 receiving metformin as compared to women treated with insulin (p = 0.004). There was no statistically significant difference in PR, IGF-1R, ß-catenin and PAX-2 expression among women receiving metformin and other hypoglycemic treatment. CONCLUSION: Although epidemiological studies suggest the beneficial role of metformin in many human cancers, there are still few studies confirming its favorable effect on endometrial cancer. Decreased ER expression in patients receiving metformin needs further research to allow evaluation of its clinical significance.

Comparison of efficiency of photodynamic diagnostics with topical use of the 3% and 15% aminolevulinic acid in the detection of vulvar lesions.

UNLABELLED: The essence of the photodynamic diagnostic method is interaction between light and chemical compounds that form in reaction to light. In order to obtain fluorescence, tissue has to be exposed to energy in the form of light with the wavelength corresponding to the bandwidth of the photosensitizer absorption. The photodynamic method allows for the detection of even small lesions. This method facilitates the process of detecting vulvar cancer, especially in its early stages when it can develop on the foundation of overgrown epithelium. At that point the vulvoscopic image is difficult to interpret, in particular when multifocal growth occurs. OBJECTIVES: The objective of the study was evaluating the efficiency of the photodynamic method PDD (photodynamic diagnosis) in the detection of vulvar lesions when two concentrations of the photosensitizer were used (3%- and 15%-aminolevulinic acid), as well as evaluating the efficiency of this method when compared to the efficiency of vulvoscopy, against the result of histological examination. METHODS: Two concentrations of the 5-ALA cream (aminolevulinic acid) - 3% and 15% - were used in the PDD testing. The study group was divided into two subgroups A and B. In subgroup A the 15% eucerine-based cream was used. In subgroup B the 3% ALA gel with and addition of 2% DSMO was used. The photosensitizer was applied to the vulva 4-6h before the examination. In order to obtain fluorescence, energy in the form of light whose wavelength was approximately 405 nm, and whose source was a SLED diode, was transmitted to vulvar tissue. The positive result of the exam was obtaining tissue fluorescence. All patients underwent vulvoscopy and a histological examination of tissue samples was performed in all cases. The efficiency of the photodynamic testing in subgroups A and B was compared with the efficiency of vulvoscopy, against the result of histological examination. Sensitivity, specificity, as well as positive and negative predictive values of the PDD examination and vulvoscopy in both subgroups, were evaluated. RESULTS: When the 15% ALA was used in detecting vulvar lesions, the photodynamic diagnostics was characterized by sensitivity of 100%, specificity of 92%, positive predictive value of 80%, negative predictive value of 100%, and correlation with the histopathological examination of 93.9%. When the 3% ALA was used, we observed: sensitivity of 100%, specificity of 91.4%, positive predictive value of 78.5%, negative predictive value of 100%, and correlation with the histopathological examination of 93.4%. Differences in the two subgroups were not statistically significant. CONCLUSIONS: High correlation was observed between the accuracy of the photodynamic method of examining vulvar lesions and the accuracy of the histological examination, especially in cases of precancerous lesions and vulvar cancer. The photodynamic examination, when the 3%-ALA/2%DSMO is used, is characterized by a greater sensitivity, comparable specificity, as well as, comparable positive and negative prognostic values, in comparison to the vulvoscopic examination. The photodynamic method, when used with other diagnostic methods, facilitates performing the needle aspiration biopsy and allows for a greater precision of histological diagnoses. The pathological fluorescence obtained during the PDD examination gives information about the spread and multifocality of vulvar lesions, which can facilitate making presurgical decisions concerning the extensiveness of surgery. The photodynamic method, when the 3% ALA/2% DSMO is applied topically, is of comparable efficiency as the 15% ALA, in the detection of vulvar lesions. High safety of the photodynamic method was shown, both in terms of the topical application of the aminolevulinic acid and the subsequent use of light.

[Value of fine needle aspiration biopsy in cervical cancer]. / Ocena wartosci celowanej cienkoiglowej punkcji przymacicz u pacjentek operowanych z powodu raka szyjki macicy.

UNLABELLED: Correct staging qualification, especially evaluation of parametrium is very useful in choosing of adequate method of treatment, and thereby in patients' survival. OBJECTIVE: The aim of study was estimation of the value of fine needle aspiration biopsy in transvaginal ultrasonography assistant in preoperative assessment of parametria in cervical cancer. We compared parametrial infiltration before treatment and to verified and confirmed staging in cervical cancer postoperatively by histopathology. MATERIAL AND METHOD: 64 women with cervical cancer in stage Ib, were included in the study. Assessment of parametrial invasion before treatment was performed by fine needle aspiration biopsy in endovaginal ultrasound assistants. The sonographic evaluation of parametria was performed by Siemens Sonoline Versa Pro with transvaginal 7 MHz mechanical transducer with the biopsy guide 14 cm long. All of patients with cervical cancer in stage Ib were operated on Wertheim-Meigs hysterectomy. The preoperative findings were compared with data obtained by histopathology findings. There were evaluated sensitivity, specificity and diagnostic accuracy of this method. RESULTS: Accuracy of fine needle aspiration biopsy of parametrial involvement was 89%, sensitivity-70%, specificity-92.6%, PPV-63.6%, NPV-94.3%. CONCLUSIONS: Transvaginal ultrasonography is superior to routine clinical examination in the assessment of parametria. Sensitivity of fine needle biopsy with ultrasound assistance is higher then of gynecological examination and ultrasound alone. Correct preoperative diagnosis may improve staging, treatment and indirectly, survival patients with cervical cancer.

[Comparison of cerclage and cerclage pessary in the treatment of pregnant women with incompetent cervix and threatened preterm delivery]. / Porównanie skutecznosci leczenia szwem szyjkowym oraz pessarium kolnierzowym szyjki macicy u ciezarnych z niewydolnoscia ciesniowo-szyjkowa i zagrazajacym porodem przedwczesnym.

UNLABELLED: Cervical incompetence is one of the causes of preterm delivery. Ultrasound examination of the cervix has given the evidence that cervical shortening, dilatation of internal cervical os and funneling observed long before term are the warning signs of preterm delivery. Early diagnosis and treatment may serve better outcome. Cerclage, which has been employed for more than 50 years is a traumatic procedure, furthermore requiring anaesthesia. Cerclage pessary can be a safe alternative to cerclage. This method seems to be less invasive. The aim of the study was to compare the effectiveness of the two methods employed in gravid patients between 22 and 27 completed weeks of pregnancy with clinically and ultrasonographically confirmed shortening of the cervix. MATERIAL AND METHODS: We analysed 57 patients, 22 treated with McDonald cerclage procedure and 35 with pessary. The primary outcome measure was prolongation of pregnancy--mean 13.4 weeks and 12.1 weeks for cerclage and pessary respectively (p = 0.06). There were no significant differences regarding the mode of delivery, rate of prematurity, mean birthweight and Apgar score. CONCLUSIONS: Cerclage and cerclage pessary are equally effective methods of prolongation of pregnancy in gravid patients with incompetent cervix and threatened preterm labor. The choice of the method does not affect the mode of delivery as well as neonatal outcome.