Iris Publishers_World Journal of Gynecology & Womens Health (WJGWH)

Determining Predictive Factors of Para-aortic Lymph Node Involvement in Low-grade Endometrial Cancer

Abstract

Objectives: The purpose of this study was to determine predictive factors of para-aortic lymph node (PALN) involvement in low-grade endometrial cancer of endometrioid type. These factors may influence treatment algorithms and determine the extent of lymph node dissection in patients with low grade endometrial cancer. Our hypothesis was that tumor size, location, and depth of myometrium invasion may be independent predictors of PALN involvement in low grade endometrial cancer.

Methods: A retrospective chart review was performed on patients with grades 1 or 2 endometrial cancer of endometroid type who underwent hysterectomy with lymph node removal from January 1, 2004 to August 1, 2014. Data was evaluated using independent t-tests, Mann Whitney U test, and chi square tests. Sensitivity, specificity, positive and negative predictive values were calculated for tumor size, location, and myometrium invasion in association with PALN and pelvic lymph node (PLN) involvement.

Results: A total of 259 patients met the inclusion criteria. Tumor size was not significantly different between positive and negative PALN samples (4.5cm vs 3.5cm, respectively; p=0.29). Location was not significantly different among positive and negative PALN groups, as the majority of patients in both groups had tumors in the fundal region (75% vs 70.5%, respectively; p=1.00). Myometrial invasion was not significantly different between positive and negative PALN groups (48% vs 28%, respectively; p=0.14). Myometrial invasion was significantly different among positive and negative PLN groups (71% vs 26%, respectively. p<0.001). Lymphovascular space invasion (LVSI) demonstrated a significant association with both positive PALN and PLN groups (100% vs 22.31%, and 81.25% vs 19.67%, respectively; p=0.003, <0.001).

Conclusions: LVSI may be an independent predictor of both PALN and PLN involvement in low grade endometrial tumors. It remains unclear whether tumor size, location, and myometrial invasion can be used to predict para-aortic nodal involvement in these cases.

Keywords: Low grade endometrial cancer; Endometrioid adenocarcinoma; Para-aortic lymph nodes; Nodal metastasis; Tumor size; Tumor location; Myometrial invasion; Lymphovascular space invasion

Introduction

Endometrial cancer is the 4th leading cause of cancer among women and the most common malignancy among the female reproductive organs in the United States [1,2]. It is essential to determine the most effective way to both correctly diagnose and subsequently treat affected patients. Treatment is founded on proper staging, and the extent of lymph node involvement is a critical determinant of tumor stage. Prior authors have attempted to identify predictive factors of pelvic lymph node (PLN) involvement in low grade endometrial cancer [3-7]. However, there is a paucity of research regarding factors such as tumor location, associated specifically with para-aortic lymph node (PALN) involvement in low grade tumors. This is likely due to variations in incidence rates. The overall frequency of PALN dissemination within endometrial adenocarcinoma has been reported as low and also as high as 17%, depending on the tumor stage [4,7-10]. Further delineation of these factors may potentially help guide surgeons in the extent of required surgical dissection. The primary purpose of this study is to evaluate the following factors and their correlation to PALN involvement in low grade endometrial adenocarcinoma of endometrioid type: myometrial invasion, tumor size, tumor location, and lymphovascular space invasion (LVSI). By characterizing these variables, we can further risk stratify patients who may require additional surgical dissection and extensive nodal biopsy.

Materials and Methods

This study was a retrospective chart review designed to assess the best predictive factors of PALN involvement in low grade endometrial cancer. The protocol and all study materials were submitted and approved by the university’s Institutional Review Board. Approval was obtained before any subjects were enrolled. The study was conducted in accordance with the protocol, applicable regulations, and guidelines governing clinical study conduct. To protect subjects’ confidentiality, all subjects were assigned a numerical study identifier.

A chart review was performed for all women admitted to Cooper University Hospital with endometrial cancer and subsequent hysterectomy in the identified time frame. Included patients demonstrated grades 1 or 2 endometrial adenocarcinoma with primary histology of endometroid type with surgical lymph node removal during hysterectomy, nonspecific to operative approach, from January 1, 2004 to August 1, 2014. Operative approaches included open total abdominal hysterectomy, robotic hysterectomy, and laparoscopic assisted vaginal hysterectomy. Patients with primary histology of endometrioid cancer and secondary histology of alternative endometrial pathology were still included. Charts were abstracted for demographics such as age, which helped to define the patient population. Exclusion criteria included patients with concurrent gynecologic malignancies such as cervical or ovarian, any non-endometrioid primary histology, and any extensively incomplete pathology or operative reports. No criteria for patient follow up was included as this was strictly a retrospective chart review.

Demographic data and presurgical tumor grade were extracted from individual charts. Size of the tumor, location of the tumor, histology, PALN involvement, PLN involvement, the number of nodes removed, lymphovascular space involvement (LVSI), tumor stage, and the depth of myometrial invasion were all collected directly from pathology reports.

Tumor size was defined as the largest dimension of the tumor listed in the pathology report, in centimeters (cm). If the tumor was listed as “unmeasurable” due to small size, it was reported as 0.1cm for statistical purposes. Final statistics categorized tumor size as greater or less than 5cm. Tumor location was categorized as “fundus” or “lower uterine segment”. By standards directly defined by the university board-certified pathologist involved in the study, if the pathology report did not clearly define either location, the measurement of < 3.5cm from ectocervix was used as a cutoff for lower uterine segment location. If no exact measurement was listed but was reported as “close to endocervical junction” or “involved in the lower uterine segment,” the specimen was categorized as lower uterine segment. Depth of myometrial invasion was reported as a percentage, either directly stated in the pathology report or calculated from the total myometrial depth.

Data was then evaluated using independent t-tests to compare continuous variables with normal distribution, Mann Whitney U to compare non-parametric continuous variables, and chi square tests to compare proportions. We also evaluated positive and negative predictive values, sensitivity and specificity to examine the predictive values of tumor size, tumor location and myometrium invasion in para-aortic lymph node and pelvic node involvement in the selected cases.

Results

In total, 498 patient charts were reviewed over the given time period. Of these charts, primary histology was reviewed providing the following findings; 418 endometrioid adenocarcinoma, 63 papillary serous carcinoma, 13 malignant mullerian mixed tumor, 2 clear cell carcinomas, and 2 specimens classified as mixed primary histology (papillary serous with clear cell and mixed papillary serous with endometrioid). Of the patients with primary histology of endometrioid adenocarcinoma, 367 were listed as grade 1 or 2 tumors, and 51 were grade 3. Pelvic and/or para-aortic lymph node sampling was performed on 269 specimens of the grade 1 and 2 tumors. Ten charts were then excluded due to concurrent ovarian or cervical cancer or an extensive amount of missing data from the chart or pathology report. These patients then met inclusion criteria and were included in this retrospective chart review. There were 162 Grade 1 tumors and 97 Grade 2 tumors. Four patients were identified with positive PALN involvement, 16 patients were identified with positive PLN involvement, and 1 patient had both positive PALN and PLN identified. All positive samples were reported by Cooper University Hospital’s Department of Pathology (Figure 1).

Tumor size

Primary outcome compared tumor size with PALN involvement, with additional findings comparing tumor size and PLN involvement. Tumor size was not found to be statistically significantly between positive and negative PALN samples. Mean tumor size for paraaortic positive tumors was 4.12cm (+/-2.0) and the median was 4.5 cm. The mean tumor size for para-aortic negative tumors was 3.9 cm (+/-3.7) with a median of 3.5 cm (p=0.29, Figure 2). Tumors measuring 5cm or more were found to have the following associations with positive PALN involvement: a positive predictive value (PPV) of 2.94%, a negative predictive value (NPV) of 98.92%, sensitivity of 50.00% and specificity of 73.60% (Figure 3). Tumors of 5cm or more were found to have the following associations with positive PLN involvement: PPV of 14.71%, NPV of 96.77%, sensitivity of 62.50% and specificity of 75.63% (Figure 4).

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Iris Publishers_World Journal of Gynecology & Womens Health (WJGWH)

A Scoping Review of the Effects of COVID-19 Medications on Pregnancy

Abstract

COVID-19 is a pandemic disease caused by the SARS-CoV-2 which began to appear around in December 2019 in Wuhan, China and spread globally in the last few months. Currently, there is no specific treatment for SARS-CoV-2 which forced clinicians to use old drugs, chosen for their efficacy against similar viruses or their in vitro activity. The majority of information comes from small case series and single center reports which showed that COVID-19 infection in pregnant women can lead to intrauterine growth restriction, premature labor and spontaneous abortion. So, in the view of the urgency of COVID-19 pandemic and the uncertainties about its management during pregnancy, we aimed to provide a literature review on the effectiveness and safety of available medications for COVID-19 in pregnant women. Here, our overview may provide useful information for physicians to choose the best available medications for treatment a pregnant case with COVID-19.

Keywords: COVID-19; Pregnancy; Medications

Introduction

In Wuhan, China, coronavirus disease-2019 (COVID-19) began to appear in December 2019 [1]. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2), this is a new type of enveloped RNA viruses characterized by mild infection in upper respiratory tract and life-threatening pneumonia [2]. The number of the affected pregnant women is increasing as pregnancy is a special immunological case in which the immune system is exposed to great challenges involving maintaining and establishing adaptation to allogenic fetus and preserving fetus from any microbial challenges. The immune system in pregnancy undergoes three stages; pro-inflammatory state in the first trimester, antiinflammatory state in the second trimester and second proinflammatory state in the third trimester [3].

During pregnancy the upper respiratory tract is swollen due to high levels of estrogen and progesterone which restrict lung expansion, and this increase the incidence of viral infection. Recent literature explains that COVID-19 infection is associated with cytokine storm in severe cases in which there is increased plasma concentration of tumor necrosis factor alpha, macrophage inflammatory protein1 alpha, monocyte chemoattractant protein1, granulocyte-colony stimulating factor, interferon gamma inducible protein10, interleukins (IL-2), (IL-7), (IL-10). Based on the proinflammatory state in third and first trimester in pregnancy and cytokine storm in COVID-19 infection the pregnant women are exposed to severe inflammatory state which can affect the fetal brain and leads to several aspects of neuronal dysfunction [3,4]. Also, elevated levels of TNF alpha in mother’s peripheral blood can be toxic to early embryo development and induce preterm delivery in non-human models [5].

Previous studies have explained that COVID-19 infection in pregnant women can lead to intrauterine growth restriction, premature labor and spontaneous abortion [6]. Therefore, treatment must be initiated when potential benefits outweigh potential risks and intra uterine development must be monitored closely during treatment and even after the treatment is stopped [7]. Due to the urgency of COVID-19 pandemic and the uncertainties about its management during pregnancy, we aimed to provide a literature review on the effectiveness and safety of available medications for COVID-19 in pregnant women. After we reviewed the guidelines and protocols from National institution of health (NIH), United Kingdom National Health Service (NHS), Egypt, Saudi Arabia, France, Italy, Spain and China, we limited our search on the most relevant medications mentioned in them. We also limited our search on English-language literature.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine are antimalarial and antirheumatoid drugs. They are weak bases and have deep volume of distribution and half-life around 50 days. These drugs cause defect in the lysosomal activity and autophagy, interfering with stability of cell membrane and causing defect in pathway of signaling and transcriptional activity leading to inhibition of cytokine production and modulating certain co-stimulatory molecules. Both drugs are enantiomers [8]. Chloroquine and hydroxychloroquine are category C according to FDA [9]. Studies showed that they have a broadspectrum antiviral effect by increasing endosomal PH required for virus\cell infusion and causing defect in glycosylation of cellular receptors of SARS-COV. They also have anti-inflammatory effect plus their anti-viral effect which are responsible for their potent effect in treating COVID-19 [10]. Chloroquine can cross the placenta and accumulate in the fetal tissues as hydroxychloroquine which tend to accumulate in melanin containing tissues as retina and choroid leading to loss of vision [11].

On follow up of infants that their mothers took hydroxychloroquine during gestation and lactation, Hart and Naughton presenting that the main complication is preterm delivery (20.5%), no significant neonatal infections or congenital anomalies were observed, including infants that were breastfed. They concluded that hydroxychloroquine seems to be safe during pregnancy and preterm delivery reflects the state of maternal disease [12]. Suhonen reported a case receiving hydroxychloroquine phosphate in the first six weeks of pregnancy to control discoid systemic lupus erythematosus and fetus was born with no anomalies and grew without any mental or physical abnormalities [13]. Ross and Garotos examined autopsy from 14-week aborted fetus as his mother taking chloroquine showing no anomalies in oropharynx [14].

Additionally, eight patients who were presented to American Rheumatism Association, these patients had 28 pregnancies, they were receiving chloroquine, three of them underwent incomplete pregnancy or neonatal death as they came during period of activity of the disease, one had still birth fetus, four underwent spontaneous abortion and six had full term standard deliveries [15]. A meta-analysis conducted on hydroxychloroquine included seven cohort studies and one randomized controlled trial showed no significant increase in the rates of major congenital, craniofacial, genitourinary, cardiovascular, nervous system malformations, stillbirth or prematurity. Unfortunately, there is no data about the effect of chloroquine on pregnant women with COVID-19.

Remdesivir

Remdesivir is small molecule broad spectrum antiviral drug which act as RdRp inhibitor targeting viral genome process of replication. It is recommended to be safe during pregnancy in COVID-19 infection as in trials conducted of Marburg virus and Ebola virus [16]. In reproductive non-clinical toxicity, there is no adverse effects were noticed on embryo-fetal development in male infertility or pregnant animal with Remdesivir. In photoactivated localization microscopy study of acute Ebola virus disease, 26% of children and 3% of pregnant women received Remdesivir without any notable adverse effect [17].

Interferons (IFN-α and IFN-β mainly)

Type I interferons (IFN-α/β) have broad spectrum antiviral activities against RNA viruses by inducing an antiviral response across a wide range of cell types and stimulating the host adaptive immune response [18]. Data from several pregnancy registries showed no association between preconception or during pregnancy exposure to interferon-beta-1b and an increased risk of adverse birth outcomes [19]. A meta-analysis conducted to observe whether type I interferon has adverse effects on pregnant women with primary thrombocytopenia. The results showed that IFN-α did not significantly increase the risk of malformations, miscarriages, stillbirths, or premature births [20]. Another large systematic review included 50 studies that identified 761 pregnancies exposed to interferon β. Results reported that exposure to interferon β was associated with shorter mean birth length, lower mean birth weight, and preterm birth (<37 weeks); however, there was no increased risk of serious pregnancy complications of spontaneous abortion, cesarean delivery or birth weight < 2.5 kg [21].

A recent study included data from 26 European countries evaluated pregnancy outcomes of 948 pregnant women with multiple sclerosis receiving IFN I-β during pregnancy or within one month before conception. Results did not show an increased risk of fetal malformations or spontaneous abortion [22]. Currently, IFN type I is classified as US FDA pregnancy category C.

Janus Kinase Inhibitors (e.g., Baricitinib)

Baricitinib is a potent and selective janus Kinase Inhibitor that is used for treatment of rheumatoid arthritis and currently being investigated for treatment of COVID-19 cases due to its antiinflammatory and antiviral activities [23] as it would likely prevent the dysregulated production of pro-inflammatory cytokines in COVID-19 cases [24]. There are limited human data on the use of baricitinib to evaluate the drug-associated risk for major birth defects or miscarriage. In animal studies of embryo-fetal development, there was increased embryo lethality in some species that were given baricitinib at very high doses, above the maximum human recommended dose [25]. Baricitinib is not assigned in the US FDA pregnancy categorization. But It is classified as AU TGA (Australian categorization) pregnancy category: D.

Interleukin-1 Inhibitors (e.g., Anakinra)

Interleukin-1 is a pro inflammatory cytokine binds to IL-1 receptor and modulate its action so inhibitors of interleukin-1 are used to treat rheumatoid arthritis and currently being investigated for treatment of COVID-19 due to its potential effect to interfere with the cytokine storm in severe cases of COVID-19 [26]. There is limited evidence about the use of Interleukin-1 inhibitors(IL-1) in pregnancy but unintentional first trimester exposure is unlikely to be harmful [27]. According to an International multi-center study of the pregnancy outcomes in pregnant women exposed to interleukin-1 inhibitors, the use of interleukin-1 inhibitors may not significantly affect pregnancy outcomes or infant development. The study identified a total of 43 pregnancies with IL-1 inhibitors exposure in 7 countries, including 8 maternal from 14 with canukinumab and 23 maternal from 29 with anakinra. Seven healthy infants of normal gestational age and birthweight delivered from eight pregnancies exposed to canukinumab. Twenty-one healthy infants, and one baby with unilateral renal agenesis and ectopic neurohypophysis delivered from 23 pregnancies exposed to anakinra [28]. Anakinra is classified as US FDA pregnancy category B and AU TGA pregnancy category: B1.

Interleukin-6 Inhibitors (e.g., Tocilizumab)

Interleukin-6 (IL-6)is a pro-inflammatory cytokine that activates its downstream Janus kinase (JAK) signal by binding the transmembrane (cis-signaling) or soluble form (trans-signaling) of the IL-6 receptor [29]. Tocilizumab is a monoclonal antibody used for the treatment of rheumatoid arthritis and currently being investigated for treatment of some cases of severe COVID-19 with good results [30]. There are insufficient data to determine if there is a drug-associated risk for major birth defects or miscarriage [31]. A study analyzed pregnancy-related reports of 399 women with Tocilizumab exposure shortly before or during pregnancy. Pregnancy outcomes were reported in 288 pregnancies (72.2%) and showed no indication for a substantially increased malformation risk but the data do not yet prove safety [32]. Another Japanese retrospective study included 61 pregnancies with rheumatic disease exposed to tocilizumab during conception. Results showed no increased rates of spontaneous abortion or congenital abnormalities [33]. Tocilizumab is classified as US FDA pregnancy category C and AU TGA pregnancy category: C.

HIV Protease Inhibitors (e.g., Lopinavir/Ritonavir Darunavir/Cobicistat)

Lopinavir and Darunavir work as competitive inhibitors through binding directly to HIV protease and prevent subsequent cleavage of polypeptides, which in turn reduce viral replication and spread. Ritonavir and Cobicistat are metabolism-based enhancer to increase the exposure of Lopinavir and Darunavir [34]. Both drugs are used for treatment of HIV-infected women during pregnancy and prevention of mother-to-child transmission. In spite of their efficacy in vitro against SARS-CoV, they have poor selectivity index requiring higher than the tolerable level to achieve the clinically significant inhibition in vivo; however, based on systemic review and clinical studies found when given early to be associated with lower hospital stay and lower mortality rates [35-37].

Lopinavir is one of the main HIV protease inhibitors recommended in pregnancy with a good safety profile. Pharmacokinetics studies reported lower exposure of LPV in pregnancy [38] due to moderate decrease of total Lopinavir concentrations despite the dose increase [39]. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose [40]. Two cohort studies of 21 women conducted with steady pharmacokinetic evaluations concluding that improving the oral bioavailability of the tablets may compensate for the reduction in exposure during the later stages of pregnancy [41]. Therefore, a population pharmacokinetic analysis conducted to assess the statically significance doesn’t show clinically meaningful difference between Lopinavir exposure in pregnant women receiving the tablet and non-pregnant receiving the capsule and dose adjustment isn’t needed [42]. However increased doses may be preferable in obesity (>100kg) and with a previous history of LPV/RTV use and/or compliance issues [43]. Bearing in mind that increasing the dose didn’t correlate with frequent adverse effects Lopinavir is one of the main HIV protease inhibitors recommended in pregnancy with a good safety profile. Pharmacokinetics studies reported lower exposure of LPV in pregnancy [38] due to moderate decrease of total Lopinavir concentrations despite the dose increase [39]. However, the exposure of unbound LPV did not change significantly regardless of trimester or dose [40]. Two cohort studies of 21 women conducted with steady pharmacokinetic evaluations concluding that improving the oral bioavailability of the tablets may compensate for the reduction in exposure during the later stages of pregnancy [41]. Therefore, a population pharmacokinetic analysis conducted to assess the statically significance doesn’t show clinically meaningful difference between Lopinavir exposure in pregnant women receiving the tablet and non-pregnant receiving the capsule and dose adjustment isn’t needed [42]. However increased doses may be preferable in obesity (>100kg) and with a previous history of LPV/RTV use and/or compliance issues [43]. Bearing in mind that increasing the dose didn’t correlate with frequent adverse effects according to a random clinical trial [44] and didn’t result in greater neurodevelopmental risks for HIV positive mothers or uninfected infants [45].

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Iris Publishers_World Journal of Gynecology & Womens Health (WJGWH)

Atwal Striae Gravidarum Score for Prediction of Perineal Tears During Vaginal Delivery: A Cross- Sectional Study

Abstract

Objective: To evaluate the value of Atwal striae gravidarum (SG) score for prediction of occurrence of perineal tears (PT) during vaginal delivery.

Methods: A cross-sectional study conducted between October 2016 and April 2018 included all multiparous women presented in the active phase of labor. Assessment of SG score was done using Atwal score in the abdomen, hips, breasts and buttocks. According to the total striae score (TSS) women were classified into two groups; group (I): mild SG (TSS ≤12) and group (II) moderate/severe SG (TSS >12). The primary study outcome was the rate of PT in both groups.

Results: The study included 421 women; 188 in group I and 233 in group II. The rate of PT was significantly higher in group II than group I (56.2% vs. 3.2% respectively, p<0.001). Additionally, para-urethral, vaginal and cervical tears were more common in group II (p=0.029, 0.025 and 0.047 respectively). Additionally, we found significantly higher TSS among women with PT versus those without PT (17.07±3.56 vs. 7.93±6.94, p <0.001). Multivariate regression analysis revealed that the presence of abdominal striae and the TSS >12 were associated with increased risk of PT.

Conclusion: Assessment of Atwal SG score could precisely predict the occurrence of PT in multiparous women during vaginal delivery.

Keywords: Striae gravidarum; Perineal tears; Vaginal delivery; Atwal score

Introduction

Perineal trauma is common during vaginal delivery varied from minor superficial mucosal lacerations to major tears involving the musculature of the perineum and rectum [1]. It can lead to a numerous complication as hemorrhage, dyspareunia, perineal abscess with subsequent rectovaginal fistula and incontinence which have a major negative effect on physical, psychological aspects and women’s quality of life [2].

During vaginal delivery, the fetal head exerts considerable pressure on the vaginal and perineal tissues. This could lead to tissue tears even with a small baby and apparently easy delivery [3]. Others can deliver with intact perineum in spite of large babies or malpresentation.

Striae gravidarum (SG) are stretch marks occurred during pregnancy that may be an indicator of poor skin elasticity [4]. Women who does not have SG may have better skin elasticity and less liable to have vaginal or perineal tears during delivery [5]. SG is caused by changes in the structural connective tissue as a result of a hormonal elect on the alignment and reduced elastin and fibrillin in the dermis [6]. SG usually occurs on the hips, buttocks, abdomen, breasts, and thighs and usually appears after the 24th week of gestation [7]. The incidence of SG is variable ranges between 43% to 88% [8].

Scoring of SG severity was published using the numerical scoring system of Atwal [9]. This score provides a rank based on observation of four common areas of SG (abdomen, hips, buttocks, and breast). The final score for each body area ranges from 0 to 6 according to the number and color of SG. The total striae score (TSS) ranges from 0 to 24. Women having TSS score ≤12 indicated mild striae, TSS score (13-18) indicated moderate striae and TSS >18 indicated severe striae [9].

In a previous study by Halperin et al., 2010 reported a significant association between the degree of PT and severity of SG. Additionally, SG especially on the hips and breast predicted the occurrence of first- and second-degree PT [5].

Therefore, the aim of the present study is to determine the value of assessment of Atwal SG score in laboring women for prediction of the occurrence of PT during vaginal delivery.

Patients and Methods

The current study was a cross-sectional study conducted in a central hospital between October 2016 and April 2018. The Institutional ethical review board approved the study protocol and informed written consent was obtained from all participants after discussing the nature of the study.

Eligible participants

All multiparous women attended the reception unit of the hospital in the active phase of labor were invited to participate in the study if they met our inclusion criteria. We included women aged 18-40 years, has spontaneous onset of labor, singleton pregnancy, fetus with cephalic presentation at gestational age 37-40 weeks and estimated fetal weight by ultrasound (2500-4000gm). We excluded women with multiple pregnancy, scarred uterus, malpresentation, suspected fetal macrosomia, preterm labor, medical disorders as diabetes or hypertension and those refused to participate in the study.

Recruitment

A detailed history was taken from all women included age, parity, gestational age, residency, educational level, previous miscarriages, previous episiotomy, gestational weight gain and body mass index (BMI) was calculated for each participant.

Intervention

Inspection of the four body areas described in the Atwal SG score (abdomen, hips, buttocks, and breast) was done and the TSS was calculated for each woman [9]. The score includes the following criteria (a) the number of SG at each body site (0=no striae signs, 1=1-4 striae, 2=5-10 striae, 3=more than 10 striae) and (b) the color of the SG which ranges from pale to purple (0=no redness, 1=pink, 2=dark red, 3=purple). The final score for each body site, relating to number and color, ranges from 0 to 6. Accordingly, the TSS ranges from 0 to 24. Women having TSS score up to 12 were considered to be having mild SG, TSS score (13-18) indicated moderate SG and TSS more than 18were considered to be having severe SG.

According to the TSS, women were classified into two groups:

Group (I): women with no or mild SG (TSS ≤12)

Group (II): women with moderate or severe SG (TSS >12)

All study participants were followed until the second stage of labor using the portogram. All women were delivered by the same obstetrician through slow assisted delivery of fetal head with perineal support. Examination of the birth canal after delivery of the placenta with the active method was done. Any perineal tear was documented as regards the degree, location, number and length. The length of perineal tear was measured by a metal graduated and sterilized ruler. Presence of any other vaginal or cervical tears was recorded. Additionally, the neonatal data (Apgar score, weight, admission to pediatric intensive care unit) was recorded.

Study outcomes

The primary outcome was the difference in the rate of PT between both groups. Secondary outcomes included the rate of perineal tears according to each degree, number and length of perineal tears, the rate of para-urethral, vaginal and cervical tears in both groups.

Statistical analysis

Data were collected, tabulated, statistically analyzed by computer using SPSS version 22 (SPSS Inc., Chicago, IL), two types of statistics were done: Quantitative data were expressed as the mean, and standard deviation (SD). Qualitative data were expressed as frequencies and percentage. Normality of the quantitative variables was assessed using the Kolmogorov-Smirnov test. Chisquare (x2) and independent t-test were used to compare both groups if the data were normally distributed. Otherwise, Mann- Whitney and Fisher’s exact tests were used. A multivariate logistic regression model was performed for the predictors of occurrence of PT including, presence of SG at each body site, parity >3, BMI>30 Kg/m2, duration of second stage of labor >5 minutes, and TSS >12. P-value <0.05 was considered statistically significant.

Receiver operating characteristics (ROC) curve was performed to detect the best cut-off value for Atwal score for prediction of PT generally, and 3rd, 4th degree PT specifically. The best cut-off on the ROC curve has the highest true positive rate together with the lowest false positive rate.

Results

Five hundred twenty-three women were approached to participate in the study. We excluded 41 cases as they did not meet the inclusion criteria. The remaining 482 women were classified according to TSS into two groups: group (I) included 217 women with TSS ≤12 and group (II) included 265 women with TSS >12. Twenty-nine women in group (I) and 32 women in group (II) were excluded from the final analysis as they did not deliver vaginally. Therefore, 188 women in group (I) and 233 women in group (II) were included in the final analysis (Figure 1).

The mean age of the study participants was 26.26±4.6 years. The mean parity was 2.84±1.7 and the mean gestational age at inclusion was 38.31±1.52 weeks. SG were present in 88.1% of the study participants. The mean TSS of the whole participants was 10.91±7.41. Of the included 421 women, 50 women (11.9%) had no striae, while 138 (32.6%), 159 (37.8%) and 74 (17.7%) women had mild, moderate and severe striae, respectively. The most common site of SG was the abdomen (85.7%); other sites were hips (63.9%), buttocks (57.7%) and breasts (49.2%).

No statistically significant difference between the baseline characteristics of both study groups (Table 1). The duration of second stage was quite similar in both study groups (5.05±1.24 vs. 5.21±1.14 min, p=0.175). No difference between both study groups regarding the neonatal birth weight (p=0.945), Apgar score at 5 minutes (p=0.072), and the need for pediatric intensive care unit admission (p=0.307) (Table 1).

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Iris Publishers_World Journal of Gynecology & Womens Health (WJGWH)

The Potential Use of Urinary CtDNA Profiling in the Treatment of Breast Cancer

Abstract

Cell-free circulating tumor DNA (ctDNA), shed into the blood stream by apoptotic or necrotic tumor cells of either primary or metastatic sites, became an extensively investigated and very promising analyte in oncology research. If passing through the kidney barrier, ctDNA is likely to occur in urine. Literature research revealed a lack of studies aiming at diagnostic use of urinary ctDNA. Most studies investigating urinary ctDNA were performed in the field of urological cancers emphasizing, however, that urinary liquid biopsies were suitable to draw conclusive real time pictures of ctDNA alterations coming from circulation and hence strengthen the hypothesis that genetic profiling of urinary ctDNA could be valuable to gain tumor-related information also in other solid tumors such as breast cancer. Usually, clinical treatment decisions are based on mutation profiles that were received from initial tissue biopsies. Though, during therapy the genetic tumor profile might change e.g. gain and loss of genetic alterations that might be relevant for targeted therapy options or treatment resistance. Particularly patients with advanced breast cancer may acquire mutations during treatment cycles and might benefit from serial ctDNA sequencing to find new targetable mutations and gain access to tailored therapy. Here, the use of urinary ctDNA might offer an opportunity for non-invasive longitudinal genotyping and testing for actionable mutations. In contrast to plasma-derived ctDNA, only a few studies were performed using urinary ctDNA from patients with breast cancer and revealed that targeted NGS appeared to be a sensitive method to detect tumor-specific genetic features. In this mini review we sought to illuminate the potential use of urinary ctDNA for longitudinal disease monitoring at frequent intervals and low effort for patients with breast cancer.

Keywords: Breast cancer; Mutation profiling; Urinary ctDNA; NGS; Targeted therapy; Disease monitoring; Recurrence; Resistance

Abbreviations: cfDNA: cell free circulating DNA; ctDNA: cell free circulating tumor DNA; CNV: Copy Number Variation; SNV: Single Nucleotide Variant; ER: Estrogen Receptor; PR: Progesterone Receptor; HER2: Human Epidermal growth factor Receptor-2; ddPCR: digital droplet PCR; NGS: Next Generation Sequencing; PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; TP53: Tumor protein p53; CDH1: Cadherin-1; MLL3: Myeloid/lymphoid or mixed-lineage leukemia protein 3; ESR1: Estrogen Receptor 1; BRCA 1/2: Breast Cancer ½; DTC: Disseminated Tumor Cell

Case Report

Cell-free circulating DNA (cfDNA) became an extensively investigated and very promising analyte in oncology research. Particularly, DNA fragments originating from the tumor cells, socalled circulating tumor DNA (ctDNA), appear to be surrogates of the primary tumor or metastatic sites thereof. Usually, clinical treatment decisions are based on mutation profiles that were received from initial tissue biopsies. Therapy, however, might alter the genetic tumor profile and cause the occurrence of genetic changes that could be relevant for targeted therapy options or treatment resistance. In breast cancer, genetic profiling of ctDNA from blood plasma was shown to have good potential for clinical use and might help to find individual treatment options and to monitor metastatic relapse. Cancer recurrence is of high relevance for both, patients diagnosed with early breast cancer and pre treated women with advanced breast cancer. Due to limited therapy options, particularly, women diagnosed with the aggressive triple negative breast cancer subtype might benefit from mutation profiling using non-invasive tools allowing disease monitoring at frequent intervals. Here, the utility of urinary ctDNA might offer promising opportunities to obtain non-invasive liquid biopsies and make access to tailored individual treatment choices possible.

About Cell Free Circulating Tumor DNA (ctDNA)

Cell free circulating tumor (ctDNA) is shed into the blood stream by apoptotic or necrotic tumor cells. Characteristic features of apoptosis are DNA fragmentation and formation of apoptotic bodies. Consequently, the release of short nuclear DNA fragments of about 167 bp was shown to have a lower molecular weight compared to DNA fragments released by necrotic cells, thus, making it possible to determine tumor-derived DNA based on size distribution [1,2]. More precise approaches to identify ctDNA originating from tumor cells are based on the molecular alterations of tumor-specific genetic features like DNA mutations, methylation and copy number variations (CNVs) [3]. If circulating cell free DNA in the blood is passing through the kidney barrier it is likely to be found in urine and also called trans renal DNA or ucfDNA [4- 6]. Urinary cfDNA might also originate from apoptotic or necrotic cells coming in direct contact with urine such as cells from the genitourinary tract. Since glomerular filtration, which takes place in the pores of the glomerular barrier, works like separation by size, only small DNA fragments with a size of about 100 bp are able to pass and might appear in urine. Molecular analysis of urinary ctDNA could be useful to gain tumor-related information not only in patients with urological cancers but also with other solid tumors such as breast cancer [4,7]. The concentration of ctDNA extracted from body fluids like blood plasma or urine might vary hugely depending on numerous patient-individual parameters such as disease stage, treatment response and further physiological and patho-logical conditions as well as the body fluid itself. Circulating ctDNA in blood can be detected in serum and plasma, with the latter one containing up to 20-fold higher concentrations [8]. Hence, a variety of ctDNA extraction and detection methods were developed [9]. At the time being there is no standard protocol for isolation and detection of urinary cell free DNA, but plenty of techniques for isolation of low-molecular weight DNA fragments are available and appear to be sensitive and reproducible [10,11]. Literature research revealed a lack of studies aiming at diagnostic use of ucfDNA. Most publications described preliminary results based on small patient cohorts. Novel molecular technologies such as targeted next generation sequencing (NGS) or digital droplet PCR (ddPCR) are offering promising opportunities for the translation of ucfDNA based tumor profiling into the clinic though [2]. Most studies investigating urinary cfDNA were performed in the field of urological cancers including renal, bladder and prostate cancer emphasizing that urinary liquid biopsies were suitable to draw conclusive real time pictures of DNA alterations coming from circulation. At this point it appears noteworthy that a close similarity was described between bladder cancer and breast cancer [12] . Based on genomic expression and mutation analyses it was shown that bladder cancer was, similar to breast cancer, distinguishable into luminal and basal tumors and that those molecular subtypes appeared to be of prognostic relevance [13].

Molecular Features of Breast Cancer Tissue

Breast cancer is a very heterogeneous disease and can be classified into distinct molecular subtypes. Luminal A type tumors are hormone-receptor positive (estrogen-receptor (ER) and/or progesterone-receptor (PR) positive), human-epidermal-growthfactor- receptor-2 (HER2) negative and show low levels of the protein Ki-67, meaning low proliferation. Usually, they are of low are lowgrade, tend to grow slowly and patients have the best prognosis. The majority of patients is diagnosed with ER positive tumors and might receive endocrine therapy. Luminal B type tumors are also hormone-receptor positive (ER and/or PR positive), and either HER2 positive or HER2 negative, with high levels of Ki-67 meaning that they grow faster. The patient’s prognosis is slightly worse compared to luminal A. Patients suffering from HER2 (also called ERBB2) amplified tumors are prone to treatment with targeted therapy such as trastuzumab or pertuzumab. Triple negative breast cancer (TNBC) is hormone-receptor negative (neither ER nor PR) and HER2 negative with poor prognosis. The majority of TNBCs are of high grade and show an aggressive phenotype. Patients usually receive chemotherapy but have an increased risk of recurrence [14]. Molecular analysis of the breast cancer subtypes revealed that luminal A tumors, although being associated with good prognosis and therapy response, were presenting the majority of driver mutations such as PIK3CA ~ 45 %, GATA3 ~ 14 %, MAP3K1 ~ 13 %, TP53 ~ 12 %, CDH1 ~ 9 % [15]. In contrast, triple negative tumors appeared to lack driver mutations (PIK3CA ~ 9 %, MLL3 ~ 5 %), but showed mutations of the tumor suppressor gene TP53 in 80 % of the cases.

Somatic and Targetable Mutations in Breast Cancer

As mentioned above mutation profiling of breast cancer tissue revealed distinct molecular subtypes presenting characteristic somatic mutations, including single nucleotide variants (SNVs) and copy number variations (CNVs). Next to a huge number of low frequency variants, the usual suspects among mutated genes in breast cancer are TP53 and PIK3CA. In addition, to broaden the understanding of tumor initiation, promotion and progression it is of high medical relevance to identify and investigate somatic mutations that drive the cancer phenotype in order to find possible therapies targeted against the products of these abnormal genomic alterations. Currently, the genes ESR1 and HER2 are not only characteristic features of the respective molecular subtype, in fact they serve as therapeutic targets for endocrine and antibody-based therapeutics such as tamoxifen and trastuzumab or pertuzumab. Further, ESR1 mutations were found to be associated with tamoxifen resistance [16]. Among TNBC a variety of subgroups has been identified including high cellular proliferation, increased immunological infiltrate, basal-like and mesenchymal phenotype as well as deficiency in homologous recombination which was partly associated with loss of BRCA1 or BRCA2 function [17]. Although challenging, the molecular analysis of TNBC gave rise to potential options for tailored therapy strategies such as modified chemotherapy approaches targeting the DNA damage response, angiogenesis inhibitors, immune checkpoint inhibitors, or even anti-androgens, all of which are currently being evaluated in phase I to III clinical studies [17].

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