Young Cervical Cancer Patients Research Articles

Sexual Behaviors and Intimate Relationships of Sexual Partners of Young Patients with Early-Stage Cervical Cancer: A Qualitative Study.

This study aimed to explore the sexual behaviors and intimate relationships of sexual partners of young patients with cervical cancer. This study employed a descriptive phenomenological research design, which falls within the realm of qualitative research methods. Qualitative research typically utilizes interview techniques for gathering participants' experiences, perceptions, and behaviors. This study conduct face-to-face semi-structured interviews with the sexual partners of 15 young cervical cancer patients receiving cancer treatment to collect their experiences and perspectives on intimate relationships and sexual behavior with cervical cancer patients, and use the Colaizzi method for data analysis. Four themes were identified through the interview analysis: (1) reduction or absence of sexual behavior, (2) unpleasant sexual experiences, (3) adjustment of intimate relationships, and (4) lack of sexual health education. The sexual partners of young cervical cancer patients have experienced significant shifts in their perspectives on sexual behavior and intimate relationships. These changes include reduction or absence of sexual behavior, unpleasant sexual experiences, adjustment of intimate relationships, and lack of sexual health education. Hospitals should pay more attention to the sexual behavior and intimate relationships of patients with cervical cancer and their sexual partners, and social support systems and psychological and emotional counselling services should be established for providing relevant knowledge and guidance.

Hormone Therapy Use Among Young Patients with Cervical Cancer in Southern Saskatchewan

ObjectiveTreatment for cervical cancer can cause cessation of ovarian function in young patients. Physician counselling practices related to premature menopause and hormonal therapy (HT) for young cervical cancer patients is not well known. The primary objective of this study was to assess the frequency of HT counselling and usage among young cervical cancer patients. The secondary objective was to assess clinical and demographic factors associated with HT use. MethodsThis retrospective review included adult women younger than age 50 years who received treatment for cervical cancer between 2007 and 2017. Patient and disease characteristics, disease outcome, and documentation of HT and bone health counselling were collected from electronic records. Descriptive statistical analysis was performed for the primary objective, and independent t tests and χ2 tests were used for secondary objective data analysis. ResultsIn this study, 67 premenopausal women with cervical cancer (stages I–III) lost ovarian function from cancer treatment, of whom 52% had received counselling on HT from their oncologists. Thirty-nine percent of patients were using HT at the time of their last review. Younger women were more likely than older women to receive HT counselling (mean age 37.3 ± 6.6 y vs. 42.4 ± 6.0 y; P = 0.001). Counselling frequency and usage of HT were not affected by cancer stage, body mass index, or smoking status. ConclusionYoung asymptomatic patients should receive HT if not contraindicated, yet half of qualified cervical cancer patients in this study received counselling on premature menopause and HT. Structured counselling on HT should be implemented as an integral part of cervical cancer care.

Significance of ovarian transposition in the preservation of ovarian function for young cervical cancer patients undergoing postoperative volumetric modulated radiotherapy.

BackgroundThis paper aimed to evaluate the effectiveness of ovarian transposition (OT) and the dose constraint for preserving ovarian function in young cervical cancer patients who underwent postoperative volumetric modulated arc therapy (VMAT).MethodsA retrospective analysis was conducted of young cervical cancer patients who accepted postoperative VMAT in the Affiliated Cancer Hospital of Nanjing Medical University from September 2015 to September 2018. VMAT plans for OT and non-OT patients were compared, and the patients’ ovarian function was followed up. The transposed position of the ovaries and the radiation dose constraint were further explored using a receiver operator characteristic (ROC) curve.ResultsA total of 51 young patients (age ≤40 years) were included in the study, 32 of whom underwent OT and 19 of whom did not. For these OT and non-OT patients, the homogeneity index (HI), conformity index (CI), organs at risk (OARs), average number of monitor units (MUs), and mean treatment time were similar and showed no statistically significant difference (P≥0.05). Through follow-up studies, the number of patients with preserved ovarian function was found to be 22 (out of 32) and 0 (out of 19) in the OT and non-OT patients, respectively. The minimal distance for preserving ovarian function was determined as 2.1 cm between the center of a transposed ovary and the planning target volume (PTV) margin. The optimal limited radiation doses were estimated as maximum dose (Dmax) 9.8 Gy and mean dose (Dmean) 4.6 Gy, respectively.ConclusionsOT shows no negative effects on dose distribution, target region conformity, protection of OARs, or treatment efficacy and is therefore a reliable method in the preservation of ovarian function for young cervical cancer patients undergoing postoperative radiotherapy using the VMAT technique. Specifically, when the distance between the center of a transposed ovary and the PTV margin is more than 2.1 cm, and the radiation dose is limited to a Dmax of less than 9.8 Gy and a Dmean of less than 4.6 Gy, the function of transposed ovaries may be preserved.

Menopausal symptoms, sexual dysfunction, and hormone therapy use in young cervical cancer patients undergoing definitive treatment at a single institution

<h3>Objectives:</h3> To evaluate the incidence of menopausal symptoms, sexual dysfunction, and hormone therapy (HT) use in cervical cancer patients at a single public hospital. <h3>Methods:</h3> This is a retrospective cohort study evaluating all patients under the age of 55 with stage IA1-IVA squamous cell carcinoma (SCC) or adenocarcinoma of the cervix who underwent definitive treatment at our institution between 2015 and 2018. Demographic data, tumor characteristics, and treatment data were collected. All gynecologic and radiation oncology visits were reviewed for documentation of menopausal symptoms, sexual dysfunction, and use of HT and vaginal dilators. The frequency of these symptoms was measured as was the time a provider first documented them and readdressed them after diagnosis and initiation of treatment. <h3>Results:</h3> A total of 59 patients were identified, with a mean age of 42 years (range 27-55, 76% ≤50 years) and 83% Hispanic. 32% had clinically early stage disease (IB1 or less) and 68% had locally advanced disease. 68% had SCC, 24% adenocarcinoma and 8% adenosquamous carcinoma. Median recurrence free survival was 20 months (range 1-53) with median follow-up of 25 months (range 4-58). Ten women (17%) underwent hysterectomy or trachelectomy with ovarian conservation, and 1 (2%) underwent bilateral salpingo-oophorectomy (BSO) at the time of radical hysterectomy. 39 women (66%) underwent definitive chemoradiation. The remaining 9 (15%) women underwent surgery (hysterectomy and/or BSO) and adjuvant radiation. A total of 827 visits (median 14 per patient) were reviewed after diagnosis. Of the 48 women who received any radiation, only 27 (56%) were ever asked about vasomotor symptoms with a median time to asking of 19 weeks (range 1-132). When first asked, vasomotor symptoms were reported 71% of the time, but symptoms were only readdressed in 20% of subsequent visits. When first asked, 55% of patients reported vaginal dryness and 60% had sexual dysfunction. 24 patients (50%) were prescribed any kind of HT, and median time to counseling on HT use was 16 weeks (range 1-184). Once initiated, ongoing HT use was readdressed at 74% of visits. Of the 35 patients (73%) ever asked about vaginal dilator use, 54% reported use. None of the 11 patients who underwent hysterectomy±BSO without radiation were asked about the domains studied in any of their 70 visits. <h3>Conclusions:</h3> When asked, the majority of young cervical cancer patients report menopausal symptoms and sexual dysfunction after undergoing definitive treatment. Once initiated, women are compliant with HT use. However, many women are not being counseled about menopausal or sexual dysfunction symptoms nor treated with hormone therapy in a timely fashion. This study identified opportunities for quality improvement at our institution and will be combined with national guidelines to change clinical practice.

COVID-19 and cancer care: What have we learned?: Despite the enormous challenges, researchers are sharing valuable lessons regarding evaluating risks, setting priorities, and communicating with patients during the pandemic.

COVID-19 and cancer care: What have we learned?: Despite the enormous challenges, researchers are sharing valuable lessons regarding evaluating risks, setting priorities, and communicating with patients during the pandemic.

The Effect of Different Surgical Methods on Female and Male Sexual Activity and Marital Quality in Patients With Early-Stage Cervical Cancer.

IntroductionSexual activity is important for marital quality, especially in cervical cancer survivors. Vagina extension following laparoscopic radical hysterectomy with bilateral ovarian preservation (VEOP), vagina extension following laparoscopic radical hysterectomy with bilateral oophorectomy (VEBO), radical hysterectomy with bilateral ovarian preservation (RHOP), and radical hysterectomy with bilateral oophorectomy (RHBO) are the common surgeries for young cervical cancer patients.AimTo investigate the effect of the 4 surgical methods on female/male sexual activity and marital quality in early-stage cervical cancer survivors.MethodsMultiple linear regression analysis was conducted in 205 patients with stage Ia1–IIa2 cervical cancer to evaluate the factors that affected male/female sexual function and marital quality.Main Outcome MeasureFemale Sexual Function Index (FSFI), modified Kupperman Index (KI), modified Sexual Life Quality Questionnaire (mSLQQ-QoL), and ENRICH marital inventory were used to reflect changes in female/male sexual function and marital quality in the 4 groups.ResultsFemale/male sexual function and marital quality were both highest in the VEOP group and lowest in the RHBO group. The regression results showed that ovarian preservation and vaginal extension were associated with female/male sexual function and marital quality. Furthermore, when vaginal extension and ovarian preservation were replaced by vaginal length, sexual psychological change, and hormone level index (KI), respectively; male sexual function was associated with vaginal length and sexual psychological change, whereas female sexual function and marital quality were only associated with hormone level and sexual psychological change. Clinical statistics found that four-fifths of the recurrent patients had vaginal extension (P = .042), and 3-quarters of these patients had large tumors.ConclusionOvarian preservation and vaginal extension are both important for male/female sexual activity and marital quality. Vaginal extension may play a positive role in female sexual life via psychology and in male sexual life via vaginal length. Vaginal extension may not be suitable for patients with large masses.Zhang Y, Sun S, Ding J, et al. The Effect of Different Surgical Methods on Female and Male Sexual Activity and Marital Quality in Patients With Early-Stage Cervical Cancer. Sex Med 2020;8:307–314.

Age-related survival disparity in stage IB and IIB cervical cancer patients.

Whether young cervical cancer patients have poorer prognosis compared to older ones has remained controversial over the past half century. The last three decades have seen a rise in morbidity and mortality among young Japanese women with cervical cancer. This reflects the fact that the importance of prevention has not been fully recognized due to limited clinical studies. We examined the relationship between age and prognosis in cervical cancer. We retrospectively examined medical records of consecutive patients with International Federation of Gynecology and Obstetrics stage IB and IIB cervical cancer at a hospital in Japan. Patients were divided into two age groups: less than or equal to 39 years (adolescent and young adult [AYA] group) and greater than or equal to 40 years (older adult group). We compared prognosis and clinical factors associated with prognosis between AYA and older adult patients. Data from 182 patients (AYA n = 71; older adults n = 111) treated between 2004 and 2011 were analyzed. The proportion of loss to follow-up was 6.0%. Significant differences were observed in stage and lymph node metastasis between the two groups at baseline. However, despite the older adult group having a higher proportion of advanced cancer patients, the overall survival rate of stage IIB patients in the AYA group at the 3-year follow-up was significantly lower (AYA 53.6%, older adults 86.3%, P < 0.05). Multivariate analysis adjusted for clinical factors revealed that AYA patients had a 3.7-3.9 times greater mortality risk compared to older adults. AYA patients with stage IB and IIB cervical cancer may have a prognostic disadvantage.

THE FIRST EXPERIENCE OF USING LAPAROSCOPIC GAMMA PROBE FOR INTRAOPERATIVE VISUALIZATION OF SENTINEL LYMPH NODES IN GYNECOLOGICAL CANCER

Visualization of sentinel lymph nodes (SLN) is now widely accepted for lymph node (LN) detection using a radioactive lymphotropic trace. Preoperative lymphoscintigraphy with intraoperative lymphatic mapping under gamma detecting probe guidance proved to be an easy and reliable method for SLN detection.Material and methods.In this article we present our experience in using laparoscopic gamma-probe for intraoperative visualization of sentinel lymph nodes in gynecological cancer.Results.Intraoperative visualization of sentinel lymph nodes in young cervical cancer patients and in patients with stage I endometrial cancer allowed us to perform radical surgery with personalization of the extent of lymph node dissection, especially for patients with low and intermediate risks of lymphogenic metastasis.

Association of HLA-DRB1, HLA-DQB1 Polymorphisms with HPV 16 E6 Variants among Young Cervical Cancer Patients in China.

Potential correlation of human papillomavirus (HPV) 16 E6 variants and human leukocyte antigen (HLA) class II polymorphisms has been suggested in patients with cervical cancer, so far little information is available about the possible interaction between E6 variants and HLA class II variability during the obviously accelerated progression to cervical cancer in young women. In this study, we aimed to explore the association between the HPV16 E6 variants and HLA-DRB1, DQB1 alleles in a Chinese young cervical cancer population. The HLA-DRB1, HLA-DQB1 polymophisms were genotyped by low-resolution polymerase chain reaction (PCR) with sequence-specific primer. HPV16 E6 DNA was tested by Sanger fluorescent dye dideoxy-termination technique. The difference of DRB1, DQB1 polymorphisms between young cervical cancer patients (≤35ys, n=61) and older ones (>35ys, n=85) and the association with E6 variants were analyzed. Results showed that the distribution pattern of HLA-DRB1, DQB1 alleles was different between young cervical cancer patients and older ones. The allele frequency of DQB1*0501 in young patients was significantly lower than older ones (6.6% vs. 23.5%, p<0.05). The HPV16 E6 A4 lineage was the exclusive type observed in young patients, and its prevalence was significantly higher than that of older cases (82.86% vs.41.94%, p<0.05). DRB1*03 was not found in young patients positive for the HPV16 E6 A4 lineage, whereas it was observed in 19.2 % older patients with A4 positive(Pc<0.05). In conclusion, specific association between certain HPV16 E6 variant and genetic polymorphisms of HLA may play a role during the progression of early onset cervical cancer in young patients. Certain HLA-DRB1 and HLA-DQB1 alleles may be related to the A4 lineage among young cervical cancer patients, which was the unique HPV16 E6 variant found in Chinese young patients. Our finding may provide an insight into the pathogenic factors that associated with cervical cancer in young women.

Young Cervical Cancer Patients May Be More Responsive than Older Patients to Neoadjuvant Chemotherapy Followed by Radical Surgery.

ObjectiveTo evaluate the effects of age and the clinical response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer who received neoadjuvant chemotherapy followed by radical surgery.MethodsA total of 1,014 patients with advanced cervical cancer who received NACT followed by radical surgery were retrospectively selected. Patients were divided into young (aged ≤35 years, n = 177) and older (aged >35 years, n = 837) groups. We compared the short-term responses and survival rates between the groups. The five-year disease-free survival (DFS) and overall survival (OS) rates were stratified by age, NACT response, and FIGO stage.ResultsThe overall response rate was 86.8% in the young group and 80.9% in the older group. The young patients had an earlier FIGO stage (P<0.001), a higher rate of adenocarcinoma (P = 0.022), and more lymph node metastasis (P = 0.033) than the older patients. The presence of adenocarcinoma as the histological type (P = 0.024) and positive lymph node metastasis (P<0.001) were identified as independent risk factors for survival. When stratified by age and clinical response, young patients with no response to NACT had a worse clinicopathological condition compared with the other subgroups. Compared with non-responders, responders to NACT had a higher five-year DFS rate (80.1% versus 71.8%; P = 0.019) and OS rate (82.6% versus 71.8%; P = 0.003) among the young patients but not among the older patients.ConclusionsResponders to NACT aged 35 years or younger benefitted the most from NACT, while the young non-responders benefitted the least. Age might represent an important factor to consider when performing NACT in patients with cervical cancer.

Quality of Life and Sexual Function after Type c2/Type III Radical Hysterectomy for Locally Advanced Cervical Cancer: A Prospective Study

The introduction of screening programs have made cervical cancer detectable at earlier stages and in younger patients. Nevertheless, only a few studies have examined the QoL and sexual function in disease-free cervical cancer survivors. The objective of this study is to evaluate the sexual function in a cervical cancer patient's group treated with neoadjuvant chemotherapy (NACT) plus type C2/type III radical hysterectomy (RH). We have enrolled in the oncologic group (OG) sexually active patients affected by cervical cancer (stage IB2 to IIIB) treated with NACT followed by RH. Included subjects were interviewed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24 Questionnaire. Two consecutive assessments were recorded: at the first evaluation postoperatively (T1) and at the 12-month follow-up visit (T2). Results were compared with a benign gynecological disease group (BG) and with a healthy control group (HG). A total of 33 patients for OG, 37 for BG, and 35 women for HG were recruited. After surgery, sexual activity has been resumed by 76% of the OG patients and 83.7% of the BG patients (P = not significant). Cancer survivors had clinically worse problems with symptom experience, body image, and sexual/vaginal functioning than controls (P < 0.05). OG patients also reported more severe lymphedema, peripheral neuropathy, menopausal symptoms, and sexual worry. For sexual activity, the score difference between cancer survivors and women with benign gynecological disease is not statically significant. Concerning sexual enjoyment assessment, our study shows comparable results for OG and BG. Nevertheless, the worsening of symptom experience, body image, and sexual/vaginal functioning, OG patients have same sexual activity and sexual enjoyment data compared with those of BG patients. Thus, NACT followed by RH could be a valid therapeutic strategy to treat and improve well-being especially in young cervical cancer patients.

A 2-year prospective study assessing the emotional, sexual, and quality of life concerns of women undergoing radical trachelectomy versus radical hysterectomy for treatment of early-stage cervical cancer

Objective To prospectively assess and describe the emotional, sexual, and QOL concerns of women with early-stage cervical cancer undergoing radical surgery. Methods Seventy-one women who were consented for radical trachelectomy (RT) or radical hysterectomy (RH) were enrolled preoperatively in this 2-year study; 52 women (33 RT; 19 RH) were actively followed. Patients completed self-report surveys composed of 4 empirical measures in addition to exploratory items. Data analyses for the 2 years of prospective data are presented. Results At preoperative assessment, women choosing RH reported greater concern about cancer recurrence (x = 7.27 [scale from 0 to 10]) than women choosing RT (x = 5.66) ( P = 0.008). Forty-eight percent undergoing RH compared to 8.6% undergoing RT reported having adequate “time to complete childbearing” ( P < 0.001). Both groups demonstrated scores suggestive of depression (based on the CES-D scale) and distress (based on the IES scale) preoperatively; over time, however, CES-D and IES scores generally improved. Scores on the Female Sexual Functioning Inventory (FSFI) for the total sample were below the mean cut-off (26.55), suggestive of sexual dysfunction; however, the means increased from 16.79 preoperatively to 23.78 by 12 months and 22.20 at 24 months. Conclusion Measurements of mood, distress, sexual function, and QOL did not differ significantly by surgical type, and instead reflect the challenges faced by young cervical cancer patients treated by RT or RH without adjuvant treatment. Points of vulnerability were identified in which patients may benefit from preoperative consultation or immediate postoperative support. Overall, patients improved during the first year, reaching a plateau between Year-1 and Year-2, which may reflect a new level of functioning in survivorship.

Young Cervical Cancer Patients and Fertility

To review the incidence of cervical cancer in reproductive age women and identify reproductive issues for these patients. To identify surgical methods of fertility preservation in cervical cancer and advanced reproductive technologies available to patients. Epidemiologic data, published research reports, and patient management guidelines. Young women with cervical cancer are a special population with unique needs regarding fertility. Nurses caring for young patients with cervical cancer must be aware of both the surgical fertility preservation options, which patients are candidates for these surgeries and the options for assisted reproductive technology. Nurses need to be able to coordinate care for these patients with gynecologic oncologists and reproductive endocrinologists in order to facilitate optimal outcomes.

Irinotecan HCl, an anticancer topoisomerase I inhibitor, frequently induces ovarian failure in premenopausal and perimenopausal women

The effects of irinotecan HCl (CPT-11) combination chemotherapies on the hypothalamus-pituitary-ovary endocrine system were examined clinically. The incidences of typical menopausal malaises and/or endocrinological findings were investigated in 32 gynecological cancer patients treated by CPT-11 combination chemotherapies. Patients who complained of menopausal malaises or had been treated by hormone replacement therapy before chemotherapy were excluded from the study. Menopausal malaise-like symptoms (MMLS) appeared in 6 of 32 patients (18.8%) during CPT-11 combination chemotherapy, and these symptoms were completely cured within a few days by administration of conjugated estrogen tablets (0.625 mg/day). All the MMLS cases were perimenopausal patients (47-57 years of age), and MMLS were not found in any of the postmenopausal patients who had exceeded 3 years since endocrinological menopause or patients who had recurrent cancer after pelvic radiotherapy. After exclusion of these 3-year-postmenopausal patients and postirradiation patients, 6 of 7 patients aged 45-59 years complained of MMLS during CPT-11 combination chemotherapy. The incidence of CPT-11-induced MMLS showed no relationships with the anticancer drugs combined with CPT-11, mean total CPT-11 dose, mean number of CPT-11 injections, mean individual CPT-11 dose, grade of CPT-11-specific diarrhea or anticancer effects of each CPT-11 combination chemotherapy. The perimenopausal cancer patients with CPT-11-induced MMLS showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. A young patient with CPT-11-induced secondary amenorrhea showed decreased serum estradiol and increased serum FSH and LH levels accompanying the CPT-11 injections. None of the postmenopausal patients with high FSH and LH levels showed any significant differences in their serum FSH, LH, PRL and TSH levels during CPT-11 combination chemotherapy. No differences in the results of LHRH and TRH tests during chemotherapy were found for postmenopausal patients. Histopathological examinations of normal ovarian tissues surgically removed from 4 young cervical cancer patients treated with preoperative CPT-11 combination chemotherapies revealed no growing ovarian follicles in the ovarian tissues. CPT-11 injections can induce estrogen-rescued MMLS in cancer patients aged approximately 50 years at a very high rate and may induce secondary amenorrhea in young women. The endocrinological and histopathological studies revealed that CPT-11 causes ovarian follicular loss and ovarian failure within a short time without affecting hypothalamic and pituitary hormone secretion. These clinical results indicate that CPT-11 has strong ovarian toxicity and that repeated CPT-11 administrations may frequently induce ovarian follicular loss and premature ovarian failure, even in young women.

Analysis of Molecular Pathological Factors of Unfavorable Prognosis for Young Cervical Cancer Patients

The aim of this study was to explore the molecularpathological characteristics of cervical cancer inwomen aged below 35, disclose the factors that indicatethe unfavorable prognosis, and provide some useful targetsfor improving therapeutic outcome. Patients andMethods: 64 cases of pathological data originating fromcervical cancer patients aged below 35 served as the studygroup to perform a retrospective research, and pathologicaldata from 90 cases of cervical cancer patients beyondage 35, who underwent treatment during the same time,were selected at random as the reference group. Immunohistochemistryand quantified image analysis were utilizedto detect synchronously the protein expression differenceof survivin and p27 between the 2 groups. Results: Thetotal 5-year survival rate of the study group was 65.6%compared to 84.4% in the reference group, while thelymph node metastasis rate was 25% compared to 12.2%in the reference group. Both differences were statisticallysignificant (p < 0.05). Survivin expression is much greaterin the study group than in the reference group (p < 0.05);there is no statistical difference of the p27 expression betweenthe 2 groups (p > 0.05), but p27 expression is relatedto lymph node metastasis. Conclusion: Younger femalepatients have a worse prognosis than older ones, and survivinexpression is associated with poor prognosis. Targetingthese molecular factors may lead to a hopeful biomedicaltherapy to improve the prognosis of young femalecervical cancer patients.

The analysis of high-risk molecular markers for cervical cancer patients under thirty–five

OBJECTIVE To explore molecular markers for cervical cancer in female patients below thirty-five years of age, so that the markers may be used to formulate a prognosis and to provide some useful targets for improving therapy. METHODS Pathological data were collected from 64 cervical cancer patients under the age of 35 from June, 1995 to June, 2000 in our institution. The data were retrospectively analyzed as a study group, and compared to data obtained from 90 cervical cancer cases over the age of 35 as controls who underwent treatment during the same time period. Immuno-histochemical and quantified image analyses were conducted to look for differences between the two groups in expression of survivin, p27, CD44v6, MMP-2 and TIMP-2. RESULTS The overall 5-year survival rate (65.6%) of the study group was significantly lower (P 0.05). CONCLUSION Young women patients with cervical cancer have a poorer prognosis compared to old women. Our study reveals that survivin, MMP-2, TIMP-2 and CD44v6 expression have a correlation with shorter 5-year survival. Improvement in the prognosis for young cervical cancer patients can be expected using biomedical therapy which targets these molecular markers.