Acceptance and Results of Cryoablation for the Treatment of Early Breast Cancer in Non-Surgical Patients.

OBJECTIVES: Evaluate acceptance of percutaneous cryoablation (PCA) treatment by patients with early breast cancer (BC) who choosed not to have surgery and present our experience in the use of PCA for the local control of BC in this group of patients. METHODS: All biopsy-proven early BC diagnosed in our institution as non-surgical patients between January 2020 and December 2023 were retrospectively reviewed. We recorded if PCA was offered and if it was accepted by the patient.PCA was performed under ultrasound (US) guidance, using a liquid nitrogen-based system. Mammography and US or contrast-enhanced mammography (CEM) follow-up was scheduled every 6 months for five years. Patient's tolerance to the procedure, adverse effects and results regarding local control of the disease were assessed. RESULTS: A total of 66 early BC were diagnosed in 63 patients who decided not to have surgery. Median age was 88 years (range 60-99 years). Forty-three (95.6%) of the 45 patients offered PCA accepted. Thirty-nine malignant tumors (median size 24 mm) underwent PCA. All cases were previously reviewed in a multidisciplinary tumor board. Complete tumoral necrosis was achieved in 81.3% of the cases followed ≥ 6 months. After a median follow-up of 16 months, the complete ablation rate in Luminal BC ≤ 25 mm was 100%. No major complications were seen. CONCLUSIONS: Non-surgical patients with early BC accepted PCA when the treatment was offered. PCA is safe effective and well-tolerated outpatient procedure. The study outcomes suggest that PCA could be an alternative to surgery for the management of BC in this group of patients. ADVANCES IN KNOWLEDGE: Patients with early BC who choose not to have surgery accept PCA This percutaneous approach probably allows local control of early BC, mainly in ≤ 25 mm Luminal tumors.

Assessment of thermohydraulic performance and entropy generation in an evacuated tube solar collector employing pure water and nanofluids as working fluids.

This study conducts a numerical comparison of the thermal performance of three distinct working fluids (pure water, TiO2, and SiO2 water-based nanofluids) within an evacuated tube solar collector using Computational Fluid Dynamics. The study evaluates thermohydraulic performance alongside global and local entropy generation rates, while considering variations in solar radiation values and inlet mass flow rates. Results indicate that nanofluids demonstrate superior performance under low solar radiation, exhibiting higher outlet temperatures, velocities, thermal efficiency, and exergy efficiency compared to pure water. However, at the higher solar radiation level, the efficiency of SiO2 water-based nanofluid diminishes due to its impact on specific heat. Furthermore, the entropy generation analysis reveals significant reductions with TiO2 water-based nanofluid in all the phenomena considered (up to 79 %). The SiO2 nanofluid performance aligns closely with pure water under high radiation value. This investigation offers valuable insights into the utilization of nanofluids in solar collectors across diverse operating conditions, emphasizing their pivotal role in enhancing overall performance.

Leader-follower formation control based on non-inertial frames for non-holonomic mobile robots.

A chain formation strategy based on mobile frames for a set of n differential drive mobile robots is presented. Considering two consecutive robots in the formation, robots Ri and Ri+1. It is intended that robot Ri+1 follows the delayed trajectory, τ units of time, of the leader robot Ri. In this way, the follower robot Ri+1 becomes the leader robot for robot Ri+ 2 in the formation and so on. With this formation policy, the trailing distance between two consecutive robots varies accordingly to the velocity of the Ri leader robot. Mobile frames are located on the body of the vehicles, in such a way that the position of robot Ri is determined with respect to the frame located on Ri+1 robot. The strategy relies on the fact that the general leader robot R1 describes any trajectory generated by bounded linear v1(t) and angular ω1(t) velocities. For the remaining vehicles in the string, the strategy considers a desired trajectory for the follower robot Ri+1 obtained by an estimation of the delayed trajectory of the leader robot Ri. This desired estimated trajectory is obtained under the knowledge of the actual and past input velocities of the Ri robot. To formally prove the convergence of the formation strategy, the equations describing the time variation of the relative posture between any pair of consecutive vehicles in the formation are obtained, and a feedback law based on local measurements is proposed to get the convergence of robot Ri+1 to the delayed trajectory, τ units of time, of the trajectory previously described by robot Ri. Lyapunov techniques are considered for this fact. The effectiveness of the chain formation solution is evaluated by means of numerical simulations and real time experiments showing an adequate convergence.

Thermoluminescent studies of GdAlO3 powders.

The increasing use of thermoluminescence (TL) materials as radiation detectors with application in different areas of ionizing radiation has motivated research on new materials with adequate luminescent characteristics. In this work, experimental results gadolinium aluminate (GdAlO3) analyzed by thermoluminescent phenomenon under beta irradiation effect are studied. To prepare GdAlO3 powders the coprecipitation method was used. TL glow curve and other luminescent characteristics were analyzed using an automatic Lexsig Smart TL/OSL luminescent reader. TL glow curve showed four peaks with three prominent and well-defined peaks centered at 140, 230, and 270 °C. TL response as a function of beta radiation dose was linearity in the range from 1.1 up to 44 Gy. Kinetic parameters such as activation energy (E), frequency factor (s), and order of kinetics after the deconvolution of the TL glow curve were also determined using Chen's peak shape method. Experimental results show GdAlO3 as a potential luminescent host material for TL studies.

Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial.

PURPOSE: This phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS). PATIENTS AND METHODS: Adults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test. RESULTS: The study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant. CONCLUSION: PC was not inferior to the active regimen PI and should be standard treatment for UCS.

Comparative effect of potentiated zinc oxide and antibiotic growth promoters on intestinal morphometry and nutrient digestibility in broiler chickens.

The comparative effects of potentiated zinc oxide (pZnO) and antibiotic growth promoters (AGP) supplementation on intestinal morphometry and nutrient digestibility in broiler chickens were studied. Four hundred straight-run Cobb 500-day-old broiler chicks were randomly allotted to four dietary treatments replicated 10 times with 10 birds per replicate. Dietary treatments were as follows: T1: basal diets without AGP (negative control; NC), T2: basal diets with 500 g/t maduramicin 10 g and 500 g/t zinc bacitracin 150 (positive control; PC), T3: NC added with 150 g/t pZnO, and T4: PC added with 150 g/t pZnO in a 2 × 2 factorial design in RCBD. At days 18 and 35, 10 birds were randomly selected per treatment for morphometry of the duodenum, jejunum, and ileum. At day 38, eight birds per treatment were used for the nutrient digestibility study. Results showed significant interaction effects (P < 0.05) of AGP and pZnO supplementation on day 35 intestinal morphometry of duodenum's villi height and villi height: crypt depth, and ileum's crypt depth; apparent CODGE, AME, CP, DM, and EE. Significant differences (P < 0.05) with pZnO supplementation were only observed on feed intake and FCR of birds fed with pZnO at days 8-14 and fecal quality at days 0-7. Results of present study suggested that pZnO has the potential to replace AGPs without negatively affecting the intestinal morphometry, digestibility, and growth performance of broiler chickens.

The Mexican consensus on the detection and treatment of early gastric cancer. / Consenso mexicano sobre detección y tratamiento del cáncer gástrico incipiente.

Gastric cancer is one of the most frequent neoplasias in the digestive tract and is the result of premalignant lesion progression in the majority of cases. Opportune detection of those lesions is relevant, given that timely treatment offers the possibility of cure. There is no consensus in Mexico on the early detection of gastric cancer, and therefore, the Asociación Mexicana de Gastroenterología brought together a group of experts and produced the "Mexican consensus on the detection and treatment of early gastric cancer" to establish useful recommendations for the medical community. The Delphi methodology was employed, and 38 recommendations related to early gastric cancer were formulated. The consensus defines early gastric cancer as that which at diagnosis is limited to the mucosa and submucosa, irrespective of lymph node metástasis. In Mexico, as in other parts of the world, factors associated with early gastric cancer include Helicobacter pylori infection, a family history of the disease, smoking, and diet. Chromoendoscopy, magnification endoscopy, and equipment-based image-enhanced endoscopy are recommended for making the diagnosis, and accurate histopathologic diagnosis is invaluable for making therapeutic decisions. The endoscopic treatment of early gastric cancer, whether dissection or resection of the mucosa, should be preferred to surgical management, when similar oncologic cure results can be obtained. Endoscopic surveillance should be individualized.

U.S. Food and Drug Administration-Approved Poly (ADP-Ribose) Polymerase Inhibitor Maintenance Therapy for Recurrent Ovarian Cancer: A Cost-Effectiveness Analysis.

OBJECTIVE: We sought to determine whether use of a poly (ADP-ribose) polymerase inhibitor is cost effective for maintenance treatment of platinum-sensitive recurrent ovarian cancer. METHODS: A decision analysis model compared four maintenance strategies: 1) observation, 2) BRCA germline mutation testing and selective treatment of carriers (gBRCA only), 3) BRCA germline and tumor homologous recombination deficiency testing and selective treatment of either BRCA carriers or those with tumor HRD (gBRCA and HRD only), and 4) treat all with niraparib to progression (treat all). Costs were estimated in 2016 U.S. dollars. Incremental cost-effectiveness ratios were in dollars per progression-free quality-adjusted life-year (QALY). One-way sensitivity analyses tested multiple assumptions. RESULTS: Maintenance poly (ADP-ribose) polymerase inhibitor was costlier and more effective than observation. Mean costs and progression-free QALYs were $827 and 3.4 months for observation, $46,157 and 5.7 for a BRCA-only strategy, $109,368 and 8.5 for a gBRCA and homologous recombination deficiency-only strategy, and $169,127 and 8.8 for a treat-all strategy. gBRCA-only had an incremental cost-effectiveness ratio of $243,092/progression-free QALY compared with observation; other strategies did not approach cost effectiveness. Using the current U.S. Food and Drug Administration label for maintenance poly (ADP-ribose) polymerase inhibitor regardless of biomarker status, the third-party payer cost per month (28-day supply) would need to be reduced from approximately $14,700 to $3,600 to be considered cost effective compared with observation using a willingness to pay threshold of $100,000/progression-free QALY. CONCLUSION: Maintenance poly (ADP-ribose) polymerase inhibitor therapy for platinum-sensitive recurrent ovarian cancer is not cost effective. Treatment of patients with BRCA mutation alone or with homologous recombination deficiency-positive tumors are preferred strategies compared with a treat-all strategy. Lowering the cost may make selective niraparib maintenance therapy cost effective compared with observation.

Urinary diversion in the genitourinary cancer survivor.

Urinary diversion has been in the scope of practice of Gynecologic Oncologists since the inception of the sub-specialty. However, many fewer urinary diversions are performed currently than in the past due to improved prevention of cervical cancer. The intent of this article is to provide a state of the art review for Gynecologic Oncologists. Surgeons performing these complex procedures must be knowledgeable about the differences between various types of continent and non-continent urinary diversions, and the principles of pre and post-operative care. This includes the indications for surgery and pre-operative considerations, types of urinary diversion including continent and non-continent diversions, and the need for long-term follow-up with patients who undergo urinary diversion requiring lifelong follow up and testing for surveillance of the upper urinary tracts and to monitor for nutritional and metabolic alterations.

Prospective Evaluation of Lymph Node Processing at Staging Surgery for High-grade Endometrial Cancer.

To determine whether the processing of additional adipose tissue collected during lymph node (LN) dissection results in the identification of additional LNs during endometrial cancer (EC) staging and to determine if the division of LNs into nodal basin-specific specimens has an effect on the number of LNs identified during EC staging. A prospective randomized controlled trial was performed on women with high-grade EC undergoing surgical staging. Subjects were randomized to collection of LNs into nodal basin-specific containers on the randomized side versus simple labeling on the nonrandomized side. The total number of LNs and total number of LNs with metastases on the randomized versus the nonrandomized side were compared. The remaining adipose tissue from each LN specimen was submitted for histologic examination. We analyzed the number of LNs with and without metastases identified from additional adipose tissue. Of 120 consented subjects, 56 had sufficient data for analysis. The additional adipose tissue contained 7.5 additional LNs per patient on average (range: 0-26). In 2/54 total cases (3.7%) and 2/5 cases with nodal metastases (40%), the additional adipose contained LNs with metastases. In both cases, metastases were also detected in grossly identified LN candidates. The mean number of LNs identified was not significantly different based on method of collection (P=0.22). The mean number of LNs containing metastases per side was not significantly different (P=0.58). Processing of adipose tissue does increase the total number of LNs identified, however, it does not influence EC stage. No difference in LN counts was noted with basin-specific collection.

Prior breast cancer and tamoxifen exposure does not influence outcomes in women with uterine papillary serous carcinoma.

OBJECTIVES: To evaluate progression-free survival (PFS) and overall survival (OS) outcomes in women diagnosed with uterine papillary serous carcinoma (UPSC) who have had (UPSCBR+) or have not had (UPSCBR-) an antecedent history of breast cancer and to correlate their outcomes to prior tamoxifen exposure. METHODS: Data were collected for women diagnosed with UPSC at two academic institutions between January 1997 and July 2012. Patient demographics, tumor histology, stage, and treatments were recorded. Patients were divided into two groups: those with and without a personal history of breast cancer. Within the UPSCBR+ cohort, we identified those with a history of tamoxifen use. Cox regression modeling was used to explore associations between selected covariates of interest and the time-to-event outcomes of PFS and OS. RESULTS: Of 323 patients with UPSC, 46 (14%) were UPSCBR+. Of these, 15 (33%) had a history of tamoxifen use. UPSCBR+ patients were older than UPSCBR- (median years, 72 vs. 68, p=0.004). UPSCBR+ women showed no significant difference in PFS or OS compared to UPSCBR- (p=0.64 and p=0.73 respectively), even after controlling for age (p=0.15 and p=0.48 respectively). Within the UPSCBR+ cohort, there was no difference in PFS or OS with or without tamoxifen exposure (p=0.98 and p=0.94 respectively). CONCLUSIONS: There was no difference in PFS or OS between the UPSCBR+ and UPSCBR- cohorts. We did not demonstrate significant OS or PFS differences in women who took tamoxifen prior to their endometrial cancer diagnosis. These findings have implications for counseling, and should be encouraging to women who are facing their second cancer diagnosis.

The role of immune checkpoint inhibition in the treatment of ovarian cancer.

The introduction of immune checkpoint inhibitors has revolutionized treatment of multiple cancers and has bolstered interest in this treatment approach. So far, emerging clinical data show limited clinical efficacy of these agents in ovarian cancer with objective response rates of 10-15% with some durable responses. In this review, we present emerging clinical data of completed trials of immune checkpoint inhibitors and review ongoing studies. In addition we examine the current knowledge of the tumor microenvironment of ovarian cancers with a focus on the significance of PD-L1 expression and tumor-infiltrating lymphocytes on predicting response to immune checkpoint blockade. We evaluate approaches to improve treatment outcomes through the use of predictive biomarkers and patient selection. Finally, we review management considerations including immune related adverse events and response criteria.

Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues.

Retinoblastoma (Rb) is a pediatric intraocular malignancy and probably the most robust clinical model on which genetic predisposition to develop cancer has been demonstrated. Since deletions in chromosome 13 have been described in this tumor, we performed next generation sequencing to test whether recurrent losses could be detected in low coverage data. We used Illumina platform for 13 tumor tissue samples: two pools of 4 retinoblastoma cases each and one pool of 5 medulloblastoma cases (raw data can be found at http://www.ebi.ac.uk/ena/data/view/PRJEB6630). We first created an in silico reference profile generated from a human sequenced genome (GRCh37p5). From this data we calculated an integrity score to get an overview of gains and losses in all chromosomes; we next analyzed each chromosome in windows of 40 kb length, calculating for each window the log2 ratio between reads from tumor pool and in silico reference. Finally we generated panoramic maps with all the windows whether lost or gained along each chromosome associated to its cytogenetic bands to facilitate interpretation. Expression microarrays was done for the same samples and a list of over and under expressed genes is presented here. For this detection a significance analysis was done and a log2 fold change was chosen as significant (raw data can be found at http://www.ncbi.nlm.nih.gov/geo/accession number GSE11488). The complete research article can be found at Cancer Genetics journal (Garcia-Chequer et al., in press) [1]. In summary here we provide an overview with visual graphics of gains and losses chromosome by chromosome in retinoblastoma and medulloblastoma, also the integrity score analysis and a list of genes with relevant expression associated. This material can be useful to researchers that may want to explore gains and losses in other malignant tumors with this approach or compare their data with retinoblastoma.

Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing.

Genes are frequently lost or gained in malignant tumors and the analysis of these changes can be informative about the underlying tumor biology. Retinoblastoma is a pediatric intraocular malignancy, and since deletions in chromosome 13 have been described in this tumor, we performed genome wide sequencing with the Illumina platform to test whether recurrent losses could be detected in low coverage data from DNA pools of Rb cases. An in silico reference profile for each pool was created from the human genome sequence GRCh37p5; a chromosome integrity score and a graphics 40 Kb window analysis approach, allowed us to identify with high resolution previously reported non random recurrent losses in all chromosomes of these tumors. We also found a pattern of gains and losses associated to clear and dark cytogenetic bands respectively. We further analyze a pool of medulloblastoma and found a more stable genomic profile and previously reported losses in this tumor. This approach facilitates identification of recurrent deletions from many patients that may be biological relevant for tumor development.

SECOND LATIN AMERICAN INTERCOMPARISON ON INTERNAL DOSE ASSESSMENT.

Internal dosimetry intercomparisons are essential for the verification of applied models and the consistency of results'. To that aim, the First Regional Intercomparison was organised in 2005, and that results led to the Second Regional Intercomparison Exercise in 2013, which was organised in the frame of the RLA 9/066 and coordinated by Autoridad Regulatoria Nuclear of Argentina. Four simulated cases covering intakes of (131)I, (137)Cs and Tritium were proposed. Ninteen centres from thirteen different countries participated in this exercise. This paper analyses the participants' results in this second exercise in order to test their skills and acquired knowledge, particularly in the application of the IDEAS Guidelines. It is important to highlight the increased number of countries that participated in this exercise compared with the first one and, furthermore, the improvement in the overall performance. The impact of the International Atomic Energy Agency (IAEA) Projects since 2003 has led to a significant enhancement of internal dosimetry capabilities that strengthen the radiation protection of workers.

Comparison of bevacizumab alone or with chemotherapy in recurrent ovarian cancer patients.

BACKGROUND: To compare the efficacy of chemotherapy (C) combined with bevacizumab (Bev) versus Bev alone in recurrent, heavily pretreated epithelial ovarian cancer (EOC). METHODS: A multicenter analysis of patients treated from 2004 to 2011 was performed. Demographic, treatment, response, and adverse event information were obtained. Progression-free (PFS) and overall survival (OS) were analyzed. RESULTS: Of 277 patients (median age: 58years), the majority had Stage III and IV (86%) disease, and 72% had serous histology. 244 (88%) were treated with C+Bev and 33 (12%) with Bev. Corresponding median progression-free survival (PFS) was 8.7 and 6.7months, and median overall survival (OS) was 14.3 and 10.5months, respectively. The chemotherapeutic agents combined with Bev and the median OS include: pegylated liposomal doxorubicin (n=19, OS of 20.4months), taxanes (n=55, OS of 20.2months), gemcitabine (n=106, OS of 14.1months), topotecan (n=43, OS of 13months), and cyclophosphamide (n=21, OS of 13months). There was no significant difference in toxicities between the C+Bev vs. Bev alone group. CONCLUSION: This retrospective analysis supports that combination chemotherapy and bevacizumab prolongs PFS and OS compared with bevacizumab alone.

Patient-reported outcomes as end points and outcome indicators in solid tumours.

Patient-reported outcome (PRO) measures, such as quality of life, have been associated with relevant clinical end points and are prognostic for survival outcomes in a variety of solid cancers in adults. In the past few years, PROs have garnered a greater influence as established and clinically relevant measures that could alter the current paradigm of practice-changing therapeutic advances, as it has been recognized that classic clinical end points do not accurately portray a full appreciation of the benefits, risks and costs of therapy. In this Review, we comprehensively assess the correlation of PROs with treatment response and survival, and explore tumour-related and patient-centric composite end points in patients with cancer participating in clinical trials. Comparisons or composite end points that consider tumour-related and PRO components might help health-care providers, patients with cancer and decision makers to better understand the total clinical benefit of therapeutic interventions.

Active disturbance rejection control in steering by wire haptic systems.

This paper introduces a steering by wired haptic system based on disturbance rejection control techniques. High gain Generalized Proportional Integral (GPI) observers are considered for the estimation of tire and steering wheel dynamic disturbances. These disturbances are on line canceled to ensure tracking between the commanded steering wheel angle and the tire orientation angle. The estimated disturbances at the steering rack are feedback to the steering wheel to provide a haptic interface with the driver. The overall system behaves as a bilateral master-slave system. Very few sensors and minimum knowledge of the dynamic model are required. Experimental results are presented on a prototype platform that consists on: (1) half of the steering rack of a beetle VW vehicle, (2) a steering wheel.

Aminooxy analog of histamine is an efficient inhibitor of mammalian L-histidine decarboxylase: combined in silico and experimental evidence.

Histamine plays highlighted roles in the development of many common, emergent and rare diseases. In mammals, histamine is formed by decarboxylation of L-histidine, which is catalyzed by pyridoxal-5'-phosphate (PLP) dependent histidine decarboxylase (HDC, EC 4.1.1.22). The limited availability and stability of the protein have delayed the characterization of its structure-function relationships. Our previous knowledge on mammalian HDC, derived from both in silico and experimental approaches, indicates that an effective competitive inhibitor should be capable to form an "external aldimine-like structure" and have an imidazole group, or its proper mimetic, which provides additional affinity of PLP-inhibitor adduct to the HDC active center. This is confirmed using HEK-293 cells transfected to express human HDC and the aminooxy analog of histidine, 4(5)-aminooxymethylimidazole (O-IMHA, IC50 ≈ 2 × 10(-7) M) capable to form a PLP-inhibitor complex (oxime) in the enzyme active center. Taking advantage of the availability of the human HDC X-ray structure, we have also determined the potential interactions that could stabilize this oxime in the active site of mammalian HDC.

Cystic fibrosis involving the cervix, mimicking a well-differentiated adenocarcinoma: a case report.

We describe clinicopathologic and immunohistochemical features of an unusual case of cystic fibrosis manifesting in the cervix as a mass lesion, mimicking cervical adenocarcinoma. A 24-year-old nulligravida with cystic fibrosis developed heavy postcoital vaginal bleeding 4 months after starting oral contraceptives and was found to have a cervical mass. She underwent a loop electrosurgical excision of the mass, and microscopic examination revealed a florid endocervical proliferation, extending to the margins. This lesion was initially interpreted as an invasive, well-differentiated endocervical adenocarcinoma. However, on subsequent review, the lesion was found to have a low rate of proliferation, no evidence of an infiltrative growth pattern, and abundant acute inflammation. Given these findings and the absence of any residual endocervical lesion on a subsequent cold knife conization, we determined that this was a benign, likely reactive, lesion. This case, together with previous studies, suggests that women with cystic fibrosis can develop proliferative endocervical lesions and that oral contraceptives may contribute to their development.